NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-.

Cover of Madame Curie Bioscience Database

Madame Curie Bioscience Database [Internet].

Show details

Fever, Pyrogens and Cancer

* and .

* Corresponding Author: Institute for Hyperthermia and Immunotherapy, Windmühlgasse 30/7, A-1060 Vienna, Austria. Email: kleef@hyperthermia.at

The observation, that cancer patients who experienced a feverish period after surgery survived significantly longer than patients without fever, and the fact that spontaneous tumor remission was observed mostly after a fever period, was the rationale for the artificial induction of fever (“fever therapy”). The history and rationale for fever therapy are presented and the immunological basis for endo- and exotoxin-induced tumor regression are discussed on the basis of nearly 800 citations of research literature. The effects and clinical research of different biological inductors of hyperthermia like Coley's Toxin (MBV), Propioni bacteria, Corynebacterium parvum, Bacillus Calmette Guerin (BCG), OK-432, Staphylococcus protein A, and Streptokinase are described. Though the biological effects of fever on tumors are well characterized and interesting biological and immunological results are obtained, and some clinical observational studies and small randomized trials show very promising results, larger controlled GCP-conform trials are still lacking. In combination of moderate and extreme whole body hyperthermia with chemotherapy, radiotherapy or immunotherapy with monoclonal antibodies, significant improvement in outcome of the treatment of cancer patients is to be expected. The toxicities of active “fever therapy” or passive “fever-range whole body hyperthermia” are tolerable.

History and Background

The history of fever therapy begun with the heroic induction of fever in the mid-19th century by the German physicians Busch,1 Fehleisen,2 and Richter3 by subcutaneous injection of toxins from erysipelas to treat cancer patients. The rational for this therapeutic approach was the observation, that cancer patients who experienced a feverish period after surgery survived significantly longer than patients without fever.4

The history of Coley's Toxin, a pyrogenic bacterial lysate from Serratia marcescens and Streptococcus pyogenes began at the turn of the 19th century at Memorial Sloan-Kettering Cancer Center in New York (Coley5-15). William B. Coley, M.D., active career 1891-1936 using a bacterial vaccine to treat primarily inoperable sarcoma, accomplished a cure rate greater than 10%. After controlling for lapse time, the time from disease onset until start of treatment with Coley toxins, significantly higher cumulative survival was found for the Coley treatment in three subgroups: (1) Ovarian cancer, distant disease - higher survival in years 2-10 (10 year follow-up); (2) Breast cancer, premenopausal distant disease - higher survival in years 2-3 and 5-8 (8 year follow-up); and (3) breast, post-menopausal regional disease - higher survival in all 5 years of follow-up.

Coley's interest in the subject developed when he lost his first cancer patient, a young girl from the Rockefeller family, with a sarcoma in her right arm. In spite of radical surgery, she later died of metastatic cancer. In the course of his work, the physician noted that patients who developed bacterial infections after sarcoma surgery faired much better than those who did not develop postoperative infections. Specifically, Coley studied the medical records of a patient with four instances of large recurrent inoperable sarcoma of the neck and noted that the patient experienced regression under the influence of erysipelas (a superficial streptococcal infection of the skin). To further his research, Coley deliberately injected erysipelas into some of his cancer patients. Due to initial complications with the formula, the formula was later changed to a combination of gram-positive heat killed streptococcus plus gram negative heat killed bacteria (Streptococcus pyogenes and Serratia marcescens) called Coley's Toxins or ‘Mixed Bacterial Vaccine’ (MBV).

Since then various researchers all over the world have used different bacterial products for the treatment of cancer patients to raise an unspecified immune response in the hope to stimulate humoral and cellular antitumor activities. Later, his daughter Helen Coley Nauts would found the Cancer Research Institute in New York, which has since pioneered the field. Coley's Toxins, consisting of the two bacteria Serratia marcescens and Streptococcus pyogenes, have been used in a variety of preparations and indications. They also came known as “fever therapy” or endogenous hyperthermia. Progress in immunology and the discovery of cytokines has led to a better understanding of the mechanisms involved. Coley Toxins and related approaches will be reviewed in respect to the variety of preparations, immunological and clinical results. Coley is credited with pioneering the field of immunotherapy.

In the mid-20th century Issels and Windstoßer continued to treat cancer patients with MBV on an empirical basis.16 Hager and Abel17 stimulated in the 1980s the clinical research and therapeutic use and basic and clinical research of endogenous, active hyperthermia (“fever therapy”) with bacterial vaccines (MBV, Vaccineurin) and passive ‘Fever-Range Whole Body Hyperthermia’ (FR-WBH) with infrared radiation by critical analysis and summary of the available literature. Heckel18 and von Ardenne672 developed heating devices for passive hyperthermia with infrared radiation.

It has been suggested19 that an important prerequisition for the successful elicitation of an immunological response and induction of tumor cytotoxicity in the host following bacterial toxin exposure is the preactivation of the host. At Coley's time, this has been the preexposure of large groups of the population to BCG. Importantly, in 1975 the group of Old detected TNF in a BCG-primed mouse. The immunologic preactivation has been confirmed by a large number of in vitro and in vivo studies as an important factor not only in respect to an effective immune response but also for the development of tolerance and toxicity.

Interestingly, the epidemiology of cancer incidence and the incidence of febrile infections have been shown to have an inverse correlation and additionally, spontaneous remissions repeatedly have been reported to be associated with febrile infections (reviewed in ref. 20). The evidence for these observations will be reviewed.

Rationale

Emerging evidence has developed that cancer is an aberrant regulatory process in which the tumor is in a dynamic disequilibrium with the host. The immunological implications of this evidence are widely accepted in the scientific community but have not found their way into applied clinical practice yet. Immunological functions not only are associated with the expression of oncogenes21 but also with prognostic factors.22 Moreover, immunosuppressive factors in cancer patients have been frequently described, as demonstrated by in vitro reactions23-31 (reviewed in ref. 32). Additionally, the exposure to endotoxins has been demonstrated to act as a powerful immune enhancer not only in immunocompromised cancer patients but also in other patient groups as demonstrated in numerous studies (i.e., reversal of virally mediated immunosuppression: Friedman et al.33).

Furthermore, cytotoxic therapies have been shown to exert often long lasting immunologic depression with the subsequent risk of secondary malignancies.34-47

Attempts to reintroduce differentiation and apoptosis is one line of research as has been shown with the successful differentiation therapies in acute promyelocytic leukemia48 or the clinical reversibility of MALT (gastric lymphomas) after successful eradication of Helicobacter pylori infection.49 Immunotherapy on the other hand aims to target the body's immune system to attack the cancer cells and has gained popularity as a treatment modality for malignant diseases in the 1960s. A large number of trials, using tumor vaccines, immunopotentiators, interferons, cytokines, and “biological response modifiers”, demonstrated antitumor effects in several malignancies, and, to date, immunotherapy plays a major role in the treatment of advanced renal cell carcinoma and superficial bladder carcinoma. Interferon or interleukin-2, which became available for large-scale clinical trials with the development of bioengineering, however, were shown to be not as effective in human trials as initially expected from animal models. The attempt of unspecific immunotherapy by raising a host response through the application of bacterially derived vaccines is a rational design opposed to the application of single cytokines. Together with our increasing knowledge of the complex immunological network this attempt, based on basic and clinical research should provide progress in treatment of human malignancies.

The rationale for the further study of endo- and exotoxin based cancer therapies will be justified as follows:

  1. Established cancer therapy has yet to be improved.50-52
  2. A new paradigm in cancer treatment is warranted.53-55
  3. There is an inverse correlation between the incidence of infectious diseases and cancer risk.20
  4. During and immediately after febrile infections remissions of malignancies have been observed.20
  5. Pyrogenic substances have been successfully administered in palliative and curative treatment protocols of metastatic cancer
  6. Cytokine secretions such as IL-1, IL-6, GM-CSF, G-CSF, IL-12 Interferons, and TNF-a mediate the immunological reactions to the administration of Coley's Toxin. Their induction and the shift from type TH1 to type TH2 cytokines can be individually monitored and the therapy adjusted accordingly. With some exception, i.e., in leukemias, the application of single or combination of cytokines has not contributed to a major breakthrough in the continuing search for a cure for cancer. Otherwise, the imitation of a phylogenetic protection mechanism as old as fever may be safely exploited in association with the powerful diagnostic tools of molecular biology, which may allow the therapist to fine-tune the immunologic response to the given challenge.
  7. Side effects of the treatment are manageable.
  8. New preparation may be more effective than preparations such as Vaccineurin and Novo-Pyrexal or Picibanil which have been used for this purpose in the past in Europe and Japan, respectively. New preparations are available.481
  9. The Office of Complementary and Alternative Medicine at the National Institutes of Health in the USA as well the German Ministry for Research list Coley's Toxins as a treatment approach with high priority for research.56,57
  10. Due to the growth in “publicity” of unconventional cancer treatments, the rigorous scientific evaluation of this treatment approach may serve the public, medical providers and third party payers. More importantly, carefully designed studies according to GLP and GCP will lend credibility to this approach and will promote only the best available treatment and bacterial products and hopefully prevent the exploitation by less scientifically qualified providers. As will be discussed, a close immunologic monitoring of the patient is paramount to prevent enforcement of immunologic blocking mechanisms.
  11. This study may add benefits to developing new methods in cancer treatments.

Epidemiology

Incidence of Malignancies and Missing History of Fever

Clinical Oncologists repeatedly report that cancer patients stress in their anamnesis that they were never ill before. As a result of this observation, a number of epidemiological studies have been conducted which shall be briefly reviewed here. Already in 1854 Laurence4 acknowledges the fact that cancer patients have a “remarkable disease-free history”. Schmidt58 corroborates these findings in stating an “afebrile diathesis” in the history of cancer patients in a study of 241 subjects followed by Engel59,60 who compared 300 cancer with 300 noncancer patients. Engels' studies demonstrate a cancer risk for people who never experienced an infectious disease calculated with odds ratio (OR) of 2.5 to 46.2. Sinek61 finds similar results in 232 cancer patients, which he compared with 2.444 controls.

More recent studies confirm the earlier work: Witzel62 obtained anamnestic data from 150 cancer patients and 150 controls. In this study cancer patients exhibited significantly less visits to their physicians, had fewer secondary illnesses and fewer in-patient hospital referrals. Also, in the five years preceding the diagnosis only two cancer patients developed fever compared to 20 subjects in the control group. Newhouse et al.63 found in a study of 300 women with cancer of the ovary amongst sociological factors like fewer marriages, fewer incidences of mumps, measles, or rubella compared to an age-matched control group. Remy et al.64 found an increased cancer risk with an odds ratio of 2.6 for missing history of infectious organ diseases, 5.7 for missing history of common colds, and 15.1 for missing history of fever. Grufferman et al.65 studied environmental factors in the etiology of rhabdomyosarcoma in childhood. It is the only paper that finds an insignificant correlation with fewer immunizations and a higher rate of preventable infections associated with cancer risk. Rønne66 could associate a missing history of measles in childhood with increased cancer risk for a variety of tumors in a historical prospective study. Out of 353 individuals with a negative history of measles 21 developed cancer versus only 1 case out of 230 controls with a positive history of measles (p < 0.001).

Van Steensel-Moll et al.67 reported evidence of a lower frequency of infections in the first year of life for children with leukemia; in this register-based case-control study, common colds, periods of fever, and primary childhood infections showed relative risks (RR) of 0.8, 0.9, and 0.8, respectively. The authors argue that stimulation of the immune system in early life may play a protective role in the development of leukemia. Chilvers et al.68 performed a retrospective study in which not the absence of fever or infectious diseases but the absence of common cold or a positive history of allergies was tested for their impact on cancer risk. In this study for missing history of common cold and positive history of allergies, no association with increased cancer risk could be established. Remy et al.,64 Abel et al.,69-71 and Schlehofer et al.72 contradicted this study. Abel et al.70 established in case-control studies with 255 cancer patients compared with 230 controls the highest risk for patients with a low “Infection-Index”. Schlehofer et al.72 investigated in a population-based, case-control study the medical risk factors of 226 patients with primary brain tumors and 418 controls. She stated a decreased RR for the development of brain tumors for those individuals who had had allergic diseases (RR 0.7; 95% confidence interval (CI) 0.5 to 1.0), diabetes (RR 0.7; 95% CI 0.3 to 1.8), and infections and cold (RR 0.3; 95% CI 0.1 to 0.8). Melanoma patients had fewer atopic symptoms than subjects did in the control group (p less than 0.05). Grossarth-Maticek et al.73 performed a ten-year prospective cohort study of 1353 persons. He concludes “episodes of high fever during the entire lifespan in the case of an acute illness as a typical reaction are inversely related to later cancer incidence when the subjective reporting of fever is accepted as valid evidence”. Kölmel and Compagnone74 investigated the role of fever and atopy among melanoma patients. There were fewer feverish infections, while patients with atopy had more feverish complications of their symptoms. Finally, Kölmel et al.75 demonstrated at 271 controls versus 139 melanoma patients an inverse relation between number of febrile infections and incidence of malignant melanoma.

The correlation between missing history of fever and cancer risk could not be confirmed for acute adult leukemia and ALL in a recent study by Cooper et al.76 The data of 624 patients with acute myeloid leukemia, 124 patients with acute lymphoblastic leukemia (AML) matched with 637 healthy population controls did not support a protective effect from antigenic stimulation in relation to the risk for acute leukemia in adults.

While discussing the incidence of malignancies and missing history of fever the same question can be asked in relation to immunosuppressive drugs. There is considerable evidence that there is a higher cancer rate after the introduction of immunosuppressive methods accompanying transplantation surgery (Cole46,47). Data for increased incidence of neoplasms following therapeutic immunosuppression exist for lung carcinoma,77 lymphoma,78-80 bladder tumors,81 next to several reviews on miscellaneous tumors.82-86 These data deserve further studies. Possible mechanisms for increased incidence of malignancies have not been elucidated yet and there consists even a controversy whether immunosuppressive or immunostimulatory events are mediating increased carcinogenesis. Furthermore the immunosuppressive effects of chemotherapy are well known and there has been association between chemotherapy and secondary malignancies.33-35,37-39,44

Spontaneous Remissions and Feverish Infections

It is of obvious interest for this review to analyze the literature on reports of spontaneous remissions in cancer following infections with or without fever. O'Regan and Hirshberg87 give an extensive overview of the field. The older literature consists mainly of the reports of Coley, meticulously documented in eighteen monographs mainly by his daughter Helen Coley Nauts.88-109

Analysis of the literature87 reveals leukemia with ≥22% being the magnitude of cases where infection was associated with remission, followed by bone and connective tissue cancers with ≥15%, melanoma with ≥11% and lymphoma with ≥7%. Spontaneous tumor remissions during or following feverish infections have been reported already in the beginning 19th century (Vautier,110 see Nowotny111). There are several older reviews112-115 which report spontaneous remissions next to more recent studies by Everson and Cole,116-119 Stephenson et al,120 Cole,121,122 Nauts.102 Remissions of leukemia following systemic infections have been noted throughout the century.123-125 Stephenson et al120 reported in their analysis that an infection or persistent fever preceded 224 cases of spontaneous remissions. Additionally, febrile infections have been shown to increase the survival expectancy of cancer patients.126-130 Nowacki and Szymendera131 state a highly unfavorable prognostic significance for postoperative fever and/or septic complications in colorectal cancer patients. Fucini et al132 disagree with this statement and show in a retrospective analysis no significant prognostic influence of postoperative fever and/or septic complications in this patient group.

Treon and Broitman133 described post-transfusional hepatitis as a common complication in patients with acute myelogenous leukemia (AML) which “paradoxically” prolonged survival. They identified the impaired hepatic endotoxin (LPS) clearance in patients with acute viral hepatitis as the reason for endotoxemia and elevated TNF-α release, a mechanism referred to as endothelial translocation (see: Translocation). They also observed virally induced IFN-γ secretion, which in turn acts in synergy with TNF-α anti-proliferative and as a mechanism inducing differentiation. Finally, in a recent monograph on spontaneous remissions of malignant melanoma Maurer and Kölmel134 list 21 cases of the world literature, where febrile infections have been associated with spontaneous regression of metastatic melanoma. These authors state further “the connection of febrile infection and tumor regression is the most frequent association found in the literature”.

The following list contains the described and additional references in most of which spontaneous infection and/or fever had been associated to remission of neoplastic disease. Some articles refer to assumed mechanisms of spontaneous regression and some articles are review papers.

Spontaneous Remission Listed Under Tumor Types

(Please see Table 1)

Table 1. Spontaneous remission listed under tumor types.

Table 1

Spontaneous remission listed under tumor types.

Fever and the Immune Response

Fever as the imminent sign of infectious diseases has been used as a diagnostic indicator since ancient times.233 It is one of the oldest nonspecific responses to infection, both in vertebrates and invertebrates.234 Temperature rise during fever establishes a cascade of host defense mechanisms that increases host survival and induces T cell proliferation and differentiation, secretion of interferons (IFNs), antibodies and neutrophil migration.235,236 Fever as a part of the acute-phase reaction and the role of cytokines in thermoregulation have been reviewed recently by Dinarello.237,238

The interest in fever as a therapeutic tool is dating back to Parmenides (ca. 540-480 B.C.) who stated: “Give me the power to induce fever and I will cure all diseases”. And in the seventeenth century the English physician Sydenham (1624-1689) described the reaction of the organism to pyrogenic substances: “Fever is a mighty engine, which nature brings into the world for the conquest of her enemies”. Ever since Burnet239,240 has postulated his theory of immunological surveillance and the first limitations of aggressive cancer treatments became obvious, research has focussed on the possible role of the immune system in cancer incidence and prognosis. As it has been shown and will be discussed further fever, as an innate and phylogenetic very old mechanism, deserves the best of our scientific attention as a powerful tool in the ongoing search for the cure of cancer.

Cytokine research has elucidated the immunological response underlying fever. Direct primary endogenous pyrogens are IL-1alpha, IL-1beta, TNF-alpha, TNF-beta (lymphotoxin-alpha), IL-6, macrophage inflammatory protein 1, and IFN-alpha.239,241 Indirect inducers are considered to be IL-2 and IFN-gamma.238 Exogenous pyrogens are considered to be the lipopolysaccharides of the cell wall of gram-negative bacteria such as Serratia marcescens and the exotoxins of gram-positive bacteria such as streptococcus and staphylococcus, which are also called bacterial superantigens. Fever-induced temperature changes have been shown to augment immunological defense mechanisms in vivo and in vitro.234,235,242-246 Increased temperatures stimulate the proliferation but not cytotoxicity of cytotoxic T lymphocytes (CTL) which then can perform their effector function at all physiological temperatures in the body.247-249 It has been shown that binding of bivalent antibody can neutralize picornaviruses by irreversibly neutralizing the virus at temperatures that are higher than physiological by disrupting the virion, leading to ejection of the RNA. Fever enhances this process in vivo, confirming the popular belief in the virtues of fever.250 Not all researchers report enhancement of immunity: Incubating temperatures of 39° C have been shown to suppress natural killer cell activity in vitro in the presence of IL-1 or interferon-alpha.250 But the immunological effects are not only depending on temperature but also on time (Figs. 1, 2, 3, 4, 5, 6, 7).

Figure 1. Time dependent exemplary induction of IL-1 in a patient after induction of fever up to 39.

Figure 1

Time dependent exemplary induction of IL-1 in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin).

Figure 2. Emigration, homing, proliferation and activation of leukocytes in a patient after induction of fever up to 39.

Figure 2

Emigration, homing, proliferation and activation of leukocytes in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin) depending on time.

Figure 3. Emigration, homing, proliferation and activation of total lymphocytes in a patient after induction of fever up to 39.

Figure 3

Emigration, homing, proliferation and activation of total lymphocytes in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin) depending on time.

Figure 4. Emigration, homing, proliferation and activation of B-lymphocytes in a patient after induction of fever up to 39.

Figure 4

Emigration, homing, proliferation and activation of B-lymphocytes in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin) depending on time.

Figure 5. Emigration, homing, proliferation and activation of T-lymphocytes in a patient after induction of fever up to 39.

Figure 5

Emigration, homing, proliferation and activation of T-lymphocytes in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin) depending on time.

Figure 6. Emigration, homing, proliferation and activation of NK-cells in a patient after induction of fever up to 39.

Figure 6

Emigration, homing, proliferation and activation of NK-cells in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin) depending on time.

Figure 7. Emigration, homing, proliferation and activation of LAK-cells in a patient after induction of fever up to 39.

Figure 7

Emigration, homing, proliferation and activation of LAK-cells in a patient after induction of fever up to 39.8°C with a biological pyrogen (Vaccineurin) depending on time.

Glucocorticoids inhibit various components of the acute phase response, particularly the increase in body temperature induced by endotoxins. Endogenous glucocorticoids function as part of an inhibitory feedback system involved in the modulation of fever by decreasing plasma IL-6, CSF, PGE2, and PGF2 alpha concentrations.251

The Immunological Basis of Endo- and Exotoxin-induced Tumor Regression

The Shwartzman Phenomenon

The Phenomenon of Local Skin Reactivity to Various Microorganisms

Shwartzman252 was the first to describe the phenomenon of local tissue reactivity, later referred as the Shwartzman phenomenon (SP). Because of the importance to the subject it shall be briefly described here:

Shwartzman injected a single intradermal cultural filtrate from B. typhosus free of exotoxins into rabbits, which was followed 24 hours later by a single intravenous injection of the same filtrate. Only four hours after the intravenous injection Shwartzman observed severe hemorrhagic necrosis at the site of skin injection. Furthermore it was shown that the second dose of the filtrate had to be given intravenously since repeated intradermal injections did not elicit the SP. Interestingly the SP induced cross-reactivity since it could also be provoked when using intravenous injections from filtrates derived from biologically and serologically unrelated microorganisms. These included Meningococcus, B. typhosus, B. paratyphosus, B. coli, b. friedlaender, B. dysenteriae, B. prodigiosus (later known as Serratia marcescens), B. lepisepticus, B. pestis, B. influenza, B. pertussis, and Vibrio cholera. Additionally Ascaris lumbricoidis elicited the SP whereas yeast, ricin and diphtheria toxin did not show strong responses. The same phenomenon of different bacterial species sharing similar mechanisms of sensitization has been observed for the induction of endotoxin tolerance, as will be described below.

Timing played a crucial role. The appropriate time between the initial skin injection and the subsequent intravenous injection for the intravenous injection ranged from eight to thirty-two hours after initial skin injection with an optimum incubation period of twenty-four hours. Outside this range no SP could be elicited.

The pretreatment of a large amount of different microorganisms revealed considerable heat resistance which, though, differed widely between different strains and even within the same strain.

Shwartzman observed fluctuations of the potency of various preparations in refrigerated storage. There was increase as well as decrease of potency upon storage of several months. It was hypothesized that fluctuations in potency of filtrates are accompanied by the formation of “toxoids”, which retain their power to combine with neutralizing antibodies.

Interestingly, SP could be elicited in rabbits, guinea pigs, goats, and horses but not in mice and rats. But, as will be discussed later, murine animals bearing sarcoma, again showed a marked SP in their tumor. Later, it became clear that interferon-gamma (IFN-gamma) plays a critical role in eliciting the SP, since monoclonal antibodies to IFN-gamma could completely prevent the SP. Also, IFN-alpha and IFN-beta had a desensitizing effect.253

Reactivity of Malignant Neoplasms to the Phenomenon of Local Skin Reactivity

Applying the same technique of sensitizing animals with intradermal injections of bacterial filtrates Shwartzman observed upon subsequent intravenous injection of bacterial filtrates into tumor bearing animals severe hemorrhagic necrosis and remissions of tumors. This observation referred to transplantable and spontaneous tumors.

Comments on the antagonism between tuberculosis,254 malaria and tick fever255 and the development of carcinoma built the early epidemiological hypothesis about the protective mechanism of infections against cancer. Gratia and Linz256 continued Coley's early work in liposarcoma-bearing guinea pigs by combined intratumoral and intraperitoneal injection of B. coli. Instead of the skin these animals were sensitized directly at the tumor site. In later experiments the authors only choose the intraperitoneal route without previous injection at the skin site and still could elicit severe hemorrhagic necrosis of tumors. No hemorrhagic lesions were observed in other visceral sites.

While the SP in nontumor bearing animals was restricted to nonmurine species, tumor-bearing rats and mice showed a marked SP in their tumors. Mouse sarcoma 180 inoculated by Shwartzman and Michailovsky257 were treated with intravenous injection of Meningococcus 44B. Hemorrhagic tumor necrosis and complete regression of tumors were observed in mice receiving repeated intravenous and intraperitoneal injection of the bacterial filtrate as early as one hour later.

Further experiments revealed “positively (1) and negatively (2) reacting tumors”:

  1. Positively responding tumors were sarcoma S/37, sarcoma 180, adenosarcoma M/63, Twort adenocarcinoma and Walker sarcoma. While “…very young, perfectly healthy tumors often gave no reaction, larger tumors gave practically 100 per cent positive results”.253 This observation is in consistency with the literature which postulates the necessity of an immune response to develop gradually as noted later by Berendt,200,201,258 and described by Wiemann and Starnes19 as window in time. Obviously immunity can not be developed in hosts bearing very young tumors.
  2. Negatively responding tumors were not further specified slow growing spontaneous or transplantable malignant tumors, which rarely or never regress, heterologous grafts of rapidly growing malignant tumors, which eventually regress, and benign, rapidly developing granulomas or embryomas, which eventually regress. Already in his time Shwartzman hypothesizes that the newly formed and highly fragile tumor vessels may have been one of the target mechanisms of endotoxin induced tumor necrosis. This observation is most interesting in the era of substances blocking VEGF and other mechanisms of nevascularization.

Shear259 performed experiments with 2000 mice. He produced profound hemorrhagic necrosis and in some cases complete regression of malignant tumors following intravenous administration of Meningococcus. It further can be stated from this work and the experiments of Shwartzman and his contemporaries, that there is a direct correlation between the ability of a filtrate from a given microorganism to prevent the development of sarcoma 180 in mice and to elicit the SP in rabbits.

Much later, in 1985 Aoki and Mori260 described a local SP (LSP) confined to the tumor and a generalized SP (GSP) spreading to different visceral sites such as kidneys, liver, spleen and lung. Using E. coli endotoxin in Vx-2 carcinoma bearing cottontail rabbits they produced a GSP additionally to the hemorrhagic necrosis of tumors (LSP). The proposed mechanism of action for this phenomenon is disseminated intravascular coagulation (DIC), resulting in fulminate hepatitis and other organ changes. While GSP and DIC have not routinely been observed in patients undergoing mixed bacterial vaccine therapy for immunotherapy of cancer, those observations are important to keep in mind.

Reflections on Immunotherapy of Cancer with Bacterial Lipopolysaccharide (LPS)

Gratia and Linz257 showed in guinea pigs the hemorrhagic necrosis of transplanted liposarcoma if the animals were treated with E. coli filtrates. Shwartzman and Michailovsky258 treating mice with the Sarcoma 180 with parenteral application of Meningococcus culture filtrates observed hemorrhagic tumor necrosis and eventually complete remissions. Shear after isolating an endotoxin later defined as LPS as the active component of gramnegative bacteria,261 subsequently induced necrosis in primary and experimental tumors.262 The discovery of LPS as the active compound of bacterial filtrates led to efforts to isolate and synthesize LPS. The group of Westphal at the Max Planck Institute in Freiburg pioneered this field (for a review see ref. 263). The endotoxin-induced necrosis is being initiated rather quickly: 4-8 hours following exposure to endotoxin the tumor tissue becomes inflamed; after additional 10-20 hours the center of the tumor necrotises.264 Additionally, numerous endotoxin induced effects upon the immune system have been observed: Stimulation of the reticulo-endothelial system (RES), activation of macrophages,265 stimulation of B cell mitogenity,266,267 increased antibody synthesis,268,269 induction of interferons, fever, leukopenia followed by leukocytosis. (For reviews of molecular mechanisms, see i.e.: refs. 270-275). It also should be mentioned that in vitro macrophage responsiveness to endotoxin does not necessarily indicate high in vivo sensitivity to endotoxin challenge.276

The immunological response to exposure of a variety of viruses and lipopolysaccharides (endotoxins) has been clearly corresponding with antineoplastic effects.19,133,200,201,263,277-289 Moore et al290 showed that post-endotoxin sera (C. parvum and S. abortus equi-Novo Pyrexal) contain high levels of myeloid colony-stimulating factor(s) (GM-CSF) and factors capable of inducing terminal granulocyte and macrophage differentiation of the murine myelomonocytic leukemic cell line WEHI-3. Also, exposure to endotoxins at work has been associated with decreased cancer risk.291

Kearney and Harrop292,293 argue that exposure to endotoxin might enhance tumor growth. They legitimately point to the importance of excluding endotoxin from solutions used in studies of experimental tumors. Other authors fear exposure to infections may lead to a process labeled “inflammatory oncotaxis”.294-297 Recently, this phenomenon has been described further by researchers identifying cytokines, leucocytes and macrophages in long standing cancers as promoters of tumor growth.298,299 These infiltrations are being compared to chronic infections whereas the attempt to induce an immune response to cancer by artificially induced fever may be compared to an acute phase reaction observed in acute infections. The literature discussed in this review does not lend itself to suggest enhancement of tumor growth following antigenic exposure to spontaneous occurring tumors in human and animal models.

Chun and Hoffmann279 reported that application of low doses of LPS could substantially increase the efficacy of TNF against murine cancers. What might be even more important is their observation that the blockage of two negative feedback responses occurring as a response to LPS treatment, namely the production of prostaglandin E (PGE2) and the generation of CD8+ suppressor T-lymphocytes (CD3+ CD16/56-), dramatically increases the ability of mice to reject tumor transplants. In humans Otto et al289 achieved only one complete remission (CR) with intravenous endotoxins from Salmonella abortus equi in 27 patients with colorectal (1 CR, 2 PR) and 15 patients with nonsmall cell lung cancer (NR). While this group clearly could not come close to the results achieved by Coley, the group has performed numerous studies with the same strain of Salmonella278,282-288 (see: Salmonella abortus equi).

Morita et al300 achieved dose-dependent inhibition of tumor growth with a synthetic lipid A analogue in a hamster pancreatic carcinoma model. Interestingly, endogenous tumor necrosis factor (TNF) activities were significantly greater in tumor than in serum, spleen and liver. Another group did not observe any antitumor effects with an isolated lipid A from Salmonella typhimurium and Salmonella Minnesota.301 TNF production by macrophages stimulated with lipid A after culture was much greater when the culture was performed in the presence of hamster pancreatic carcinoma cells (no cell-to-cell contact). Anti-TNF neutralizing antibodies inhibited the cytotoxic activity of TNF secreted by macrophages. The authors hypothesize that lipid A displays antitumor effects by stimulating production of endogenous TNF in tumor macrophages, through activation and production of soluble macrophage-stimulating factors in cancer cells.

Goto et al302 administered LPS intradermally in animal and human tumor models together with Cyclophosphamide, known for it's synergistic effect with LPS (prostaglandins). After completion of dose escalation, the treatment was continued for at least 4 months, and it was found that 1800 ng/kg LPS was well tolerated. A significant level of cytokines was observed in the sera for at least 8 h. These results indicate higher tolerable doses and remarkably more continuous induction of the cytokines than were reported in a previous study by others using intravenous administration. Three of the five evaluable tumors showed a significant response to therapy.

Jimbo et al303 showed that intravenous administration of a synthetic lipid A derivative significantly inhibited the growth of transplanted tumors in the liver of rabbits. These results suggest that systemic administration of lipid A induced selective tumor microcirculatory blood flow reduction via local endogenous TNF production. In contrast, local administration of human recombinant TNF alpha through the hepatic artery induced blood flow reduction not only in the tumor region but also in nontumorous liver tissue.

Nowicki et al304 treated C57Bl/6 mice bearing transplantable Lewis lung cancer (nonmetastatic subline) implanted either subcutaneously or intraperitoneally with macrophage colony stimulating factor (M-CSF), Escherichia coli lipopolysaccharide or both. LPS administered daily once a day for up to 30 days impaired both subcutaneous and intraperitoneal tumor growth and prolonged survival of tumor bearing mice. Macrophage colony stimulating factor administered daily, inhibited only subcutaneous tumor growth, both when administered alone and in combination with lipopolysaccharide, and had no effect on intraperitoneal tumors. Moreover, it did not prolong survival of tumor bearing mice, when administered alone, and nullified the effects of lipopolysaccharide when administered concomitantly. These data suggest that macrophage colony-stimulating factor, at least in this tumor model and in this dose schedule, offers little benefit. In contrast, the present data confirm earlier suggestions on the therapeutic usefulness of bacterial lipopolysaccharides in neoplastic disease.

It has to be noted that hemorrhagic necrosis of tumors is to be distinguished from tumor regression.305 Endotoxin-induced tumor necrosis takes place in the center of solid tumors, often leaving a ring of viable tumor cells behind which eventually will lead to further cancer progression. Endotoxin-induced hemorrhagic necrosis always precedes tumor regression but is by itself only rarely followed by complete regression, i.e., tumor necrosis and tumor regression are mechanistically two separate events. It further has been shown that endotoxin-induced tumor regression requires a state of T cell mediated immune response that is only induced in response to immunogenic tumors as classically defined.19,200,201 Human tumor rejection antigens, which are recognized by T cells, may play an important role in the unspecific as well as specific immunotherapy for cancer.306-310 The hemorrhagic necrosis is thought to create conditions within the tumor, that are facilitating the entry and functioning of effector T cells, an observation in accordance with the abilities of endo- and exotoxins to induce the expression of cell adhesion molecules311-314 and of TNF to induce capillary leaks.315-318 This T cell response again needs as an activation signal a prestimulation with antigenic substances such as BCG, corynebacterium parvum319,320 or the tumor antigens itself.200 The prestimulation has been associated with a highly activated macrophage system, which elicits the release of TNF and plays an important role in removing tumor cell debris.

It is important to realize that the acquisition of concomitant immunity precedes endotoxin susceptibility. This process is generated over time following successive tumor growth and has been described as “window in time” when mice become susceptible to subsequent endotoxin challenge.19

In summary the following endogenous mediators have been identified which are relevant to endotoxin-induced tumor necrosis: TNF, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, granulocyte-macrophage differentiation factor (GM-DF), colony-stimulating-factor-1 (CSF-1), granulocyte-macrophage (GM-CSF), granulocyte-stimulating-factor (G-CSF), interferon-beta, and interferon-gamma (for a review see ref. 321). Moreover, the IL-12 mediated balance between TH1 and TH2 cytokines on the one hand and the functional balance between prostaglandins and IL-1 mediated effects on the other side determines the type of immune response. Structural requirements of endotoxic reactions can be summarized as follows. (1) Lipid A structures proved to be the carrier of the toxic properties of endotoxin. (2) Conversely, beneficial reactions can be initiated not only by the complete structures but also by structural remains, which are no longer toxic. (3) Some of the split products in the lipid-free and polysaccharide-rich preparations can induce beneficial reactions. (4) Gram-negative bacteria can produce endotoxin-unrelated and beneficial compounds. Conventional endotoxin preparations are heterogeneous and often contain some of these unrelated substances.

Coley Toxins Used in the Treatment of Cancer

Helen Coley Nauts, in an admirable effort, has compiled the work of her father William B. Coley in numerous articles and 18 monographs (Nauts HC: Monographs #87-108). The following critical points shall be mentioned from the analysis of Helen Coley Nauts work:

Variability of the Preparations Used

For the period between 1891 and 1953 Nauts reported the use of 14 different preparations of Coley toxins (Nauts105): (see Table 2).

Table 2. Mechanisms following stimulation of humoral and cellular defense.

Table 2

Mechanisms following stimulation of humoral and cellular defense.

The variability of the preparations used makes it desirable to determine which preparation reveals the biggest benefit in which cancer type. The importance of this fact has been stressed by Nowotny et al.272,322 Also, it is important to know which cytokine pattern is being induced by various techniques of growth and preparation. This research has been taking place in the nineties at the laboratories of Memorial Sloan-Kettering Cancer Center (personal communication: Nauts 1997) and awaits publication.

Mikolasek323 demonstrated rejection of tumor allografts in mice treated with enzymes of (grampositive) Streptococcus pyogenes (streptolysine, streptokinase, streptodornase and hyaluronidase). He observed high antistreptolysine (ASLO) titers in the serum of mice and strong inhibition of subcutaneously implanted cystic adenocarcinoma following exposure to antigens. In addition, the author describes a complete spontaneous remission of a human adenocarcinoma of the uterus surviving 19 years since a Wertheim operation. Interestingly, this patient had had a high ASLO titer (595 IU/ml serum) which leads the author to speculate that an intercurrent Streptococcus pyogenes infection had taken place resulting in functional mitral valve impairment and induction of immunity against metastatic disease. Although, as it is pointed out, the mouse tumor was allogenic and human tumors are autologous, the association between his observations appears to be valid. It might be interesting to look at epidemiological and clinical data to compare cancer incidence and ASLO titers in humans.

Techniques and Timing of Administration

Site and dosage of application of the Toxins are of considerable interest. Whereas Coley choose the intratumoral approach in his early years beginning in 1892 it was not until 1925 that Coley used the intravenous approach, which elicited stronger febrile reactions with smaller dosages. He also used intramuscular and subcutaneous administration, some of which have been questioned to be effective due to poor resorption.103 It might be advisable to test small amounts of the toxins subcutaneously to rule out hypersensitivity reactions (personal observation). Of special interest is the intraperitoneal application since several cases of dramatic tumor regression in ovarian cancer have been reported following this route of administration.105 Application other than the intravenous route bears the advantage of slower release of endotoxins and more continuous stimulation of the host immune system.105

Frequency and duration of injections of Coley Toxins obviously play another crucial part in the outcome of therapy. Daily or every other day injections often produced the best results.105 However, the general condition of the patient, compliance issues, the phenomenon of tolerance (see: Tolerance) and hypersensitivity (see: Toxicity) suggest at least a 48-hour interval between injections. Coley suggested a six-month period during which treatment should be continued often performed by the attending family physician even after remission might have occurred. Only in later years Coley14 attributed treatment failures after initial tumor regression to a too early stop of therapy.105,108

Recent experiments confirm the importance of timing of toxine administration in experimental animal models.324 In this study it appeared that early intravesical BCG toxine therapy of bladder tumors, initiated after tumor inoculation resulted in slower progression rate than treatment initiation after a longer waiting period. Moreover, single injections of endotoxins in tumor bearing animals have been shown to induce periodically changing periods of enhanced beneficial effects, followed by phases of responsiveness below normal towards the immunological challenge.325 Further Nowotny et al272 recently showed that the time intervals between endotoxin treatment and tumor challenge are of utmost importance to the capability of animals to reject a subsequent tumor challenge. While previous experiments used allogenic tumors and the elicited immune response was based on allogenic recognition and destruction of these tumors,326 in this study endotoxin-induced rejection of less immunogenic tumors also was shown to be possible. However, there was a small time frame (-5 days until +1 days) when endotoxin inoculation elicited protection against subsequent tumor challenge. Later inoculation did not protect animals and higher doses even showed reduced immunity against leukemia L1210 cells. Conclusions from these observations for the therapy of established syngeneic tumors only can be speculative.

Stage of Disease

The inverse relation between tumor load and immunological function is well established. 327,328 Chasseing et al329 could demonstrate that the immunosuppression associated with later stages of tumor development might be due to direct effects on monocytes, by down regulating IL-1 production. Also, in this study an increase in the levels of prostaglandin E2 and serum immune complexes could be detected. Related studies of the prognostic significance of circulating immune complexes (CIC) in malignant tumours of head and neck revealed a correlation between the level of CIC and stage of disease in head and neck cancer patients: Seropositivity for CIC increased quantitatively with stage of disease.330 However, CIC containing MUC-1 encoded polymorphic epithelial mucin (PEM.CIC) was decreased in advanced breast cancer, i.e., there was an inverse correlation between positivity for PEM.CIC and extent of disease.331 Mucins, encoded by the MUC1 gene, and CD43 (leukosialin) as the core protein, secreted or expressed in the plasma membrane of cancer cells could interfere with NK cell-mediated lysis in a dose-response-dependent way.332 The CTL response against differentiation antigens of the melanocyte lineage correlated inversely with antigen expression (Melan A/MART-1).333 Here, metastases increasing in size over time showed a loss of Melan A/MART-1 expression in the presence of CTL.

Studies on natural killer (NK) cell activity showed a significantly lower cytotoxic activity in patients with laryngeal carcinoma who had histologically confirmed nodal involvement.334 The study of serum immunoglobulins correlated with tumor load, while the estimation of CIC and blocking effect of cancer sera on normal lymphocytes was of diagnostic and prognostic significance.335 Wiltschke et al21 showed reduced mitogenic stimulation of peripheral blood mononuclear cells as a prognostic parameter for the course of breast cancer in correlation to tumor size and axillary lymph node involvement. Thus, it is desirable to decrease the tumor burden prior to initiation of immunological therapies. If this attempt includes the use of chemotherapy, treatment related changes in the phenotype of target cells should be considered.336-340

Radiation and Toxin Therapy

Before the era of chemotherapy started in the 1950, irradiation was the treatment of choice for many inoperable tumors. The review of Coley's work shows that a large number of his patients received concomitant radiation therapy.97,100-105,107,108 Already in 1942 Shoulders341 noted beneficial effects by combining the toxin therapy with irradiation in a series of far-advanced malignancies. Interestingly, toxins protected animals from otherwise lethal total body irradiation.342 Donaldson et al343 observed the effect of Coley's Toxins and irradiation on the A. melanoma # 3 tumor in the golden hamster. She concludes: (1) toxin therapy does not affect survival; (2) toxin pretreatment potentiates X-ray therapy; (3) metastases are not affected; (4) normal tissues do not show increased radiosensitivity; (5) toxins plus X-ray therapy do not affect the prognosis or survival of the host; (6) toxins plus X-ray therapy show a synergistic effect”. Nauts several times points to the radiation-sensitizing effect of the toxins while normal tissue was better protected from side effects of radiation. Chandler344 achieved beneficial results in six out of eight patients with rhabdomyosarcoma, melanoma, and sarcoma. These tumors were usually considered radio resistant. The radioprotective effect later has been described by Behling and Nowotny,324 and Nowotny.270,345

Tang et al346 used Mixed Bacterial Vaccine (MBV) in the multi-modality treatment of hepatocellular carcinoma (HCC). Patients undergoing palliative resection and cisplatin therapy and radiotherapy, which were randomized to receive MBV, had an improved one and two year survival. In addition, MBV improved the “second look” resection rate to 40% as compared to 17% in the control. MBV could also prevent decrease of macrophage activity caused by radiotherapy.

Kempin et al182,183 demonstrated improved remission rate and duration in nodular non-Hodgkin lymphoma (NNHL) and advanced Nodular Lymphoma (NL) with the use of mixed bacterial vaccine (MBV) in combination with radiotherapy.

Other Toxins, Bacterial and Viral Products Used in the Treatment of Cancer

Toxins and bacterial products in the treatment of cancer shall only be briefly mentioned because it would be beyond the scope of this review, which shall mostly focus on Coley toxins (for reviews see refs. 347-354).

Bacillus Calmette Guerin

Old et al355 were the first to report upon beneficial effects of treating tumor bearing mice with Bacillus Calmette-Guerin in the USA. Howard et al356 confirmed earlier studies of the effect of BCG infection on the sensitization of mice to bacterial endotoxin and Salmonella enteritidis infection. They found that mice infected two weeks previously with BCG were extremely susceptible to the lethal action of endotoxin. On the other hand mice were more resistant than normal to infection with Salmonella enteritidis. Without BCG administration the phenomenon of endotoxin tolerance would have occurred (discussed under: Tolerance). Ruddle and Waksman357 demonstrated increased lymphocytic cytotoxicity after sensitization with tuberculoprotein. Schwartz et al194 inhibited murine sarcoma virus oncogenesis with living BCG. Bluming and Ziegler143 and Mastrangelo358 successfully treated melanoma patients but observed different immunological effects of BCG depending on the route of administration. Hakim359,360 points to the possibility of enhanced tumor growth by BCG; he assumes that the serum from BCG-treated sarcoma-bearing animals blocks the spleen lymphocyte-mediated cytotoxic activities directed against proliferation and growth of the sarcoma. Remissions of skin melanoma metastases following BCG injection have been shown by Remy et al.198 Vosika361 gives a comprehensive review of clinical immunotherapy trials of bacterial components derived from Mycobacteria and Nocardia: Preparations of isolated mycobacterial cell wall or cell wall skeleton attached to oil or to trehalose dimycolate have been favored over crude extracts and caused regression of disease and established tumor-specific immunity.

Hence, BCG has been approved for the treatment of superficial bladder cancer.362-364 Recently upregulation of Inter-celluar-cell-adhesion-molecule-1 (ICAM-1) expression as an important mechanism of action of this treatment has been described on bladder tumours.310,311 The ICAM-1 – CD11a pathway can render bladder tumour cells vulnerable to nonantigen specific cytotoxicity mediated by activated lymphocytes. Recent results of local BCG treatment for T1 G3 bladder cancer, after TUR-B, showed a reduced risk of recurrence and mortality.288 Conti et al288 and Jackson et al365 could further show that BCG potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor, soluble tumour necrosis factor receptors and interleukin-1, but not interleukin-6 in bladder cancer patients. Also, exposure to BCG has been shown to enhance interleukin-8 release in macrophages, a major inflammatory cytokine associated with enhancement of the immune response.366 It should be mentioned here that the group of Old discovered TNF in a BCG primed mouse.319

Propioni Bacteria

Propioni Bacteria (PB) (Synonym: Corynebacterium parvum) (CP) are amongst the potent immunomodulators stimulating cell populations involved in nonspecific resistance. Generally, the activated immune system provides protection from infectious pathogens and malignancies via mechanisms of recognition and elimination. Accordingly, administration of Propionibacteria could be shown to be of benefit in the treatment of neoplastic and infectious diseases. Thus, it may be recommended for further clinical investigations (for reviews see refs. 367-369).

In vitro research showed induction of lymphokine-activated killer (LAK)-like cells capable of killing both natural killer (NK)-sensitive and NK-resistant tumor cells as well as syngeneic macrophages (M phi) (Chen et al370). Anti-interleukin-2 (IL-2) or anti-interferon (IFN) alpha, beta antibody significantly inhibited this induction of LAK-like activity by CP, suggesting that the generation of killer cells by CP was dependent on IL-2 and IFN(s) produced in the culture.

Bursuker et al371 showed, in accordance with Keller et al,372 that CP could render a murine nonimmunogenic tumor (M109) immunogenic. This immunity was tumor-specific and T-cell-dependent. T cells from mice whose progressive M109 tumors had been excised were capable, on passive transfer, of inhibiting adoptive immunotherapy of T-cell-deficient recipients by spleen cells from mice immunized with an admixture of M109 cells and CP. The authors argue, that the lack of anti-tumor immunity in this tumor model was not due to the absence of tumor-associated antigens but, instead, due to a shift of the balance from effector and suppressor arms of the immune response. Shifting the balance in favor of the effector arm by means of CP resulted in a measurable immune response to a nonimmunogenic tumor.

Karashima et al373 showed that modification of NK cell activity is a possible basis for modulation of anti-metastatic activity by CP. Administration of CP showed a biphasic change in NK activity of the spleen cells and the peritoneal exsudate cells (PEC) in mice. Initially after administration of CP, the NK activity of the spleen cells and PEC was significantly augmented. At a later phase (14 days) after CP administration, the NK activity was deeply depressed.

Further animal experiments with Propionibacterium acnes-metabolites revealed stimulation of proliferation, maturation and emigration of thymocytes and lymphocytes,374 and inhibition of experimental lung metastasis of murine sarcoma L-1 in BALB/c-mice.375 Pulverer et al376 further demonstrated a protective effect of combined treatment (CP and liver lectin blocking by D-galactose administration) on the liver colonization of RAW 117-H10 lymphosarcoma in BALB/c-mice. Both, immunomodulation with CP as well as liver lectin blocking by D-galactose treatment significantly decreased the number of liver tumor colonies in this experimental model. The authors favor the combination of CP and D-galactose, which proved superior to each monotherapy since the liver colonization by RAW 117-H 10 lymphosarcoma could be completely inhibited.

Lipton et al377 demonstrated CP versus BCG as adjuvant immunotherapy of stage II malignant melanoma as superior over BCG when measuring disease-free and survival times. Foresti378 showed beneficial results in treating malignant pleural effusions with intrapleural instillations of CP. Of 20 patients with malignant pleural effusions (MPE) treated with intrapleural CP, 18 (90%) had a CR and 2 patients (10%) had a PR. Preoperative immunostimulation by Propionibacterium granulosum KP-45 in colorectal cancer resulted in resistance to the spread of cancer during operation.379 In this study PB was administered intravenously between the seventh and third day prior to surgical treatment for colorectal cancer. For stage I carcinoma the survival rates, were 91% in the treated and 63% in the control group respectively. For stage II carcinoma the survival rate was 90% for the treated group with distant spread in 1 case and 45% in the control group where the rate of recurrence was 55%. For stages III and IV there was no statistically significant difference in survival between the treated and the control groups. Raica380 studied 96 patients with superficial bladder tumors treated by transurethral resection in order to investigate the value of intravesical CP to prevent recurrences. Patients were studied in a 3-year follow-up. Recurrences were observed in 21.1% of cases in the CP treated group and in 54.5% of cases in the untreated group. Chronic lymphocyte infiltrates appeared to be the mediating event for the action of CP as an adjuvant therapy in urinary bladder cancer. These observations are in contrast with the recently elucidated tumor growth promotion by immune components;298,299 thus the stage of the disease may be a critical factor since intravesical tumor cells only would recur in situ.

Salmonella Abortus Equi

Salmonella abortus equi has been studied for its antineoplastic effect by many authors in murine and human models278,282-291 (for reviews see refs. 263,275,321,381). Lipid A as the active compound has been isolated from the cell wall of Salmonella abortus equi.278,382,383

The isolated product was known in Germany as Novo-Pyrexal. Engelhardt et al281 determined dose-limiting toxicities including chills and fever (WHO grade III) following intravenous application at 1.0 ng/kg of body weight (maximal tolerated dose-1, MTD-1). The interesting finding was that endotoxin could be administered intravenously using 4,0 ng/kg body weight when the patient was protected by 1,600 mg ibuprofen. The induction of high amounts of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF) was not influenced by ibuprofen administration. Conversely, repeated injections of LPS at daily intervals resulted in marked downregulation of the cytokine induction (see: Tolerance) with the exception of IL-1 beta and G-CSF.287 Interestingly, cancer patients pretreated with 50 μg Interferon-γ 12 hours prior to endotoxin administration exhibited not only prevention of downregulation of endogenous cytokines (IL-6, IL-8, G-CSF, TNF alpha) normally observed after repeated endotoxin application, but showed enhanced secretion of these cytokines to levels even higher than those achieved after the first LPS challenge.284 As mentioned earlier, only moderate antitumor activity was observed in different trials.283,284,286,287,290 Further results of studies with Salmonella abortus equi will be discussed in the cytokine and tolerance section of this paper.

OK-432

OK-432 is the benzylpenicillin-treated lyophilized powder of Streptococcus pyogenes group A cell wall extract. The product is known in Japan as Picibanil, Chugai Pharmaceutical Company, Tokyo, Japan. The TNF inducing properties of OK-432 are well known384 (for reviews see: refs. 385-392). OK-432 has been widely tested in at least 18 randomized clinical trials. Caution in regard to validity and generalizability of these trials are indicated in reference to several aspect according to Abel:389 “(1) the overwhelming majority of trials has been conducted in the same geographical region, Japan; (2) the intention to treat was violated in most studies; (3) case numbers in most studies were very small; (4) careful statistical analysis revealed a null hypothesis in most studies; (5) randomization was conducted by the participating clinicians”.

Nonetheless, the antitumor effects of the substance are well established and warrant further careful designed prospective, randomized studies. Studies have been performed for cervical cancer,393-395 bladder cancer,396,397 gastric carcinoma,398-405 lung cancer,406-410 liver cancer,411,412 malignant gliomas,413 chylothorax following esophageal cancer.414

In basic research and animal models Nio et al415 demonstrated antitumor activity of orally administered OK-432 on murine solid tumors. Noda et al416 induced Interferon-gamma in human peripheral blood mononuclear cells by OK-432. Sekimoto et al417 showed the production of TNF by monocytes from cancer patients and healthy subjects induced by OK-432 in vitro, and its augmentation by human interferon gamma. OK-432 activated mononuclear cells were shown to be able to kill T98G glioblastoma cells by apoptotic mechanism through the Fas ligand/Fas system.418 Moreover, it has been demonstrated that the intrapleural administration of OK-432 in 70-80% of patients with malignant pleural effusion from metastatic lung cancer stimulated clinical improvement but more importantly, mediated a reduced suppressor macrophages and increased NK cell activity and cytokine production such as IL-1, MCF by macrophages and IL-2 and NK cytotoxicity factor by lymphocytes.419,420 These authors achieved similar results earlier in patients suffering from cancer of the stomach or the lung.421

Proteolytic Enzymes with Special Reference to Streptokinase

Streptokinase is one of the active enzymes of the streptococcus strain used by William B. Coley and has a long history in cancer research ever since. Additionally, streptokinase has become an important tool in measuring plasminogen activation.422 However, there are scientists who think of streptokinase and other proteolytic enzymes to augment metastasis and others, who think of those enzymes as a promising adjuvant in cancer therapy. Both lines of thinking shall be briefly elucidated.

While the external use of (proteolytic) enzymes in preclinical and clinical research has been long a domain of substituting genetically deficient enzymes (reviewed in: ref. 423), considerable evidence is mounting for their usefulness in a variety of immunologically mediated diseases including cancer and there has been increasing interest in the clinical use of proteolytic enzymes.424,425 Clinical trials have examined the therapeutic efficacy of both single and combined application of these enzymes in individuals with a number of different conditions, including trauma, inflammatory and autoimmune diseases, mastopathy and cancer.424,428

The fact that tumors show enhanced fibrin deposits especially in the invasive periphery has been noted as early as 1958426 and has subsequently been used for targeting porphyrins as photosensitizers to tumor cells.427 Hence, the well known fibrinolytic effects of proteolytic enzymes have been suggested as a therapeutic rationale in tumor therapy. Additionally, numerous additional molecular mechanisms in support of this rationale have been elucidated lately.

There is an increasing body of knowledge for the immunological mechanisms underlying the effects following exposure to proteolytic enzymes in vivo and in vitro. (For brief comments on the rationale of therapeutic use of proteolytic enzymes, see refs. 428,429). As for the oral forms of proteolytic enzymes their enteric resorption as biologically intact macromolecules has been described.424,430-432

Already more than 20 years ago rejection of tumor allografts following treatment with enzymes from streptococcus pyogenes was demonstrated by Mikolasek,433 activation of cellular immunity in cancer patients and enhanced activity of E rosette forming lymphocytes following proteolysis in vitro by Holland et al434 and Thornes.435 These authors described anergic states in cancer patients, which were reversed by administration of proteolytic enzymes. Conversion back to an anergic state after stop of therapy however, resulted in recurrence of the disease. Later, Tomar et al436 reported activation of NK cells in vitro by streptokinase. (See discussion of the observations by Mikolasek323 also in C.1 of this review). Additionally, successful therapy of accessible tumors like basal cell carcinomas, mycosis fungoides, and cutaneous metastasis of breast cancer have been reported by local application of streptokinase-dornase.437

Alteration of CAM expression has been described recently438,439 and may be one underlying mechanism for clinical effects of application of proteolytic enzymes. Recently, enzyme-induced upregulation of lymphocyte beta2 integrins, and downregulation of L-selectin and CD44 has been observed in vitro,440 which may explain some of the immunologically mediated anti-tumor effects of proteolytic enzymes.423,441-444 NK cells utilize these beta2 integrins (CD11/CD18) for firm binding to tumor target cells,445-447 and this class of cell adhesion molecules becomes rapidly increased on human NK cells upon activation.448 Furthermore, cytotoxicity of lymphocytes against tumor cells has been shown to be greatly inhibited when lymphocytes were treated with anti- CD11a and anti- CD18, but not when treated with anti- VLA-4 antibodies.449 Moreover, decreased CD11a/CD18 cell surface expression has been shown to correlate with a decrease in NK cell activity,450 and an increase in CD11b/CD18 expression has been shown to enhance adherence of neutrophils to tumor cells.451

Additional clinical relevance for cancer therapy might be provided by these studies, which showed reduced expression of CD44 following enzyme treatment. High levels of CD44 expression on cancer cells facilitate malignant cell adherence to the extracellular matrix and thus are promoting metastatic tumor growth.452,453 Compatible with this observation, an antimetastatic effect of in vivo application of bromelain441,442 and of streptokinase454,455 was observed in mice. It is well known that arresting tumor cell emboli in the microcirculation facilitates the development of blood borne metastases. Hence, additionally to the effects on cell adhesion molecule expression, it has been suggested, that enzyme-induced increased fibrinolysis caused a decrease in metastatic seeding. Uster et al444 showed bromelain to be effective in decreasing the attachment of human bladder and melanoma cells to extracellular matrix components. In this respect it is also of interest to note that the fibrinolytic system in aged rats, and its reactivity to endotoxin and cytokines shows significant decrease in activity which makes the individual more susceptible to endotoxin-induced effects, including microthrombosis and platelet aggregation.456

Consistent with these observations is also a study by Murthy et al457 who demonstrated a decreased tumor formation of TA3Ha mammary tumor cells in healing hepatic wounds of syngeneic strain A mice following treatment with human plasmin B-chain-streptokinase complex (B-SK) and recombinant tissue plasminogen activator (PA). Urokinase and heparin had no effect upon tumor formation in this model. PA was suggested to produce plasmin which, in turn, digests cell adhesion molecule protein structures and in due course inhibits tumor cell attachment. Similar studies of the inhibitory effects of orally and systemically applied proteolytic enzymes on cancer growth and metastasis have been performed by Maruyama et al458 on sarcoma-180 ascites cells in vivo and by Thornes459 in clinical studies of postmenopausal patients with breast cancer and colorectal carcinoma. Thornes435,459 provided evidence that streptokinase treatment attenuated lymphocyte depletion following surgery and increased cellular immune functions. Szreder460,461 demonstrated remissions of different cancer types in humans and animals following artificially induced abacterial erysipelas and chronic aseptic abscesses.

L-asparaginase has been proven to be a useful adjunct in the treatment of acute lymphoblastic leukemia, but additional experience also suggests a role in acute nonlymphoblastic leukemia.422 Higher levels of plasma fibronectin in patients with acute myeloid leukemias and blast crisis have been reported to decrease following streptokinase therapy.462 Earlier studies, which included streptokinase in an attempt to increase the response to chemotherapy with cyclophosphamide did not show a beneficial effect of the enzyme treatment in that model,463,464 reported no increased effectiveness of electromagnetic radiation by the use of a single intravenous application of 350,000 IU of streptokinase.

The other line of evidence is concerned with possible enhancement of tumor growth and metastasis induced by administration of proteolytic enzymes. Teuscher and Pester465 i.e., showed in an in vitro model that the application of antifibrinolytic drugs mediated the inhibition of vascularization of tumors. These authors hypothesized that inhibitors of serine proteinases and of plasminogen activators reduced the migratory behavior of tumor cells and that streptokinase, conversely stimulated cell migration. An earlier study reported increased spontaneous pulmonary metastasis in rabbits following treatment with human serum plus streptokinase, an effect, which these authors attributed to fibrinolysis.466 McKinna and Rowbotham467 reported intravascular dissemination following streptokinase injection in an in vitro tumor colon cancer model.

Staphylococcus Protein A

The antitumor property of Staphylococcus protein A (PA) is well documented in the literature in various transplantable murine tumor models (reviewed in refs. 328,468,469). Protein A (PA) is an immunostimulating glycoprotein (mol. wt. 43,000 kDa) obtained from Staphylococcus aureus cowan I and attaches to the Fc fragment of IgG 1, 2 and 4, and preferentially binds to IgG included in immune complexes. Plasma absorption over PA has been shown to effectively reduce high levels of pathologic soluble circulating immune complexes (CIC), a method which has considerable less side effects and toxicity opposed to plasmapheresis.

Animal and some human studies showed encouraging results in increasing cellular immunity, reduction in blocking activities and tumor regression with the use of plasma absorption over PA and direct administration of PA.470-473 Interestingly, some of these authors later reported that a leakage of bacterial products from staphylococcus species during plasmapheresis resulted in a general and unspecific immunostimulation and partially explained the beneficial effects of plasma absorption over PA.474 Additionally, similar results have been observed when PA has been injected directly into tumor bearing animals.475,476 It is of interest to note that this approach did not elicit generalized toxicity. Also, PA injection has been shown to suppress the onset of tumorigenesis by inhibiting initiation and promotion of carcinogenesis.477,478 The indirect action by which PA may foster immunity and reduce CIC has been expressed by Zaidi et al.479 They suggest that the PA-induced depletion of B-lymphocytes leads to a decreased production of antibodies and subsequently reduced levels of soluble immunosuppressive CIC.

Furthermore, PA has been shown to exhibit potent cytokine stimulating properties and to enhance LAK cell induction and activity in lymphocytes from healthy volunteers and melanoma patients.480 These studies recently led to the promising application of superantigen staphylococcal enterotoxin A (SEA) combined with the Fab fragment of a tumor-specific antibody308 as efficient immunotherapy for lung melanoma micrometastasis309 and lymphoma therapy307 in mice.

A new development for the administration of a staphylococcus derived enterotoxin has been investigated in China recently. Researchers in China found that the Highly Agglutinative Staphylocoin (HAS), a super antigen biological product made by Shenyang-based Xiehe Group in China known as Gaojusheng, can activate the patient's T-cells and repair damaged tissues by promoting or stabilizing the interaction between antigen-presenting cells and T cells.481 It has been demonstrated that there is a clear relationship between the affinity of Superantigens for the T-Cell Receptor and their biological activity.482 Xiehe Group had put the super-antigen products into preclinical research in 1989 when the theory of super-antigen was proposed. In Western countries, super-antigen based research was first reported in 1997 for phase I clinical trials.

Other Toxins

Cholera toxin has been shown to effectively inhibit mammary cancer growth in vivo and in vitro.483 This rejection has been associated with an increase in intracellular cyclic adenosine3”:5”-monophosphate.

Freund's adjuvant has a long history in active specific and nonspecific immunotherapy in cancer and is beyond the scope of this review to be discussed. NK-cell reactivity, i.e., in stage I and II nonsmall-cell lung carcinoma receiving adjuvant immunotherapy with Freund's adjuvant after surgery, was increased nonspecifically as demonstrated by Maroun et al.484

Keyhole limpet hemocyanin (KLH) is derived from an inedible mollusk found on the pacific coast. Immunotherapy with ganglioside-KLH has been performed mainly in superficial bladder cancer and malignant melanoma next to BCG (for reviews see refs. 485,486,487). Gangliosides, containing glycosphingolipids that are anchored into the lipid bilayer of the plasma membrane, and which are overexpressed on tissues of neuroectodermal origin can be targets for the KLH-therapy of melanomas, sarcomas, neuroblastomas and astrocytomas. KLH acts as a potent vaccine targeted at these gangliosides to induce cytotoxic IgM antibodies, which are able to initiate complement mediated cytotoxicity. Intralesional KLH significantly reduced tumor incidence, growth rate, and mortality in the mouse bladder tumor model (MBT2).488 Moreover, instillation of KLH into the bladder has been found to have fewer side effects than BCG.489 It has been suggested that a local cytokine release of IL-2, IFNs, and TNF is involved in the effector pathway of KLH application. Sargent and Williams490 suggest that the lack of endogenous cytokine activity secondary to immunosuppressive events following cancer growth may be overcome by direct, local application of KLH. Interestingly, prevention of bladder recurrence correlated significantly with cutaneous delayed type hypersensitivity testing.491

Viral Approaches

There is an extensive literature on the use of viral approaches for the treatment of cancer (for reviews see refs. 492-499). First reports of leukemia treatments with viruses date back to mid sixties500,501 of the 20th century. Wheelock and Dingle achieved febrile responses to repeated administration of six different viruses and observed clinical and hematological improvement in a patient suffering from AML. Importantly, in this patient, each treatment was followed by significant temperature surges.

Recombinant viral protein derived vaccines for specific immunotherapy of cancer aim at the attempt to specifically target a T cell mediated immune response to cancer antigens. The vaccines are used to enhance the immunogenicity of cancer antigens. The lysis of carcinoma cells by T cells (CD8+ and or CD4+/CD8+) was shown to be HLA restricted. Incorporating virus in autologous tumor vaccines has enhanced the antigenicity of tumor vaccines. Among viral treatments the Newcastle Disease virus (NDV) has most widely been used as a crude agent as well as using viral vectors.493,502,503 The Newcastle Disease virus has been shown to be superior in preventing side effects over BCG admixed tumor vaccines.504 Antigenic targets include normal antigens that have a limited health-tissue distribution or expression (i.e., carcinoembryogenic antigen), viral proteins (i.e., E6 protein of human papillomavirus), and mutated oncogens. Recent research has focused on peptide recognition by cytotoxic T-cells, the expression of antigenic peptides bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells, and the requirement for a second signal for T cell activation, such as the costimulatory molecule B7. It has been shown that viruses attached to autologous tumor vaccines deliver these costimulatory signals to tumor-reactive T cells following postoperative vaccination of tumor bearing hosts.505

Viral oncolysates induce two different types of immune response. NK cells induce target cell lysis primarily by the production of granzymes and poreforming proteins and do not need help from memory cells. In contrast, T cells lyse target cells primarily by the MHC-restricted release of lymphotoxin (TNF beta) causing programmed cell death (apoptosis) through endonuclease activation and target cell DNA fragmentation, a process which needs the assistance of memory cells.498 Shillitoe et al496 used human papillomaviruses for gene therapy of cancer to target antisense or ribozyme molecules directed against these genes. The viruses are present in many cervical and oral cancers, and are likely to be etiological agents of the tumor. Recently Hodge et al506 could show that the combination of a recombinant vaccinia virus containing the gene for the costimulatory molecule B7 and a recombinant vaccinia virus containing a tumor-associated antigen gene resulted in enhanced specific T-cell responses and antitumor immunity.

Lately, defective presentation of MHC class I restricted antigens on a murine sarcoma have been identified by the failure of these tumor cells to present influenza virus antigen to virus-specific cytotoxic T cells.507 This approach in the future could lead to ex vivo assessment of immunogenicity of tumors. Otherwise, it should be considered that MHC class I antigen defective cells are more likely to be detected by Natural Killer cells.508-514

Proposed Mechanism of Action

Shear et al262 discovered in Coley's mixed bacterial vaccine (MBV) lipopolysaccharides (LPS) as the active substances. LPS, which are potent pyrogens, are the component of the outer membrane of gram-negative bacteria. Endotoxins do not kill tumor cells in vitro and therefore their antineoplastic effects have to be mediated by host-dependent mechanisms. These immunologic mechanisms include the activation of macrophages, natural killer cell (NK) (CD3-CD16/56+), cytotoxic T cells (CD3+ CD16/56-) and the release of cytokines.515

The prominent cytokines being secreted by activated macrophages and the RES are interleukin 1 (IL-1), interleukin-6 (IL-6), Tumor Necrosis Factor alpha (TNF α), IL-12, GM-CSF and additionally TNF β (Lymphotoxin).516,517

LPS Binding Sites

At least five signal transducing binding sites expressed on the lymphocyte plasma membranes have been identified as LPS receptors including two proteins of 70-80 kDa and of 30-40 kDa, CD14, the CD11/18 family of adhesins and the 95 kDa scavenger receptor.518-523 The predominant discussed molecule in the literature is a circulating molecule named lipopolysaccharide binding protein (LBP) which forms a complex with endotoxins and was first thought to bind as a complex to the monocyte differentiation antigen, CD14.518,524-529 Binding of the complex to monocytes and macrophages activates the cytokine secretion cascade of these cells.

Lately it could be demonstrated that the picture is more complex. The LPS receptor CD14 is a protein expressed on the surface of monocytes, macrophages, and polymorphonuclear leukocytes and a soluble, circulating protein in the blood. Both forms of CD14 partake in the LPS response. Studies with recombinant LBP (rLBP) suggested that LBP functions catalytically, as a lipid transfer protein function basically to accelerate the binding of LPS to CD14. On the other hand LPS and rsCD14 complexes formed in the absence of LBP stimulate integrin function on PMN and expression of E-selectin on endothelial cells, indicating that LBP is not necessary for CD14-dependent stimulation of cells.530

Recently a novel receptor for Escherichia coli heat-stable enterotoxin (ST) has been identified as a highly selective biomarker for metastatic colon cancer.531-533 ST-receptor interaction was coupled to activation of guanylyl cyclase C (GCC) in all normal tissue samples of colon and rectum and all primary and metastatic colorectal tumors examined. However, neither ST binding nor ST activation of GCC was detected in any extraintestinal tissues examined. It may be hypothesized that these receptors may serve as a target for directing therapeutic administrations of bacterial vaccines to GCC expressing tumors in vivo.

Furthermore, intracellular binding sites have been identified recently at microtubule proteins.534 This binding site is shared with the microtubule acting agent taxol.535 Microtubules are constructed from the heterodimers of alpha- and beta-tubulin along with microtubule-associated protein-2. They are mediating mitosis and protein trafficking.536,537

Cell Adhesion

The upregulation of cell adhesion molecules (CAM) following exposure to inflammatory cytokines and lipopolysaccharides has been established on a variety of cell types like endothelial cells, fibroblasts, synoviocytes, Langerhans cells, melanocytes, keratinocytes, mast cells, monocytes and eosinophils.538-545 CAM play a crucial role in endo-and enterotoxin-mediated lymphocyte distribution and target signaling. Alterations in the expression of CAM may have a profound impact on a wide range of immunologic processes (reviewed in: refs. 566,563). Four major groups of cell adhesion molecules have been identified. First, members of the immunoglobulin superfamily (i.e., ICAM-1, ICAM-2, LFA-2), which facilitate cell adhesion by T and B lymphocytes. Second, members of the integrin family (i.e., LFA-1, MAC-1, p-150,95, VLA-1-6), whose function is the dynamic regulation of adhesion and migration. Third, the selectin family (i.e., L-selectin, PADGEM, ELAM-1, LAM-1), which selectively targets leukocyte and neutrophil migration to tissues like lymph nodes or sites of acute inflammation. Last, CD44 which predominantly acts as the hyaluronate receptor, also functions as a general cell adhesion molecule and, additionally, regulates activation thresholds for T cells.546 Thus, an endotoxin-mediated modulation of CAM can be expected to have crucial effects on leukocyte distribution and function.

When T cells (CD3+ CD16/56-) and NK cells (CD3- CD16/56+) encounter an antigen, mast cells secrete TNF α and IL-1 which in turn induces T- and NK cells to secrete IL-2 and Interferon-γ (IFN-γ).547,548 IFNγ has been shown to affect the expression of MHC class II molecules by endothelial cells,549 to increase the binding of T cells to endothelial layers,550 and to enhance the recirculation of lymphocytes through the lymph nodes.551 Furthermore it has been shown that IL-1, TNF and endotoxins enhance the binding of lymphocytes and neutrophils to endothelial cell monolayers.552,553

Pyrogenic substances are known to induce leukopenia followed by leukocytosis.554-559 This recruitment of lymphocytes from and to the blood stream occurs via the postcapillary venules.560-563 Cell adhesion molecules, expressed on lymphocytes and the endothelial cell layer, mediate rolling, adhesion and subsequent migration of lymphocytes.561,564-566 This process is regulated by cytokines and is fundamental in understanding the early events following exposure to pyrogenic substances.567 Leukocyte cell adhesion is mediated by exposure to stimuli such as antigen for lymphocytes or complement factors and leukotriens for monocytes and granulocytes. The forming of cell aggregates or clusters to each other or to other cell types such as vascular endothelial cells appears to be regulated by the activation state of the cell.568,569

When inflammatory mediators such as cytokines, thrombin and histamines are released following antigenic exposure (such as endotoxins) they cause the activation of blood vessel endothelium. Cytokines (IL-1, TNF) induce the expression of E-Selectin on endothelial cells after 3-6 hours,570 whereas thrombin and histamine lead to the release of P-Selectin on endothelial cells within minutes. Additionally, in response to inflammatory cytokines such as IL-1, IL-4, TNF and IFN VCAM-1 and ICAM-1 are induced on vascular endothelium within 6-12 hours and 12-24 hours respectively.561 Protein kinase C is a mediator of endothelial cell activation by LPS, TNF, and IL-1.571 The recruitment of lymphocytes into gut-associated tissues of Peyer's patches and nonlymphoid villus regions of the small bowel is also mediated by cell adhesion molecules alpha 4-integrins and beta 2-integrins.572

IL-4, for example, a product of activated T cells, can interact with TNF to selectively elevate VCAM-1 expression and the induction of T cell-rich infiltrates.573 It could be shown that the enterotoxin of Staphylococcal A (SEA) increased the cytotoxic T cell response to target cells by binding to major histocompatibility complex (MHC) class II molecules.574 The cytotoxic activity clearly was mediated by HLA-DR2/ICAM-1 expressed on target cells binding to the integrin heterodimer CD11a/CD18 expressed on effector cells as could be shown by anti-CD11a or anti-CD18 monoclonal antibodies (mAb), but not by anti-CD11b, anti-CD11c, or anti-CD2. Furthermore, it could be shown that resistance of choriocarcinoma cells575 and melanoma cells576 to lysis by lymphocytes was partially due to a low expression of ICAM-1 and VCAM-1, respectively. Cell adhesion cell deficient mice exhibited impaired immune responses.577

Heat-inactivated gram-negative bacterium Brucella abortus not only has been shown to induce the secretion of IL-12 to differentiate Th1 and Th2 cells but also to rapidly increase the expression of the costimulatory molecules B7.1 (CD80), B7.2, and ICAM-1.578,579 In these studies induction of IL-12 was confirmed by IL-12 p40 mRNA expression and protein secretion by isolated human monocytes. This initiation was blocked by an anti-CD14 monoclonal antibody, suggesting that monocytes bound B. abortus via their LPS receptor. Additionally, NK cell cytotoxicity against K562 target cells was enhanced.579 Interestingly, LPS induction of B7-1 on human monocytes was superior to IFN-gamma and no response was obtained with isolated IFN-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-alpha and GM-CSF+TNF-alpha.576 LPS, rhIL-1, and rhTNF-alpha act via common pathways in endothelial cell activation, a process that is being regulated by protein synthesis.580

Increased expression of cell adhesion molecules induced by endotoxins is mediated via elevation of intracellular cAMP concentration ([cAMP]i).581,582 This activation in turn is sequentially mediated by proteinkinase C in the early phase of activation and by proteinkinase A in the later adhesion of lymphocytes.583 The adhesion augmented by increased [cAMP]i is due to LFA-1/ICAM-1 interactions between cells because it can be blocked by either anti-CD11a or anti-ICAM-1 mAb. A differential role of protein kinase C (PKC) in cytokine induced lymphocyte-endothelium interaction was established by Eissner et al584 in vitro. TNF-alpha and LPS-induced ICAM-1 expression on a human endothelium-derived cell line (EA.hy926) was unaffected by the PKC-inhibitor and thus appeared to be independent of PKC activation. In contrast, PKC-inhibitor significantly reduced ICAM-1 expression induced by IFN-gamma and IL-1.

The functional implications of increased CAM expression on lymphocytes and endothelial cells following LPS challenge remain controversial. CAM clearly have been shown to costimulate cytotoxic T cells,585,586 TIL cells587,588 and NK cells.437,589,590 NK cells utilize the beta 2-integrins (CD18/CD1) for firm binding to target cells.445-447,591 Upon activation, CD11b and CD11c are rapidly increased on human NK cells.448 Rat Kupffer cells mediated cytotoxicity against a syngeneic hepatoma cell line both by the production of nitric oxide and cell-to-cell adhesion via ICAM-1/CD18.592 This cytolytic activity of lymphocytes against tumor cells is greatly attenuated when the lymphocytes are treated with anti- CD11a and anti- CD18.449 However, peritoneal PMNs derived from patients with bacterial peritonitis have been shown to have increased ICAM-1 levels but were functionally inactive to protect the host from microbial invaders. The authors speculate that an interaction between ICAM-1 and its' counter receptor CD18/CD11a may hinder effector functions. Furthermore, treatment of head and neck SCC cells with recombinant human interferon gamma (rHuIFN), a well known enhancer for the expression of CAM, did increase the ICAM-1/CD11a/CD18 mediated binding of both LAK cells and PBM cells to tumor cells. But on the other hand, cytotoxicity of LAK cells against head and neck SCC cells was reduced after rHuIFN treatment. Additionally, shedding of ICAM-1 from cultured tumors is able to inhibit the CD11a/CD18/ICAM-1 interaction between cytotoxic effector cells and ICAM-1+ target tumor cells. It is known that shedding of CAM follows activation of resting leukocytes with subsequent upregulation of CAM from intracellular storages.593,594

Hershkoviz et al595 showed that heat-stressed CD4+ T lymphocytes exhibit differential modulations of adhesiveness to extracellular matrix glycoproteins, proliferative responses and TNF-α secretion. Heat-shock treatment of activated CD4+ T cells induced a decrease in the surface expression of beta 1 integrins, which in turn reduced T cell adhesion to fibronectin and laminin. On the other hand the potential of heat-stressed T cells to proliferate and to secrete TNF-alpha was increased.

It should be noted that the expression of cell adhesion molecules not only mediates lymphocyte adherence, migration, extravasation and target cell recognition but also cancer cell metastasis.596 Analysis of soluble and target cell bound expression of cell adhesion molecules may be an important tool to measure the molecular effects of a given therapeutic intervention. In acute endotoxin overstimulation such as in patients with septic multiple organ failure levels of soluble adhesion molecules (sICAM-1, sELAM-1, sVCAM) were significantly elevated.597

Cytokines

Exposure of the host to endo- and exotoxins initiates a complex und multidirectional cytokine cascade. The physiological role of cytokines in our understanding of the cellular and humoral immune mechanisms involved in antitumor activities is a continuously growing body of knowledge and has been extensively reviewed.567,598-600 Cytokines include the interleukins, the interferons, tumor necrosis factor and the colony-stimulating factors. Clinically, the highest response rates to exogenous cytokine immunotherapy have been seen in malignant melanoma and renal cell cancer.601 It has been shown that a variety of cytokines are needed for an effective CD8+ T cell mediated cytotoxicity by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, and interferon gamma.602 They have been widely used for immunotherapeutic approaches in cancer treatment (for reviews i.e., refs. 492,603-608).

Recently, different groups attempted to increase the therapeutic potential of these agents with genetic manipulation by introducing genes encoding cytokines into tumour-infiltrating lymphocytes and certain tumor cells.609 In this chapter some basic mechanisms of LPS induced cytokine secretion and their relevance to immunological responses to cancer shall be briefly summarized. Shieh et al610 for example, showed that LPS modulated CSF-1, granulocyte-macrophage (GM)-CSF, G-CSF, IL-1, TNF, and Kit Ligand receptors on murine bone marrow cells (BMC) in vivo and in vitro. In vivo, LPS and LPS-induced cytokines (IL-1 and TNF) elicited the secretion of glucocorticoid and CSF activities, which revealed a mechanism for LPS up-modulation of IL-1R on BMC in vivo. Interestingly, application of single cytokines like IFN-gamma could not activate macrophages for tumor cell killing, but required a second stimulus from endotoxin.611,612

The cytokines shall be mentioned successively, although this mode of description is certainly not ideal since almost all immunological responses to LPS or other antigens involve a whole cascade of cytokines being induced and secreted.

Not only LPS but also antigens from grampositive organisms evolve powerful immune responses. Two types of cytokine pattern and kinetics have been described after exposure of lymphocytes to (grampositive) Staphylococcus aureus enterotoxin A (SEA) and (gramnegative) lipopolysaccharide (LPS).613 First, LPS stimulation provoked strong production of IL-1 alpha, IL-1 beta, TNF-alpha, IL-6 and IL-8. After LPS exposure IL-1 alpha, IL-1 beta, TNF-alpha and IL-8 were peaking at or before 4 hours after cell stimulation. Also, IL-10 production was evident after 12 hours of cell stimulation. TNF-beta, IL-2, IFN-gamma and IL-4 were not detected in these cultures. All cytokine production, except IL-8, was downregulated at 96 hours. Second, SEA-stimulated cultures showed the highest point in production of IL-1 alpha, IL-1 beta and IL-8 later, after 12 hours. In addition, significant production of TNF-beta, TNF-alpha, IFN-gamma and IL-2 by T lymphocytes was found with peak production 12-48 hours after initiation of SEA. IL-6 was only discovered in low amounts. Although in the original formula of Coley's Toxin the ratio endotoxin/exotoxin was 7300:1 this observation may in part explain the higher success rate Coley observed after concomitantly administrating endotoxins and exotoxins to his cancer patients.

As mentioned earlier exotoxins, also termed superantigens,614 are well known inducers of cell adhesion molecules in the inflammatory response574 and TNF.615 Recently, superantigens could be shown to complex with the crystal structure of a T cell receptor beta chain.616 Furthermore, staphylococcal enterotoxin B superantigen conjugated to tumor cells induced strong antitumor activity against Meth A-bearing mice, the antitumor effector cells having been V beta 7- 8- CD4+ T cells.617 Moreover, even though endotoxin tolerance can be transferred between different bacterial species, it has been shown that the inflammatory response to grampositive and gramnegative infections differs profoundly. Riesenfeld-Orn et al618 i.e., showed that different cell wall components of grampositive organisms such as pneumococcus exhibited different cytokine induction profiles. Pneumococcal cell surface component did strongly induce IL-1 secretion, being up to 10.000-fold more potent than endotoxin, but did not induce TNF. Table 3 briefly summarizes the effects of the different effector cells and cytokines.

Table 3. Mechanisms following stimulation of humoral and cellular defense.

Table 3

Mechanisms following stimulation of humoral and cellular defense.

Tolerance

The phenomenon of tolerance to repeated administrations of LPS in human and animals is an important chapter in the history of cancer treatment with bacterial products, since patients have been exposed to repeated vaccinations, often over prolonged periods of time. Beeson619 and Thomas620 give early reports on tolerance to bacterial antigens. Subsequent research concentrated on the role of the RES621,622 and demonstrated that splenectomized rabbits and humans show the same tolerance response as controls.623 Since splenectomy impairs the production of circulating anti-endotoxin antibodies, it could be concluded that early tolerance up to 72 hours is not antibody mediated. For an early (review see refs. 234,621,624).

More recent studies elucidated the molecular mechanisms of tolerance induction. Lindberg et al625 showed that tolerance could be induced with a nonpyrogenic, LPS-free O-antigenic polysaccharide hapten, when coupled to an immunogenic carrier protein. Johnson and Greisman626 established that endotoxin tolerance can be divided temporally in an early and a late phase response. Early tolerance occurs within 24-96 hours following endotoxin exposure and is nonspecific and transient. Late-phase tolerance is mediated by the production of anti-O-specific antibodies, occurs from one week to several weeks following initial endotoxin challenge and lasts for weeks to months. Williams,627 Madonna and Vogel,628 and Freudenberg and Galanos629 established that the early phase tolerance as well as lethality to LPS is a macrophage-mediated phenomenon. Haas et al630 demonstrated in vitro that monocytic cell lines can be prevented from a TNF response measured by decreased TNF mRNA by preincubating cells with low doses of LPS (10 ng/ml). Interestingly however, preincubation with the same dosage of LPS resulted in increased phagocytosis for the exotoxins of Staphylococcus aureus, indicating that some monocyte functions are still active whilst in a state of endotoxin tolerance. Furthermore, repeated administration of endotoxins in murine and human models showed downregulation of TNF-alpha and IL-6, and upregulation of IL-1-beta and G-CSF.287,631,632 Decrease of TNF-alpha and IL-6 production resulted from an inhibition of gene transcription. Another study found different regulation pathways: Downregulation of TNF-alpha, IL-8, G-CSF, M-CSF and WBC count, and upregulation of IL-6.286 Other experiments showed that, preexposure of macrophages to very low doses of LPS (≤1 ng/ml) inhibited the expression of TNF-alpha mRNA but not of IL-1 beta mRNA through a noncyclooxygenase-dependent mechanism.633

In vitro experiments, however, showed downregulation of the genes for TNF, IL-1 and IL-6 following preexposure of monocytes with low doses of LPS.634 Also, these authors noted again that the LPS tolerance could be transferred to resistance of a grampositive organism such as Staphylococcus aureus, an observation later confirmed by Zhang and Morrison635 and in contrast to Haas et al630 and Mathison et al.636 Interestingly, the amount necessary for inducing a tolerant state is 1.000 time lower than required for the initial induction of TNF production, before tolerance is induced, (picograms vs. nanograms) as pointed out by Mathison et al.636

In contrast also, LaRue and McGall637 demonstrated that endotoxin tolerance is manifested by decreased LPS-induced IL-1-beta transcription. Protection against mucosal injury, nonelevated levels of ileal xanthine oxidase activity and no signs of bacterial translocation in response to repeated administration of LPS was shown by Deitch et al.638 The same principle could be demonstrated for the administration of TNF-alpha alone. By daily intravenous injections of recombinant human TNF-alpha (250 ug/kg per diem) healthy rat and mice became resistant to the hemorrhagic effect in the gastrointestinal system. While on the contrary, treatment at 5- or 10-d intervals produced similar results as the initial hemorrhage-causing injection.639 These results could not be confirmed by Vogel et al,640 who administered TNF and IL-1 and could not observe a tolerance-like reaction to single application of both cytokines. Combined administration however, induced synergistic toxicity in high doses but could reduce secondary CSF production and reduced the increase of macrophage progenitor cells in lower doses. These results were extended later by Gorgen et al,641 who showed that pretreatment of mice with recombinant human granulocyte CSF (G-CSF) protected mice against septic shock, a mechanism mediated by reduced LPS-induced serum TNF activity. Interestingly, when tolerant macrophages were incubated with G-CSF in vitro, LPS induced high levels of TNF. These findings implicate that the protective effect of G-CSF is not directly acting on macrophages but acts as a negative feed back signal in vivo. Similar findings were published by Erroi et al,642 who could not achieve complete endotoxin tolerance by administering IL-6, TNF, or IL-1 alpha in an attempt to mimic LPS-induced tolerance.

Some researchers found additional partial evidence for the molecular mechanisms involved in the phenomenon of endotoxin tolerance at the level of the LPS receptor CD14. Mengozzi et al643 observed a 50% decrease in the CD14 expression following repeated LPS exposure. Interestingly, cAMP, which is otherwise known to control TNF synthesis, was not affected by preexposure of monocytes to LPS.

Wakabayashi et al644 demonstrated that pyrogenic tolerance in the rabbit after a single LPS injection is associated with decreased circulating IL-1 beta and TNF levels as well as decreased production of these cytokines in vitro. However, after 7 days pyrogenic hyperresponsiveness to LPS was observed, which was associated with increased synthesis and secretion of IL-1 beta from PBMC in vitro.

As mentioned earlier, pretreatment of cancer patients with IFN-gamma receiving intravenous administration of purified LPS from Salmonella abortus equi prevented the downregulation of cytokine secretion, demonstrating that endotoxin tolerance is reversible.284 In this study, patients pretreated with 50 ug IFN-γ 12 hours prior to endotoxin administration exhibited not only prevention of downregulation of endogenous cytokines (IL-6, IL-8, G-CSF, TNF alpha) normally observed after repeated endotoxin application, but also showed enhanced secretion of these cytokines to levels even higher than those achieved after the first LPS challenge. Therapeutic implications of this fact have been elucidated by Takahashi et al.645 As already mentioned, the phenomenon of decreased TNF anti-tumor activity resulting from tolerance to repeated applications of exogenous TNF in vivo has been shown to be dependent on the histological tumor type, since this phenomenon has not been observed in all tumors.643 If tolerance induced decreased anti-tumor activity occurred (i.e., MCA sarcomas, Lewis lung carcinoma), it could be attenuated by addition of IFN-gamma.643 The same authors further showed that tolerance is a TNF-R55 mediated effect and selectively blocks the TNF-R75-mediated pathway, including IL-1 and glucocorticoid mediated pathways.646

As already mentioned, LPS exhibits selective and inverse priming effects on TNF alpha and nitric oxide (NO) production in mouse peritoneal macrophages. Low doses of LPS pretreatment of mouse macrophages increases LPS-dependent IL-6 and TNF alpha production in vitro, and decreases the synthesis of NO by macrophages.633,647,648 Priming of macrophages with pertussis toxin has exactly opposite effects: increased LPS-induced TNF-alpha production and inhibited LPS-dependent NO production.649

Furthermore, glucocorticoids have been shown to play an important role in the phenomenon of tolerance to bacterial products. Adrenalectomized mice do not develop endotoxin tolerance as demonstrated by Evans and Zuckerman650 and Zuckerman et al.631 They could show that LPS tolerance involved glucocorticoid-dependent and -independent mechanisms, since corticosterone levels in LPS-treated galactosamine-sensitized and not-adrenalectomized mice were similar to LPS-stimulated normal mice. The glucocorticoid antagonist RU-38486 abolished the development of tolerance induced by TNF644 and LPS.651 Furthermore, adrenalectomized mice exhibited an increased sensitivity to IL-1 and TNF.652 Glucocorticoids are known to suppress the synthesis of inflammatory cytokines,653,654 and eicosanoids655 and downregulate inducible nitric oxide synthase.656

Although most studies on endotoxin induced tolerance have concentrated on fever and lethality phenomenon, recent evidence suggests that tolerance in response to repeated endotoxin exposure also develops systemically as metabolic,657 pulmonary,658 and hemodynamic tolerance.655

Translocation

Systemic endo- and exotoxin exposure also leads to increased bacterial translocation from the gut which in turn may compromise the ability of the liver to clear translocated circulating LPS.659 Bacterial translocation from the gut first to the mesenteric lymph nodes and then to the systemic circulation may play an important role in repeated administration of endo- and exotoxin based vaccines.19,660,661 The underlying mechanism for this phenomenon is mucosal injury, widening of the intercellular spaces due to tight junction failure below the brush border and capillary leakage.658,662-664 Disruption of the normal gut flora results in overgrowth with gramnegative, enteric bacilli or aerobe species leading to bacterial translocation. In this respect it is interesting to note, that intraepithelial lymphocytes in the human gut have been shown to possess lytic potential and Th1 and cytotoxic T cell functions, as measured by their cytokine profile.665 Translocation often has been seen after thermal666 or mechanical667 injury, and has been associated with altered host defense capability519 and multiple organ failure.668,669

Tolerance to endotoxin-induced bacterial translocation in response to repeated administration of LPS has been shown by Deitch.636 This protection against mucosal injury was mediated by nonelevated levels of ileal xanthine oxidase activity, since mucosal injury is known to be mediated by xanthine oxidase-generated production of free oxygen radicals.660,661

Most interesting, translocation has been associated with prolonged survival in patients with acute myelogenous leukemia (AML).133 These authors observed a “paradoxically prolonged survival” in AML patients suffering from a common complication: post-transfusional hepatitis. They alleged the impaired hepatic endotoxin clearance in patients with acute viral hepatitis as the reason for endotoxemia and elevated TNF-α release and also observed virally induced IFN-γ secretion, which in turn acts in synergy with TNF-α anti-proliferative and differentiation inducing.

Hyperthermia

Exogenous induced Hyperthermia as an attempt to mimick the physiological response to fever shall be briefly mentioned (for a review see ref. 670). During the last decades a substantial body of laboratory and animal tumor data has been generated to evaluate the effects of heat on cell survival and growth. Temperature elevation in febrile response has been associated with effects on the recognition, recruitment, and effector phases of the immune response. Temperature elevation appears to affect primarily the phase of recognition and sensitization or activation of mononuclear leukocytes.

Hyperthermia is directly cytotoxic to tumor cells and inhibits repair of radiation damage. These effects are increased by physiological conditions in the tumor bed including acidosis and hypoxia. Tumor blood flow often is reduced in relation to normal tissues, and hyperthermia leads to a further decrease in blood flow depending on temperature and thus augments heat sensitivity by reducing thermal outwash.671 A pioneer of hyperacidification in combination with hyperthermia has been von Ardenne in Germany.672-675 He proposed the concept of hyperacidification plus hyperthermia, since hyperthermia is known to induce an acidic microenvironment, a concept later to become known as the cancer multiple-step therapy.676,677

Roberts and Steigbigel247 demonstrated enhanced mitogen response and bactericidal capacity of polymorphonuclear leukocytes following in vitro exposure to febrile like temperatures. A number of in vitro and in vivo studies revealed specific effects of hyperthermia mimicking physiological temperature elevations seen in the febrile response (reviewed in ref. 678). Yonezawa et al679 observed hyperthermia-induced apoptosis in malignant fibrous histiocytoma cells in vitro. Ensor et al680 demonstrated a differential secretion of TNF-alpha and IL-6 in vitro in LPS-stimulated human macrophages (HuMoM phi) during 18-h incubation at 40 degrees C. While hyperthermia nearly completely inhibited TNF alpha release, IL-6 secretion remained unchanged. Also a 75-fold increase in the levels of the inducible heat-shock protein 72 (HSP-72) mRNA was observed. Another in vitro study showed increased NK cell cytotoxicity at febrile range (< or = 40 degrees C), but decreased cytotoxicity after exposure of cells to 1 h at 42 degrees C.681 Niitsu et al244 reported the synergy of hyperthermia and rTNF on cytotoxicity and artificial metastasis in vitro and in vivo. Whole body hyperthermia increased natural killer cell activity,682 and cellular immunity in cancer patients,683 and demonstrated antitumor effects in synergy with exogenous TNF.684,685

Synergistic anti-tumor effects of combined hyperthermia and immunotherapies have been documented by a variety of authors. Synergy of local water-bath hyperthermia and TNF alpha in cytotoxicity but also systemic toxicity were found by van der Zee et al.686 The combination of local but not whole body hyperthermia and immunotherapy with LAK cells and IL-2 in the treatment of multiple pulmonary metastases in mice provided a significant reduction of pulmonary metastasis from MCA-105 sarcoma cells compared to the control group in a study by Strauch et al.687 Ex vivo experiments of Kappel et al688 showed no influence of whole body hyperthermia in subsequent in vitro stimulation of LPS-stimulated mononuclear (BMNC) cells on cytokine production. However, the study suggested that hyperthermia may have altered the sensitivity of BMNC to prostaglandins and in vivo significant cytokine induction was observed for G-CSF, IL-1 beta, IL-6, IL-8, IL-10, and TNF-alpha by Robins et al.689 Conversely, an earlier study found elevation of IL-1 alpha but not TNF-alpha following whole body hyperthermia.690

Heat Shock Proteins

The increased expression of heat shock proteins (HSPs) after hyperthermia treatment or LPS challenge has been shown to correlate with increased immunogenicity of cancer cells through their lysis by alpha/beta T cells.691 HSPs belong to a group of “stress proteins” secreted after a wide range of stimuli such as oxidative injury, heavy metals, exogenous heat and bacterial toxins. They are classified on the basis of their molecular weight and are divided in five families: low molecular weight family, hsp65, hsp70, hsp90 and hsp100 (for reviews see refs. 586,692,693). HSP have been suggested to act as molecular chaperones in presenting protein structures to the lymphatic system. In this respect they may serve as carriers for antigenic tumor peptides and thereby increase the natural immunity to cancer.694

Cancer cells have been reported to have increased expression of HSPs695 and it is well established that LPS challenge leads to increased expression of HSPs in macrophages,696,697 blood vessel endothelium698 and enterocytes.699 Most interestingly for this review, hsp70 induction has been shown following fever therapy with endotoxins in melanoma patients in vivo and in vitro.700 However, this study revealed hsp70 induction in vivo only in 50% of the cases exposed to a Coley Toxin like preparation (Vaccineurin), while in vitro 100% of peripheral blood mononuclear cells could be shown to express hsp70 following endo- and exotoxin challenge, indicating additional mechanisms for control of expression in vivo.

Increasing evidence suggests that HSPs could confer protection against oxidative injury, noxious molecules, and bacterial toxins.701-703 In stressed cells HSPs 72 appears to be essential for survival during and after exposure to cellular injury. HSPs furthermore have been suggested to present cancer antigens to the human immune system, especially CD8+ T lymphocytes704 and have been suggested as potent cancer vaccines.705 Moreover, it has been shown that exogenous cell components which normally are only presented in association with MHC class I proteins, can be directed into the endogenous pathway, conferred by MHC class I molecules, and also recognized by CTL.706 Furthermore, it was shown that LPS induced a HSP 60 mediated increase in expression of ICAM-1 on blood vessel endothelial cells.698 This finding bears important implications for the attraction of leukocytes following the use of bacterial vaccines.

HSP gene transcription increases during or direct after heating; a correlation between the synthesis of HSP and thermotolerance has been found in normal and malignant cells.707 HSPs appear after the activation of a so-called heat-shock transcription factor. This protein has been isolated and purified by Zimarino and Wu,708 and Wiederrecht et al.709 Nuclease digestion studies have clearly demonstrated that, until the cell is stressed, the protein does not bind to the appropriate promoter region of the gene. Upon activation, the factor binds to the heat-shock element and gene activation results. It is assumed that ubitiquin is involved in the activation process. It has further been suggested that the signal for the induction of the heat shock response relates to the cell's reaction to the presence of abnormal proteins. Yet, a common way of gene activation is not known. Most organisms use transcription as the primary control, and translation control for “fine tuning” for individual HSP synthesis.710 Signals involved in HSP synthesis use the second messenger cascades which possibly is triggered by an intra-membrane protein aggregation. However, it is not known which steps lead to the activation of the transcription factor. Structure of genes and promoter regions and the transcription factor are known.

Interestingly, it has been shown that prior induction of HSPs protect the organism from subsequent LPS induced hypotension by inhibition of the overproduction of nitric oxide via reduced iNOS mRNA induction711-713 and endothelial cells from apoptosis in vitro via hsp70 and inhibition of LPS-mediated O2–generation.714,715 However, while prior induction of HSPs exerted a posttranslational control of TNF alpha release in LPS-stimulated alveolar macrophages,716,717 concomitant application of TNF alpha enhanced LPS-induced heat shock protein production in vivo.696 Moreover, the myocardium has been shown to be protected from endotoxin induced ischemia by prior induction of HSPs.718 Additionally, macrophages exposed repeatedly to LPS and IFN-gamma have been shown to become resistant to the deleterious effects of nitric oxide by expressing hsp70.697 It also should be noted that HSPs contribute to the development of drug resistance against chemotherapeutic against in cancer therapy and therefore extreme hyperthermia should not be applied immediately before chemotherapy.719

From the preceding remarks on hyperthermia and HSPs it is tempting to speculate, that in the treatment of cancer patients with hyperthermia and bacterial vaccines it may be meaningful to expose patients first to hyperthermia and secondly to an endotoxin/exotoxin challenge. As it has been shown by Hotchkiss et al,720 the protective effects of hyperthermia beginning 1 to 2 hours after heat exposure and reach a maximum at 12 hours. In this way patients would raise their core temperature first by induction of whole body hyperthermia and be prevented from experiencing unpleasant shivering and muscle cramps often following administration of fever induction. Additionally, it may be speculated that the protective effects of hyperthermia, i.e., induction of HSPs may aid in preventing the often intense side effects like hypotension and endothelial cell damage.

Alpha2 Macroglobulin

Endotoxins and exotoxins have been shown to affect alpha2-macroglobulin (alpha2M) with their proteolytic enzymes.721 Although it has been shown that streptokinase suppresses some immune functions such as chemotactic activity,722 or trypsin the IL-2 mediated proliferation of T cells,723 these enzymes may have interesting qualities on regulating the cytokine metabolism by activating alpha2M as shall be discussed further. The hypothesis is postulated that enzyme-activated alpha2M downregulates overexpressed cytokines and lymphocyte reactions in vivo, but may stimulate normal and desired immune responses. In this respect it has to be noted that most immunosuppressive actions of activated alpha2M and the respective enzymes have been reported in in vitro systems for T lymphocyte proliferation without724,725 and with726 IL-2. Streptokinase has been shown to have inhibitory effects on in vitro tumoricidal activity of human serum,433 and in vivo it has been demonstrated to be a powerful inhibitor of tumor growth.423

Alpha2M is the regulator of distribution and activity of many cytokines including TNF alpha,727 TGF-beta 1,728-731 TGF-beta 2,724-726 platelet derived growth factor (PDGF),732,733 IL-1 beta734,735 and IL-6736 (reviewed in refs. 737,738). Importantly, the alpha2M-bound cytokines and alpha2M-bound proteolytic enzymes both keep their biological activity.739

Alpha2M is a high molecular weight (Mrhuman =718,000) major plasma proteinase inhibitor and reacts with a broad diversity of endopeptidases.740 The enzymes are getting “trapped” in a well defined region of the alpha2M molecule, which then undergoes dramatic conformational changes, while the enzymes keep their proteolytic function.741 An enzyme carrying form of alpha2M is called the activated or “fast” form of alpha2M.742,743 The fast form of alpha2M preferentially binds TNF alpha, TGF-beta 1 and -beta 2, and IL-1 beta while PDGF, NGF and IL-6 bind to the native or “slow” form.744 Importantly, the fast form of alpha2M becomes activated for increased receptor-mediated endocytosis by exposing a latent alpha2M receptor-recognition domain to hepatocytes,745 macrophages,746-748 and fibroblasts.749,750 The cytokine carrying alpha2M then undergoes rapid clearance by binding to hepatic-, macrophagic-, and fibroblastic-alpha2M-receptors.751-753 It is further suggested that alpha2M plays an important role in cytokine testing bioassays, which may has been underestimated.754

However, in vitro exposure of macrophages to LPS and IFN gamma, but not to TNF, TGF beta-1or IL-6 induced a significant downregulation of the alpha2M-receptor/low density lipoprotein receptor.755 These studies need to be confirmed in vivo, but allow the hypothesis that the downregulation of the alpha2M-receptor/low density lipoprotein receptor may act as an inhibitory feedback mechanism for the binding of proteolytic enzymes.

Toxicity

Toxicity of endo- and exotoxin-based cancer therapies can be considerable. The administration of such therapies therefore only should be performed by qualified medical providers and should include immediate access to conventional emergency support. Self-administration of salmonella endotoxin has been reported resulting in shock and multiple-organ dysfunction.756 In the experienced hand however, the administration of this therapeutic approach does not impose a greater risk to the patient than conventional procedures such as chemotherapy. Informed consent may help to increase compliance and reframe the understanding of the patient in respect to beneficial effects of “fever-therapy”. Additionally, psychoneuroimmunology research has shown that compliance with and possibly efficacy of therapy can be increased if the patient is fully informed. Even more, numerous authors report induction of fever and immunopotentiation with endotoxin without any toxic reactions (reviewed in refs. 106,757,758).

Endo- and exotoxin mediated toxicities can include hypotension, hepatotoxicity, induction of herpes labialis, muscle spasms and cramps, and in severe cases shock and circulatory failure (cardiovascular effects reviewed in ref. 759). These side effects always should be noted and classified according to WHO criteria.760 High doses of endotoxin result in systemic effects such as circulatory failure and death.761 A number of treatments have been suggested to diminish the dose limiting toxicities. In attempts to limit exogenous TNF toxicities Brouckaert et al762 suggested “methylene blue, an inhibitor of the nitric oxide (NO)-induced activation of the cytosolic guanylate cyclase, without the indispensable protective properties of NO being affected” to prevent hypotension. Furthermore, they suggested anti CD11a to prevent IL-12 mediated sensitization to TNF and alpha 1-acid-glycoprotein and alpha 1-antitrypsin to protect against TNF-induced hepatotoxicity by reducing the release of platelet-activating factor.763 LPS mediated toxicity and what is more lethality however, can not be explained by TNF induction alone.176

Further toxicity is mediated by IL-1 as has been shown by the successful blocking of lethal LPS challenge with a recombinant receptor antagonist protein to IL-1.764 The same authors demonstrated manganous superoxide dismutase induced protection against lethal LPS challenge but not against LPS-mediated toxicities with a 24-hour pretreatment of a single dose of TNF.765 Recombinant IL-1 receptor antagonist also protected against TNF-induced lethality.766 Moreover, IL-1 alpha has been demonstrated to mediate the microcirculatory changes in the intestinal mucosa observed after systemic endotoxin exposure, including increased adhesiveness of leukocytes and mucosal damage.767

Recently, the vascular pathophysiology of endo- and exotoxin induced hypotension and extravasation has been described as being the result of activation of the bradykinin-Hageman-factor-kallikrein cascade.768 Inhibitors of kinin and kallikrein have been suggested subsequently to block the shock induced by bacterial proteases by blocking the kallikrein-kinin cascade. Another study explained bacterial-associated vasculitis by IL-1 alpha mediated secretion of IL-6 and IL-8.769

Possible effects of endotoxin induced lung injury have been shown at the level of alveolar macrophages for enhanced secretion of IL-1, TNF-alpha, and prostaglandin E2.770 Finally, it is of interest to note that nontoxic polysaccharide derivatives free of lipid A have been shown equally effective in enhancing humoral immunity in FLV immunocompromised animals, both in vivo and in vitro.33,771,772 The nontoxic polysaccharide derivative however, did not induce TNF, and cells needed to be stimulated with IL-2 prior to LPS exposure to produce IFN.272 On the other hand the same authors reported effective inhibition of Meth A sarcoma with the use nontoxic LPS derivatives low in endotoxin.773

There are numerous substances, which efficiently counteract the toxicities of endotoxin- and exotoxin-based immunotherapies but it is important to keep the possible interactions with immunological effects in mind, which these preparations might elicit additionally and thus interfere with the efficacy of the treatment approach. The classical antipyretics include prostaglandin synthesis inhibitors indomethacin, ibuprofen and glucocorticosteroids next to antipyretics such as aspirin and paracetamol. Endogenous glucocorticoids play an important role in protecting the host against TNF mediated LPS sensitization.774 Additionally, chlorpromazine has been shown to protect against endotoxic shock by inhibiting peripheral and brain TNF, and upregulating IL-10 production.775 Furthermore, the cytokine inhibitor pentoxifylline has been suggested as an antipyretic by lowering TNF and IL-6 levels.776

Acknowledgements

The authors gratefully acknowledge the work of Dr. Helen Coley Nauts, Founder of the Cancer Research Institute in New York, who researched for over half a century the historical and clinical evidence of the use of mixed bacterial vaccines in medicine and who made so many of her records freely available to us.

References

1.
Busch W. Einfluβ von Erysipel. Berliner Klin Wschr. 1866;3:245–246.
2.
Fehleisen V. VI. Über die Züchtung der Erysipelkokken auf künstlichem Nährboden und Ihre Übertragbarkeit auf den Menschen. Dtsch Med Wochenschr. 1882;8:533–554.
3.
Richter PF. Leukemia and Erysipel. Charite-annalens. 1896;21:299–309.
4.
Laurence JZ. The diagnosis of surgical cancer (Lister Prize say for 1854) London: Churchill. 1854;56
5.
Coley WB. The therapeutic value of the mixed toxins of the streptococcus of erysipelas and bacillus prodigiosus in the teratment of inoperable malignant tumors. With a report of 160 cases. Am J Med Sci. 1896;112:251–281.
6.
Coley WB. Treatment of inoperable malignant tumors with toxins of erysipelas and the bacillus prodrigiosus. Trans Am Surg Assoc. 1894a;12:183–212.
7.
Coley WB. The treatment of inoperable malignant tumors with the toxines of erysipelas and the bacillus prodrigiosus. Am J Med Sci. 1894b;108:50–66.
8.
Coley WB. Further observations upon the treatment of malignant tumors with the Toxins of erysipelas and Bacillus prodigious with a report of 160 cases. Bull John Hopkins Hospital. 1896a;7:175.
9.
Coley WB. The therapeutic value of the mixed toxins of the streptococcus of erysipelas and bacillus prodigiosus in the teratment of inoperable malignant tumors. With a report of 160 cases. Am J Med Sci. 1896;112:251–281.
10.
Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: With a report of ten original cases. Am J Med Sci. 1899;105:487–511. [PubMed: 1984929]
11.
Coley WB. Inoperable sarcoma: A further report of cases successfully treated with the mixed bacterial toxins of erysipelas and bacillus prodrigiosus. Med Rec. 1907;72:129–137.
12.
Coley WB. The treatment of inoperable malignant tumors with the toxines of erysipelas and the bacillus prodrigiosus. Am J Med Sci. 1894b;108:50–66.
13.
Coley WB. A report of recent cases of inoperable sarcomas successfully treated with mixed toxines of erysipelas and bacillus prodigiosus. Surg Gynec Obstetr. 1911;13:174–190.
14.
Coley WB, Coley BL. Primary malignant tumors of the long bones Archiv Surg 192613780–836/14. 63-141.
15.
Coley WB. Endothelioma myeloma of tibia: Long-standing cure by Toxin treatment. Ann Surg. 1931;94:447–452.
16.
Issels J. Immunotherapy in progressive metastatic cancer. Clin Trials J. 1970;3:357–366.
17.
In: Hager ED, Abel U, eds. Biomodulation und Biotherapie des Krebses II. Endogene Fiebertherapie und exogene Hyperthermie in der Onkologie. Heidelberg: Verlag für Medizin Dr. E. Fischer. 1987
18.
Heckel M. Ganzkörper-Hyperthermie und Fiebertherapie. Hippokrates Verlag Stuttgart. 1990
19.
Wiemann B, Starnes CHO. Coley's Toxins, Tumor necrosis factor and cancer research: A historical perspective. Pharmac Ther. 1994;64:529–564. [PubMed: 7724661]
20.
Kleef R, Jonas WB, Knogler W. et al. Fever, cancer incidence and spontaneous remissions. Neuroimmunomodulation. 2001;9(2):55–64. [PubMed: 11549887]
21.
Wiltschke C, Krainer M, Budinsky AC. et al. Reduced mitogenic stimulation of peripheral blood mononuclear cells as a prognostic parameter for the course of breast cancer: A prospective longitudinal study. Br J Cancer. 1995;71(6):1292–6. [PMC free article: PMC2033813] [PubMed: 7779726]
22.
Wiltschke C, Tyl E, Speiser P. et al. Increased natural killer cell activity correlates with low or negative expression of the HER-2/neu oncogene in patients with breast cancer. Cancer. 1994;73(1):135–9. [PubMed: 7903907]
23.
Brunson KW, Goldfarb RH. In: Kaiser HE, ed. “Cancer growth and Progression” Dordrecht, the Netherlands: Kluwer Academic Publishers. 1989:133–138.
24.
Cianciolo GJ. In: Gallin JI, Goldstein IM, Snyderman R, eds. “Inflammation: Basic Principles and Clinical Correlates” New York: Raven Press. 1988:861–876.
25.
Nelson M, Bremner JA, Nelson DS. Tumour cell products inhibit both functional and immunoreactive interleukin 2 production by human blood lymphocytes. Br J Cancer. 1989;60(2):161–3. [PMC free article: PMC2247037] [PubMed: 2788451]
26.
Nelson M, Nelson DS. Inhibition of cell-mediated immunity by tumour cell products: Depression of interleukin-2 production and responses to interleukin-2 by mouse spleen cells. Immunol Cell Biol. 1988;66(Pt 2):97–104. [PubMed: 2972606]
27.
Schulof RS, Goldstein AL, Sxtein MB. In: Oldman RK, ed. “Principles of Cancer Biotherapy” New York: Raven Press. 1987:93–162.
28.
Nelson DS, Nelson M. Evasion of host defences by tumours. Immunol Cell Biol. 1987;65(Pt 4):287–304. [PubMed: 3315983]
29.
Aune TM. Role and function of antigen nonspecific suppressor factors. Crit Rev Immunol. 1987;7(2):93–130. [PubMed: 2438085]
30.
Kamo I, Friedman H. Immunosuppression and the role of suppressive factors in cancer. Adv Cancer Res. 1977;25:271–321. [PubMed: 68658]
31.
Stutman O. Immunodepression and malignancy. Adv Cancer Res. 1975;22:261–422. [PubMed: 766581]
32.
Sulitzeanu D. Immunosuppressive factors in human cancer. Adv Cancer Res. 1993;60:247–67. [PubMed: 7678060]
33.
Friedman H, Blanchard DK, Newton C. et al. Distinctive immunomodulatory effects of endotoxin and nontoxic lipopolysaccharide derivatives in lymphoid cell cultures. J Biol Response Mod. 1987;6(6):664–77. [PubMed: 2453617]
34.
Bokemeyer C, Kuczyk MA, Kohne CH. et al. Risk of secondary neoplasia after treatment of malignant germ cell tumors of the testis. Med Klin. 1996;91(11):703–10. [PubMed: 9036294]
35.
Malpas JS. Long-term effects of treatment of childhood malignancy. Clin Radiol. 1996;51(7):466–74. [PubMed: 8689820]
36.
Shapiro CL, Recht A. Late effects of adjuvant therapy for breast cancer. J Natl Cancer Inst Monogr. 1994;(16):101–12. [PubMed: 7999452]
37.
Krainer M, Wolf H, Michl I. et al. Natural killer cell activity in long-term survivors of testicular cancer. Influence of cytostatic therapy and initial stage of disease. Cancer. 1995;75(2):539–44. [PubMed: 7529130]
38.
Rutqvist LE. Long-term toxicity of tamoxifen. Recent Results Cancer Res. 1993;127:257–66. [PubMed: 8502824]
39.
Albanell J, Gallego OS, Bellmunt J. et al. Bladder neoplasm in a patient with panarteritis nodosa treated with cyclophosphamide. Rev Clin Esp. 1992;190(9):463–5. [PubMed: 1352640]
40.
Forbes JF. Long-term effects of adjuvant chemotherapy in breast cancer. Acta Oncol. 1992;31(2):243–50. [PubMed: 1622641]
41.
Zielinski CC, Muller C, Kubista E. et al. Effects of adjuvant chemotherapy on specific and nonspecific immune mechanisms. Acta Med Austriaca. 1990;17(1):11–4. [PubMed: 2353562]
42.
Zielinski CC, Muller C, Tichatschek E. et al. Decreased production of soluble interleukin 2 receptor by phytohaemagglutinin-stimulated peripheral blood mononuclear cells in patients with breast cancer after adjuvant therapy. Br J Cancer. 1989;60(5):712–4. [PMC free article: PMC2247293] [PubMed: 2508736]
43.
Zielinski CC, Stuller I, Dorner F. et al. Impaired primary, but not secondary, immune response in breast cancer patients under adjuvant chemotherapy. Cancer. 1986;58(8):1648–52. [PubMed: 3019506]
44.
Tichatschek E, Zielinski CC, Muller C. et al. Long-term influence of adjuvant therapy on natural killer cell activity in breast cancer. Cancer Immunol Immunother. 1988;27(3):278–82. [PubMed: 2460239]
45.
Kempf RA, Mitchell MS. Effects of chemotherapeutic agents on the immune response. II. Cancer Invest. 1985;3:23–33. [PubMed: 2578859]
46.
Cole WH, Humphrey L. Need for immunologic stimulators during immunosuppression produced by major cancer surgery. 1985. pp. 9–20. [PMC free article: PMC1250830] [PubMed: 3893336]
47.
Cole WH. The increase in immunosuppression and its role in the development of malignant lesions. J Surg Oncol. 1985;30:139–144. [PubMed: 3908826]
48.
Miller Jr WH. Differentiation therapy of acute promyelocytic leukemia: Clinical and molecular features (see comments) Cancer Invest. 1996;14(2):142–50. [PubMed: 8597899]
49.
Wotherspoon AC, Doglioni C, Diss TC. et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori (see comments) Lancet. 1993;342(8871):575–7. [PubMed: 8102719]
50.
Bailar IIIrd JC, Smith EM. Have we reduced the risk of getting cancer or of dying from cancer? An update. Med Oncol Tumor Pharmacother. 1987;4(3-4):193–8. [PubMed: 3326981]
51.
Abel U. Die zytostatische Chemotherapie fortgeschrittener epithelialer Tumoren: Eine kritische Bestandsaufnahme. Stuttgart: Hippokrates-Verl. 1990
52.
Abel U. Chemotherapy of advanced epithelial cancer-a critical review. Biomed Pharmacother. 1992;46(10):439–452. [PubMed: 1339108]
53.
Schipper H, Goh CR, Wang TL. Shifting the cancer paradigm: Must we kill to cure? (editorial) J Clin Oncol. 1995;13(4):801–7. [PubMed: 7707104]
54.
Schipper H, Turley EA, Baum M. A new biological framework for cancer research. Lancet. 1996;348(9035):1149–51. [PubMed: 8888171]
55.
Sporn MB. The war on cancer (see comments) Lancet. 1996;347(9012):1377–81. [PubMed: 8637346]
56.
Office of Alternative Medicine: Expanding Medical Horizons: Report to the National Institutes of Health on Alternative Medical Systems and Practices in the United States. P.170 1992. ISBN 0-16-045479-4.
57.
Teichert J, Schulze-Pillot T, Matthiessen PF. Zehn Jahre Forschungsförderung - “Unkonventionelle Methoden zur Krebsbekämpfung” Deutsches Ärzteblatt 199491A–3332-3336. (Heft 48)
58.
Schmidt KL. Krebs und Infektionskrankheiten. Med Klinik. 1910;43:1690–1693.
59.
Engel P. Über den Infektionsindex der Krebskranken. Wien Klin Wschr. 1934;47:1118–1119.
60.
Engel P. Über den Einfluß des Alters auf den Infektionsindex der Krebskranken. Wien Klin Wschr. 1935;48:112.
61.
Sinek F. Versuch einer statistischen Erfassung endogener Faktoren bei Carcinomerkrankungen. Z Krebsforsch. 1936;44:492–527.
62.
Witzel L. Anamnese und Zweiterkrankungen bei Patienten mit bösartigen Neubildungen. Med Klin. 1970;65:876–879. [PubMed: 5508252]
63.
Newhouse ML, Pearson RM, Fullerton JM. et al. A case control study of carcinoma of the ovary. Brit J Preventive Social Med. 1977;31:148–153. [PMC free article: PMC479015] [PubMed: 588853]
64.
Remy W, Hammerschmidt K, Zänker KS. et al. Tumorträger haben selten Infekte in der Anamnese. Med Klinik. 1983;78:95–98.
65.
Grufferman S, Wang HH, DeLong ER. et al. Environmental factors in the etiology of rhabdomyosarcoma in childhood. J Natl Cancer Inst. 1982;68:107–113. [PubMed: 6948120]
66.
RØnne T. Measles virus infection without rash in children is related to disease in adult life. The Lancet. 1985;8419i:1–5. [PubMed: 2856946]
67.
van Steensel-Moll HA, Valkenburg HA, van Zanen GE. Childhood leukemia and infectious diseases in the first year of life: A register based case-control study. Am J Epidemiol. 1986;124:590–594. [PubMed: 3463201]
68.
Chilvers O, Johnson B, Leach S. et al. The common cold, allergy, and cancer. Br J Cancer. 1986;54:123–126. [PMC free article: PMC2001646] [PubMed: 3730250]
69.
Abel U. Incidence of infection and cancer risk. Dtsch Med Wschr. 1986a;111:1987–81.
70.
Abel U, Becker N, Angerer R. et al. Common infections in the history of cancer patients and controls. J Cancer Res Clin Oncol. 1991;117(4):339–344. [PubMed: 2066354]
71.
Abel U. Cancer occurrence from the biometric viewpoint. Fortschr Med. 1986b;104(8):158–62. [PubMed: 3957210]
72.
Schlehofer B, Blettner M, Becker N. et al. Medical risk factors and development of brain tumors. Cancer. 1992;69:2541–2547. [PubMed: 1568177]
73.
Grossarth-Maticek R, Frentzel-Beyme R, Kanazir D. et al. Reported Herpes-virus infection, fever and cancer incidence in a prospective study. J Chronic Dis. 1987;40:967–976. [PubMed: 3038944]
74.
Kölmel KF, Compagnone D. Melanom und Atopie. Dtsch Med Wschr. 1988;113:169–71. [PubMed: 3338399]
75.
Kölmel K, Gefeller O, Haverkamp B. Febrile infections and malignant melanoma: Results of a case-control study. Melanoma Res. 1992;2:207–211. [PubMed: 1450674]
76.
Cooper GS, Kamel F, Sandler DP. et al. Risk of adult acute leukemia in relation to prior immune-related conditions. Cancer Epidemiol Biomarkers Prev. 1996;5:867–872. [PubMed: 8922293]
77.
Goldstein DJ, Austin JH, Zuech N. et al. Carcinoma of the lung after heart transplantation. Transplantation. 1996;62(6):772–5. [PubMed: 8824476]
78.
Swinnen LJ. Transplant immunosuppression-related malignant lymphomas. Cancer Treat Res. 1993;66:95–110. [PubMed: 8102866]
79.
Hoover RN. Lymphoma risks in populations with altered immunity—a search for mechanism. Cancer Res. 1992;52(19 Suppl):5477s–5478s. [PubMed: 1394157]
80.
Thomas JA, Crawford DH. B-cell lymphoma in organ transplant recipients. Semin Thorac Cardiovasc Surg. 1990;2(3):221–32. [PubMed: 1964395]
81.
Shiba T, Noguchi S, Yao M. et al. Carcinoma of the urinary bladder in a patient receiving cyclophosphamide for Wegener's granuloma: A case report. Hinyokika Kiyo. 1991;37(4):393–6. [PubMed: 1891999]
82.
Forbes A, Reading NG. Review article: The risks of malignancy from either immunosuppression or diagnostic radiation in inflammatory bowel disease. Aliment Pharmacol Ther. 1995;9(5):465–70. [PubMed: 8580265]
83.
Penn I. Posttransplant malignancies in pediatric organ transplant recipients. Transplant Proc. 1994a;26(5):2763–5. [PubMed: 7940870]
84.
Penn I. Malignancy. Surg Clin North Am. 1994b;74(5):1247–57. [PubMed: 7940072]
85.
Penn I, Draper GJ. General overview of studies of multigeneration carcinogenesis in man, particularly in relation to exposure to chemicals IARC Sci Publ 198996:275–88. (Cancers after cyclosporine therapy Transplant Proc 1988 20(1 Suppl 1)276-9) [PubMed: 2680949]
86.
Tan-Shalaby J, Tempero M. Malignancies after liver transplantation: A comparative review. Semin Liver Dis. 1995;15(2):156–64. [PubMed: 7660168]
87.
O'Regan B, Hirshberg C. Spontaneous remission: An annotated bibliography. Institute of Noetic Sciences, Sausalito, ISBN 0-943951-17-8. 1993
88.
Nauts HC. Bacterial vaccine therapy of cancer Dev Biol Stand 197738487–494. (S Karger Basel 1978) [PubMed: 608541]
89.
Nauts HC. Bacterial products in the treatment of cancer: Past, Present and Future (Meeting paper) International Colloquium on Bacteriology and Cancer. 1982a
90.
Nauts HC. Bacterial pyrogens: Beneficial effects on cancer patients. Prog Clin Biol Res. 1982b;107:687–696. [PubMed: 7167519]
91.
Nauts HC. Breast Cancer: Immunological, factors affecting incidence, prognosis and survival New York: Cancer Research Institute Inc. 1984261 (Monograph # 18)
92.
Nauts HC. Immuntherapie des Krebses. International Symposium on Endotoxin: Structural aspects and immunbiology of host responses Giovinazzo, Bari, Italien: Riva del Sole 1986 . (2905-010686)
93.
Nauts HC. Bacteria and cancer-antagonisms and benefits. Cancer Surv. 1989;8:713–723. [PubMed: 2701726]
94.
Nauts HC. Beneficial effects of immunotherapy (Bacterial Toxins) on sarcoma of the soft tissues, other than lymphosarcoma New York: Cancer Research Institute Inc. 1975 . (Monograph # 16)
95.
Nauts HC. Bibliography of reports concerning the clinical or experimental use of Coley Toxins (streptococcus pyogenes and serratia marcescens), 1893-1984. New York: Cancer Research Institute Inc. 1997
96.
Nauts HC. New York: Cancer Research Institute Inc 1975 . (Monograph # 3 = Monograph # 16)
97.
Nauts HC. Ewing's Sarcoma of Bone: End results following immunotherapy (Bacterial Toxins) combined with surgery and/or radiation New York: Cancer Research Institute Inc. 1974 . (Monograph # 14)
98.
Nauts HC. Giant cell tumor of bone: End results following immunotherapy (coley toxins) alone or combined with surgery and/or radiation - 66 cases and concurrent infection - 4 cases New York: Cancer Research Institute Inc. 1976 . (Monograph #4)
99.
Nauts HC. Historical perspective on the development of inbred mice. Introductory remarks In: Morse III HC, ed. Origins of inbred mice. New York: Academic Press 197823–4. (QY 60R6 O69 1978)
100.
Nauts HC. Host resistance and cancer. New York: Cancer Research Institute, Inc., Monograph #5 (unpublished)
101.
Nauts HC. Osteogenic Sarcoma: End Reults following immunotherapy with bacterial vaccines, 165 cases or following bacterial infections inflammation or fever, 41 cases New York: Cancer Research Institute Inc. 1974 . (Monograph # 15)
102.
Nauts HC. The beneficial effects of bacterial infections on host resistance to cancer. End results in 449 cases. A study and abstracts of reports in the world medical literature (1775-1980) and personal communications New York: Cancer Research Institute Inc. 1980((1032 references) Monograph No 8 2nd ed)
103.
Nauts HC, Fowler GA. End results in lymphosarcoma treated by toxin therapy alone or combined with surgery and/or radiation or with concurrent bacterial infection New York: Cancer Research Institute Inc. 1969 . (Monograph #6)
104.
Nauts HC, McLaren JR. Coley Toxins - the first century. Adv Exp Med Biol. 1990;267:483–500. [PubMed: 2088067]
105.
Nauts HC, Swift WE, Coley LB. Treatment of malignant tumors by bacterial toxins as developed by the late William B. Coley, M.D., reviewed in the light of modern research. Cancer Res. 1946;6:205–216. [PubMed: 21018724]
106.
Nauts HC, Fowler GA, Bogatko FH. A review of the influence of bacterial infection and of bacterial products (Coley's Toxins) on malignant tumors in man Acta Med Scand 1953146suppl 2761–103. (New York Cancer Research Institute Inc 1953 Monograph #1) [PubMed: 13039964]
107.
Nauts HC. Beneficial effects of acute concurrent infection, inflammation, fever or immunotherapy (bacterial toxins) on ovarian and uterine cancer New York: Cancer Research Institute Inc. 1977 . (Monograph # 17)
108.
Nauts HC. Enhancement of natural resistance to renal cancer: Beneficial effects of concurrent infections and immunotherapy with bacterial vaccines New York: Cancer Research Institute Inc. 1970 . (Monograph #12)
109.
Nauts HC. Multiple myeloma: Beneficial effects of acute infections or immunotherapy (bacterial vaccines) New York: Cancer Research Institute Inc. 1975 . (Monograph #13)
110.
Vautier AH. Vue générale sur la maladie cancéuse. Thèse de Paris. 1813;43:11.
111.
Nowotny A. Antitumor effects of Endotoxins. In: Berry LJ (Hrsg.), ed. Handbook of Endotoxin. Vol. 3 Cellular Biology of Endotoxin. New York: Elsevier Science Inc. 1985:389–448.
112.
Bruns P. Die Heilwirkung des Erysipels auf Geschwülste. Beitr Z Klin Chirug. 1887;3:443–466.
113.
Eschweiler R. Die Erysipel-, Erysipeltoxin- und Serumtherapie der bösartigen Geschwülste. C.G. Naumann, Leipzig. 1897
114.
Rohdenburg GL. Fluctuations in the growth energy of malignant tumors in man, with especial reference to spontaneous regression. J Cancer Res. 1918;3:193–225.
115.
Wolfenheim W. Über den heilenden Einfluß des Erysipels auf Gewebsneubildungen, insbesondere bösartige Tumoren. Z Klin Med. 1921;92:507–526.
116.
Everson TC, Cole WH. Spontaneous regression of cancer: Preliminary report. Ann Surgery. 1956;144:366–383. [PMC free article: PMC1465423] [PubMed: 13363274]
117.
Everson TC. Spontaneous regression of cancer. Ann New York Acad Sci. 1964;114:721–735. [PubMed: 5220109]
118.
Everson TC. Spontaneous regression of cancer. Prog Clin Cancer. 1967;3:79–95. [PubMed: 4867093]
119.
Everson TC, Cole WH. Spontaneous regression of cancer. A study and abstract of reports in the world medical literature and personal communications concerning spontaneous regressions of malignant disease. Philadelphia, London: W.B. Saunders Co. 1966
120.
Stephenson HE, Delmez JA, Renden DI. et al. Host immunity and spontaneous regression of cancer evaluated by computerized data reduction study. Surg Gynecol Obstetr. 1971;133:649–655. [PubMed: 5106992]
121.
Cole WH. Spontaneous regression of cancer and the importance of finding its cause. NCI Monogr. 1976;44:5–9. [PubMed: 799760]
122.
Cole WH. Efforts to explain spontaneous regression of cancer. J Surg Oncol. 1981;17:201–209. [PubMed: 6166811]
123.
Dock G. The influence of complicating diseases upon leukemia. Am J Med Sci. 1904;127:563–592.
124.
Pelner, Fowler GA, Nauts HC. Effects of concurrent infections and their toxins on the course of leukemia Acta Medica Scand 1958162suppl 3384–47. (New York Cancer Research Institute Inc Monograph #2) [PubMed: 13605619]
125.
Kizaki M, Ogawa T, Watanabe Y. et al. Spontaneous remission in hypoplastic acute leukemia. Keio J Med. 1988;37(3):299–307. [PubMed: 3199634]
126.
Huth EF. Die Rolle der bakteriellen Infektionen bei der Spontanremission maligner Tumoren und Leukosen. In: Lampert H, Selawry O, eds. Körpereigene Abwehr und bösartige Geschwülste. Ulm: Haug-Verlag. 1957:23–37.
127.
Takita H. Effect of postoperative empyema on survival of patients with bronchogenic carcinoma. J Thorac Cardiovasc Surg. 1970;59(5):642–4. [PubMed: 5439684]
128.
Ruckdeschel JC, Codish SD, Stranahan A. et al. Postoperative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. N Engl J Med. 1972;287(20):1013–7. [PubMed: 4650967]
129.
Matzker J, Steinberg A. Tonsillectomy and leukemia in adults (author's transl) Laryngol Rhinol Otol (Stuttg) 1976;55(9):721–5. [PubMed: 135899]
130.
Kapp JP. Microorganisms as antineoplastic agents in CNS tumors. Arch Neurol. 1983;40:637–642. [PubMed: 6688521]
131.
Nowacki MP, Szymendera JJ. The strongest prognostic factors in colorectal carcinoma. Surgicopathologic stage of disease and postoperative fever. Dis Colon Rectum. 1983;26(4):263–8. [PubMed: 6839898]
132.
Fucini C, Bandettini L, D'Elia M. et al. Are postoperative fever and/or septic complications prognostic factors in colorectal cancer resected for cure? Dis Colon Rectum. 1985;28(2):94–5. [PubMed: 3971813]
133.
Treon SP, Broitman SA. Beneficial effects of post-transfusional hepatitis in acute myelogenous leukemia may be mediated by lipopolysaccharides, Tumor necrosis factor α and Interferon γ Leukemia. 1992;6:1036–1042. [PubMed: 1405756]
134.
Maurer S, Kolmel K. Spontaneous regression of melanoma New York: Cancer Research Institute Inc. 1997 . (Monograph #19)
135.
Levin EJ. Spontaneous regression (cure?) of a malignant tumor of bone. Cancer. 1957;10:377–381. [PubMed: 13426995]
136.
Cole WH. Spontaneous regression of reticulum-cell sarcoma of bone. J Bone Joint Surg. 1959;41-A:960–965. [PubMed: 13664730]
137.
Callan JE, Wood VE, Linda L. Spontaneous resolution of an osteochondroma. J Bone Joint Surg (Am) 1975;57(5):723. [PubMed: 1150728]
138.
Copeland RL, Meehan PL, Morrissy RT. Spontaneous regression of osteochondromas. Two case reports. J Bone Joint Surg (Am) 1985;67(6):971–3. [PubMed: 4019547]
139.
Eisenbud L, Kahn LB, Friedman E. Benign osteoblastoma of the mandible: Fifteen year follow-up showing spontaneous regression after biopsy. J Oral Maxillofac Surg. 1987;45(1):53–7. [PubMed: 3467037]
140.
Collignon JC, Kalangu K, Flandroy P. Benign osteoblastoma of the spine. Apropos of 4 cases with a case of spontaneous recovery Neurochirurgie 198834(4):262–70. (Regression) [PubMed: 3200366]
141.
Margolis J, West D. Spontaneous regression of malignant disease: Report of three cases. J Am Geriatr Soc. 1967;15(3):251–3. [PubMed: 6018380]
142.
Rao S, Constantini S, Gomori JM. et al. Spontaneous involution of an intra-axial brain stem lesion: A case report Pediatr Neurosurg 199523(5):279–81. (discussion 282) [PubMed: 8688354]
143.
Bluming AZ, Ziegler JL. Regression of Burkitt's lymphoma in association with measles infection. Lancet. 1971;2(715):105–6. [PubMed: 4103972]
144.
Rebollo J, Llorente I, Yoldi A. Spontaneous tumor regression in a patient with metastatic gastric cancer. Communication of an additional case. Rev Med Univ Navarra. 1990;34(3):141–2. [PubMed: 2151656]
145.
Zambrana Garcia JL, Torres Serrano F, Lopez Rubio F. et al. Spontaneous tumor regression and gastric cancer (letter) An Med Interna. 1996;13(1):47–8. [PubMed: 8679829]
146.
Friedrich Jr EG. Reversible vulvar atypia. A case report. Obstet Gynecol. 1972;39(2):173–81. [PubMed: 4333392]
147.
Temesrekasi D. Complete regression of 2 nonoperated hypopharyngeal carcinomas. Arch Klin Exp Ohren Nasen Kehlkopfheilkd. 1969;194(2):323–8. [PubMed: 5372598]
148.
Woods JE. The influence of immunologic responsiveness on head and neck cancer. Therapeutic implications. Plast Reconstr Surg. 1975;56(1):77–80. [PubMed: 1144550]
149.
Chien RN, Chen TJ, Liaw YF. Spontaneous regression of hepatocellular carcinoma. Am J Gastroenterol. 1992;87(7):903–5. [PubMed: 1319672]
150.
Grossmann M, Hoermann R, Weiss M. et al. Spontaneous regression of hepatocellular carcinoma (see comments) Am J Gastroenterol. 1995;90(9):1500–3. [PubMed: 7544955]
151.
Markovic S, Ferlan-Marolt V, Hlebanja Z. Spontaneous regression of hepatocellular carcinoma (see comments) Am J Gastroenterol. 1996;91(2):392–3. [PubMed: 8607517]
152.
Tarazov PG. Spontaneous necrosis of liver cancer: One more possible cause (letter; comment) Am J Gastroenterol. 1996;91(9):1872–3. [PubMed: 8792728]
153.
Hart S. Chronic lymphatic leukemia complicated by pneumonia. New York State J Med. 1903;78:220–227.
154.
Dreyfus B. Les Remissions de la leucemie aigue. Sangre. 1948;1:35–40. [PubMed: 18902583]
155.
Bassen FA, Kohn JL. Multiple spontaneous remissions in a child with acute leukemia. The occurrence of agranulocytosis and aplastic anemia in acute leukemia and their relationship to remissions. Blood. 1952;7:37–46. [PubMed: 14886408]
156.
Paolino W, Sartoris S. Due casi di leucemia migliorati a seguito di complicazioni infettive. Minerva Med (Torino) 1960;51:34554–3456.
157.
Vladimirskaia EB. A case of prolonged spontaneous remission in a patient with chronic lymphatic leukemia. Problemy Gematologii I Perlevaniya Krovi. 1962;7:51–54. [PubMed: 13926345]
158.
Hardisty RM. Splenic aspiration in acute leukaemia. Lancet. 1968;1(540):472–3. [PubMed: 4169802]
159.
Burgess MA, Gruchy GC de. Septicemia in acute leukemia. Med J Aust. 1969;1(22):1113–7. [PubMed: 4893254]
160.
Wyszkowski J, Armata J, Cyklis R. et al. Remissions in acute leukemia resistant to treatment complicated with steroid diabetes and severe infection. Ploski Tygodnik Lekarski. 1969;24:1974–1975. [PubMed: 5262765]
161.
Wiernik PH. Spontaneous regression of hematologic cancers. Natl Cancer Inst Monogr. 1976;44:35–38. [PubMed: 1030780]
162.
Barton JC, Conrad ME. Beneficial effect of hepatitis in patients with acute myelogenous leukemia. Ann Int Med. 1979;90:188–190. [PubMed: 286572]
163.
Conrad ME, Barton JC. Hepatitis and leukemia (letter) Ann Int Med. 1979;90:988. [PubMed: 286574]
164.
Foon KA, Yale C, Clodfelter K. et al. Posttransfusion hepatitis in acute myelogenous leukemia: Effect on survival. JAMA. 1980;244:1806–1807. [PubMed: 6932517]
165.
Vinogradova IuE, Ivanina EK. Indicators of cellular immunity and the incidence of infectious-inflammatory diseases during clinicohematological remission in patients with acute leukemia. Ter Arkh. 1984;56(6):46–50. [PubMed: 6332389]
166.
Sanz GF, Sanz MA. Complete spontaneous remission in acute myeloblastic leukemia. Revista Clin Espanola. 1986;178:229–230. [PubMed: 3459216]
167.
Zhu XQ, Qian JW. Remission of acute lymphoblastic leukemia of childhood following acute infectious disease. A case report. Chin Med J (Engl) 1986;99(5):433–4. [PubMed: 3100181]
168.
Maekawa T, Fujii H, Horiike S. et al. Spontaneous remission of four months duration in hypoplastic leukemia with tetraploid chromosome after blood transfusion and infection. Acta haematologica Japonica. 1989;52:849–857. [PubMed: 2588945]
169.
Frick S, Frick P. Spontaneous remission in chronic lymphatic leukemia. Schweiz Med Wochenschr. 1993;123(8):328–34. [PubMed: 8451615]
170.
Delmer A, Heron E, Marie JP. et al. Spontaneous remission in acute myeloid leukaemia (letter; comment. Br J Haematol. 1994;87(4):880–2. [PubMed: 7986738]
171.
Musto P, D'Arena G, Melillo L. et al. Spontaneous remission in acute myeloid leukaemia: A role for endogenous production of tumour necrosis factor and interleukin-2? (letter; comment) Br J Haematol. 1994;87(4):879–80. [PubMed: 7986737]
172.
Jono K, Ikebe Y, Inada K. et al. A case of spontaneous remission in chronic B-cell leukemia with virus infection. Nippon Naika Gakkai Zasshi. 1994;83(12):2159–60. [PubMed: 7876709]
173.
Lefrere F, Hermine O, Radford-Weiss I. et al. A spontaneous remission of lymphoid blast crisis in chronic myelogenous leukaemia following blood transfusion and infection. Br J Haematol. 1994;88(3):621–2. [PubMed: 7819077]
174.
Greentree LB. Anaplastic lung cancer with metastases. Case report of a 15-year survival. Ohio State Med J. 1973;69(11):841–3.
175.
Marcos Sanchez F, Juarez Ucelay F, Bru Espino IM. et al. A new case of spontaneous tumor regression (letter) An Med Interna. 1991;8(9):468. [PubMed: 1958788]
176.
Sanchez-Cantu L, Rode HN, Yun TJ. et al. Tumor necrosis factor alone does not explain the lethal effect of lipopolysaccharide. Arch Surg. 1991;126(2):231–5. [PubMed: 1899559]
177.
Mentzer SJ. Immunoreactivity in lung cancer. Chest Surg Clin N Am. 1995;5(1):57–71 (spontaneous remission REVIEW ARTICLE 59 REFS). [PubMed: 7743148]
178.
Zygiert Z. Hodgkin's disease; remissions after measles. Lancet. 1971;1:593. [PubMed: 4100922]
179.
Ziegler JL. Spontaneous remission in Burkitt's lymphoma. Natl Cancer Inst Monogr. 1976;44:61–5. [PubMed: 799761]
180.
Gattiker HH, Wiltshaw E, Galton DA. Spontaneous regression in nonHodgkin's lymphoma. Cancer. 1980;45(10):2627–32. [PubMed: 7378996]
181.
McClain K, Warkentin P, Kay N. Spontaneous remission of Burkitt's lymphoma associated with herpes zoster infection. Am J Pediatr Hematol Oncol Spring. 1995;7(1):9–14. [PubMed: 3876039]
182.
Kempin S, Cirrincione C, Straus DS. et al. Improved remission rate and duration in nodular nonHodgkin lymphoma (NNHL) with the use of mixed bacterial vaccine (MBV) Proc Am Soc Clin Oncol. 1981;22:514.
183.
Kempin S, Cirrincione C, Myers J. et al. Combined modality therapy of advanced nodular lymphoma (NL) - The role of nonspecific immunotherapy (MBV) as an important determinant of response and survival. Proc Am Soc Clin Oncol. 1983;24:56.
184.
Grem JL, Hafez GR, Brandenburg JH. et al. Spontaneous remission in diffuse large cell lymphoma. Cancer. 1986;57(10):2042–4. [PubMed: 3955512]
185.
Drobyski WR, Qazi R. Spontaneous regression in nonHodgkin's lymphoma: Clinical and pathogenetic considerations. Am J Hematol. 1989;31(2):138–41. [PubMed: 2660545]
186.
Wolf JW. Prolonged spontaneous remission of case of malignant lymphoma. Mo Med. 1989;86(5):275–7. [PubMed: 2668726]
187.
Sureda M, Subira ML, Martin Algarra S. et al. Spontaneous tumor regression. Report of 2 cases. Med Clin (Barc) 1990;95(8):306–8. [PubMed: 2283912]
188.
De Berker D, Windebank K, Sviland L. et al. Spontaneous regression in angiocentric T-cell lymphoma. Br J Dermatol. 1996;134(3):554–8. [PubMed: 8731688]
189.
Sawada M, Ohdama S, Umino T. et al. Metastasis of an adenocarcinoma of unknown origin to mediastinal lymph nodes, and transient regression. Nippon Kyobu Shikkan Gakkai Zasshi. 1994;32(9):867–72. [PubMed: 7799557]
190.
Heinzlef O, Poisson M, Delattre JY. Spontaneous regression of primary cerebral lymphoma. Rev Neurol (Paris) 1996;152(2):135–8. [PubMed: 8761621]
191.
Tsubura E, Hirao F, Fujisawa T. et al. Tumor and infection. Saishin Igaku. 1967;22(10):2281–90. [PubMed: 4871486]
192.
Bagshawe KD. Tumor growth and anti-mitotic action. The role of spontaneous cell losses. Br J Cancer. 1968;22:698–713. [PMC free article: PMC2008372] [PubMed: 5705140]
193.
Muckle DS, Dickson JA, Johnston ID. High fever and cancer Lancet 19718972 (regression) [PubMed: 4102300]
194.
Schwartz DB, Zbar B, Gibson WT. et al. Inhibition of murine sarcoma virus oncogenesis with living BCG. Int J Cancer. 1971;8:320–325. [PubMed: 4943924]
195.
Cho-Chung YS, Gullino PM. Mammary tumor regression. V. Role of acid ribonuclease and cathepsin. J Biol Chem. 1973a;248(13):4743–9. [PubMed: 4198062]
196.
Cho-Chung YS, Gullino PM. Mammary tumor regression. VI. Synthesis and degradation of acid ribonuclease. J Biol Chem. 1973b;248(13):4750–5. [PubMed: 4198063]
197.
Cho-Chung YS, Gullino PM. Mammary tumor regression. VI. Synthesis and degradation of acid ribonuclease. J Biol Chem. 1973c;248(13):4750–5. [PubMed: 4198063]
198.
Remy W, Stuttgen G, Bockendahl H. et al. Remission of skin melanoma metastases following BCG injection (letter) Dtsch Med Wochenschr. 1976;101(39):1435–6. [PubMed: 985659]
199.
Berendt MJ. The immunological basis of endotoxin-induced tumor regression. Requirement for T-cell mediated immunity. J Exp Med. 1978a;148:1550–1559. [PMC free article: PMC2185110] [PubMed: 309921]
200.
Berendt MJ. The immunological basis of endotoxin-induced tumor regression. Requirement for a preexisting state of concomitant anti-tumor immunity. J Exp Med. 1978b;148:1560–1569. [PMC free article: PMC2185097] [PubMed: 309922]
201.
Pedersen NC, Johnson L, Theilen GH. Biological behavior of tumors and associated retroviremia in cats inoculated with Snyder-Theilen fibrosarcoma virus and the phenomenon of tumor recurrence after primary regression. Infect Immun. 1984;43(2):631–6. [PMC free article: PMC264346] [PubMed: 6319286]
202.
Bolande RP. Spontaneous regression and cytodifferentiation of cancer in early life: The oncogenic grace period. Surv Synth Pathol Res. 1985;4(4):296–311. [PubMed: 3014631]
203.
Baker HW. Biologic control of cancer. The James Ewing lecture. Arch Surg. 1986;121(11):1237–41. [PubMed: 3778194]
204.
Stone OJ. Acute local inflammation causing generalized increased ground substance viscosity: Guttate psoriasis, Reiter's syndrome, adjuvant disease, cancer regression. Med Hypotheses. 1988;25(3):141–5. [PubMed: 3130552]
205.
Jarpe MA, Hayes MP, Russell JK. et al. Causal association of interferon-gamma with tumor regression. J Interferon Res. 1989;9:239–244. [PubMed: 2497201]
206.
Seachrist L. Spontaneous cancer remissions spark questions (news) J Natl Cancer Inst. 1993;85(23):1892–5. [PubMed: 8230276]
207.
Halliday GM, Patel A, Hunt MJ. et al. Spontaneous regression of human melanoma/nonmelanoma skin cancer: Association with infiltrating CD4+ T cells. World J Surg. 1995;19(3):352–8. [PubMed: 7638987]
208.
Gunale S, Tucker WG. Regression of metastatic melanoma. Mich Med. 1975;74:697–698. [PubMed: 1196147]
209.
Wormald RP, Harper JI. Bilateral black hypopyon in a patient with self-healing cutaneous malignant melanoma. Br J Ophthalmol. 1983;67(4):231–5. [PMC free article: PMC1040025] [PubMed: 6830741]
210.
Wagner Jr RF, Nathanson L. Paraneoplastic syndromes, tumor markers, and other unusual features of malignant melanoma J Am Acad Dermatol 1986142 Pt 1249–56. (Spontaneous regression) [PubMed: 2869074]
211.
Cook MG. The significance of inflammation and regression in melanoma (editorial) Virchows Arch A Pathol Anat Histopathol. 1992;420(2):113–5. [PubMed: 1549899]
212.
Grafton WD. Regressing malignant melanoma. J La State Med Soc. 1994;146(12):535–9. [PubMed: 7844465]
213.
Motofei IG. Herpetic viruses and spontaneous recovery in melanoma. Med Hypotheses. 1996;47(2):85–8. [PubMed: 8869920]
214.
London RE. Multiple Myeloma: Report of a case showing unusual remission lasting two years following severe hepatitis Ann Int Med 195543191–201. (Regression) [PubMed: 14388551]
215.
Schurmans JR, Blijenberg BG, Mickisch GH. et al. Spontaneous remission of a bony metastasis in prostatic adenocarcinoma. J Urol. 1996;155(2):653. [PubMed: 8558693]
216.
Katz SE, Schapira HE. Spontaneous regression of genitourinary cancer - an update. J Urol. 1982;128:1–4. [PubMed: 7050408]
217.
Mangiapan G, Guigay J, Milleron B. A new case of spontaneous regression of metastasis of kidney cancer (letter) Rev Pneumol Clin. 1994;50(3):139–40. [PubMed: 7724977]
218.
Edwards MJ, Anderson JA, Angel JR. et al. Spontaneous regression of primary and metastatic renal cell carcinoma. J Urol. 1996;155(4):1385. [PubMed: 8632583]
219.
Hunter WS. Unexpected regressed retinoblastoma. Can J Ophthalmol. 1968;3(4):376–80. [PubMed: 5303811]
220.
Verhoeff FH. Retinoblastoma undergoing spontaneous regression. Calcifying agent suggested in treatment of retinoblastoma. Am J Ophthalmol. 1966;62(3):573–4. [PubMed: 5922000]
221.
Jain IS, Singh K. Retinoblastoma in phthisis bulbi. J All India Ophthalmol Soc. 1968;16(2):76–8. [PubMed: 5733912]
222.
Dobson L, Dickey LB. Spontaneous regression of malignant tumors. Am J Surg. 1956;92:162–173. [PubMed: 13340067]
223.
Sindelar WF. Regression of cancer following surgery. Natl Cancer Inst Monogr. 1976;44:81–84. [PubMed: 1025476]
224.
Challis GB, Stam HJ. The spontaneous regression of cancer. A review of cases from 1900 to 1987. Acta Oncol. 1990;29(5):545–50. [PubMed: 2206563]
225.
Kaiser HE. Biological viewpoints of neoplastic regression. In Vivo. 1994;8(1):155–65. [PubMed: 8054505]
226.
Watson AL. A case of recurrent sarcoma with apparently spontaneous cure and gradual shrinking of the tumour. Lancet. 1902;1:300–301.
227.
Shore BR. Spontaneous cure of congenital recurring connective tissue tumor. Am J Cancer. 1936;27:736–739.
228.
Penner DW. Spontaneous regression of a case of myosarcoma. Cancer. 1953;6:776–779. [PubMed: 13059772]
229.
Berner RE, Laub DL. The spontaneous cure of massive fibrosarcoma. Plastic Reconstructive Surg. 1965;36:257–262. [PubMed: 14339185]
230.
Weintraub LR. Lymphosarcoma. Remission associated with viral hepatitis. JAMA. 1969;210:1590–1591. [PubMed: 5394892]
231.
Mizuno S, Fujinaga T, Hagio M. Role of lymphocytes in spontaneous regression of experimentally transplanted canine transmissible venereal sarcoma. J Vet Med Sci. 1994;56(1):15–20. [PubMed: 8204742]
232.
Lei KI, Gwi E, Ma L. et al. Spontaneous' regression of advanced leiomyosarcoma of the urinary bladder. Oncology. 1997;54(1):19–22. [PubMed: 8978587]
233.
Atkins E. Fever: Its history, cause and function. Yale J Biol Med. 1982;55:283–289. [PMC free article: PMC2596465] [PubMed: 6758374]
234.
Kluger MJ. Fever: Role of pyrogens and cryogens. Physiol Rev. 1991;71(1):93–127. [PubMed: 1986393]
235.
Roberts Jr NJ. The immunological consequences of fever. In: Mackowiak PA, ed. In Fever: Basic mechanisms and management. New York: Raven. 1991::125.
236.
Roberts Jr NJ. Impact of temperature elevation on immunologic defenses. Rev Infect Dis. 1991;13(3):462–72. [PubMed: 1866550]
237.
Dinarello CA. Endogenous pyrogens. In: Mackowiak PA, ed. Fever: Basic mechanisms and management. New York: Raven. 1991:23.
238.
Dinarello CA. Thermoregulation and the pathogenesis of fever. Infect Dis Clin North Am. 1996;10(2):433–49. [PubMed: 8803628]
239.
Burnet FM. The concept of immunological surveillance Progr Exp Tumor Res 1970131–27. (Karger Basel/München/New York) [PubMed: 4921480]
240.
Burnet FM. Implications immunological surveillance for cancer therapy. Israel J Medical Sci. 1971;7:9–16. [PubMed: 4101103]
241.
Hanson DF, Murphy PA. Demonstration of interleukin 1 activity in apparently homogeneous specimens of the pI 5 form of rabbit endogenous pyrogen. Infect Immun. 1984;45(2):483–90. [PMC free article: PMC263268] [PubMed: 6611312]
242.
Rodbard D, Wachslicht-Rodbard H, Rodbard S. Temperature: A critical factor determining localization and natural history of infectious, metabolic, and immunological diseases. Perspect Biol Med Spring. 1980;23(3):439–74. [PubMed: 6994063]
243.
Hanson DF, Murphy PA. Temperature sensitivity of interleukin-dependent murine T cell proliferation: Q2 mapping of the responses of peanut agglutinin-negative thymocytes. J Immunol. 1985;135(5):3011–20. [PubMed: 3876372]
244.
Niitsu Y, Watanabe N, Umeno H. et al. Synergistic effects of recombinant human tumor necrosis factor and hyperthermia on in-vitro cytotoxicity and artificial metastasis. Cancer Res. 1988;48:654–657. [PubMed: 2825981]
245.
Yamauchi N, Watanabe N, Maeda M. et al. Mechanism of synergistic cytotoxic effect between tumor necrosis factor and hyperthermia. Jpn J Cancer Res. 1992;83:540–545. [PubMed: 1319987]
246.
Hanson DF. Fever and the immune response The effects of physiological temperatures on primary murine splenic T-cell responses in vitro. J Immunol 1993151436–448. [PubMed: 8326136]
247.
Roberts Jr NJ, Steigbigel RT. Hyperthermia and human leukocyte functions: Effects on response of lymphocytes to mitogen and antigen and bactericidal capacity of monocytes and neutrophils. Infect Immun. 1977;18(3):673–9. [PMC free article: PMC421288] [PubMed: 412788]
248.
Dinarello CA, Conti P, Mier JW. Effects of human interleukin-1 on natural killer cell activity: Is fever a host defense mechanism for tumor killing? Yale J Biol Med. 1986a;59(2):97–106. [PMC free article: PMC2590122] [PubMed: 3488622]
249.
Dinarello CA, Dempsey RA, Allegretta M. et al. Inhibitory effects of elevated temperature on human cytokine production and natural killer activity. Cancer Res. 1986b [PubMed: 2430693]
250.
Boeye A, Delaet I, Brioen P. Antibody neutralization of picornaviruses: Can fever help? Trends Microbiol. 1994;2(7):255–7. [PubMed: 8081653]
251.
Coelho MM, Luheshi G, Hopkins SJ. et al. Multiple mechanisms mediate antipyretic action of glucocorticoids. Am J Physiol. 1995;269(3 Pt 2):R527–35. [PubMed: 7573552]
252.
Shwartzman G. Phenomenon of local tissue reactivity. New York: PB Hoeber. 1937
253.
Heremans H, Van Damme J, Dillen C. et al. Interferon gamma, a mediator of lethal lipopolysaccharide-induced Shwartzman-like shock reactions in mice. J Exp Med. 1990;171(6):1853–69. [PMC free article: PMC2187952] [PubMed: 2112583]
254.
Centanni E, Rezzesi F. Etude Experimentale sur l'antagonisme entre la tuberculose et le cancer. Neoplasmes. 1926;5:211–225.
255.
Daels F. Beitrag zum Studium des Antagonismus zwischen den Karzinom-, Spirillen- und Trypanosomeninfektionen. Arch Hyg. 1910;72:257–306.
256.
Gratia A, Linz R. Le phénomène de Shwartzman dans le sarcome du Cobaye. Compt rend Seanc Soc Biol Ses Fil- 1931;108:427–428.
257.
Shwartzman G, Michailovsky N. Proc Soc Exp Biol Med. 1936;34:323.
258.
Berendt MJ, Saluk P. Tumor inhibition in mice by lipopolysaccharide-induced peritoneal cells and an induced soluble factor. Infection Immunity. 1976;14:965–969. [PMC free article: PMC415479] [PubMed: 992877]
259.
Shear MJ. Studies on the chemical treatment of tumors. II. The effect of disturbances of fluid exchange on the transplanted mouse tumors. Am J Cancer. 1935;25:66–88.
260.
Aoki N, Mori W. Effects of endotoxin administration on tumor and host: An experimental observation on tumor-bearing rabbits. In: Homma Y, Kanegasaki S, Luederitz O, Shiba T, Westphal O (Hrsg.), eds. Bacterial Endotoxin. Weinheim, S: Verlag Chemie. 1987:205–221.
261.
Shear MJ, Turner FC, Perrault A. Chemical treatment of tumors. Isolation of haemorrhage-producing fraction from Serratia marcescens (Bacillus prodrigiosus) culture filtrate. J Natl Cancer Inst. 1943;4:81–97.
262.
Shear MJ. Chemical treatment of tumors. IX. Reactions of mice with primary subcutaneous tumors to injection of a hemorrhage-producing bacterial polysaccharide. J Natl Cancer Inst. 1944;4:461–476.
263.
Westphal O. Bacterial endotoxins. The second carl prausnitz memorial lecture. Int Arch Allergy Appl Immunol. 1975;49(1-2):1–43. [PubMed: 1095497]
264.
Andervont HB. The reaction of mice and various mouse tumours to the injection of bacterial products. Am J Cancer. 1936;27:77–83.
265.
Alexander P, Evans R. Endotoxin and Double stranded RNA render macrophages cytotoxic. Nature New Biol. 1971;232:76–78. [PubMed: 5285341]
266.
Hofstad T, Skaug N, Sveen K. Stimulation of B lymphocytes by lipopolysaccharides from anaerobic bacteria. Clin Infect Dis. 1993;16(Suppl 4):S200–2. [PubMed: 8324119]
267.
DeFranco AL, Gold MR, Jakway JP. B-lymphocyte signal transduction in response to anti-immunoglobulin and bacterial lipopolysaccharide. Immunol Rev. 1987;95:161–76. [PubMed: 3032773]
268.
Jacobs DM. Immunomodulatory effects of bacterial lipopolysaccharide. J Immunopharmacol. 1981;3(2):119–32. [PubMed: 6802902]
269.
McGhee JR, Kiyono H, Alley CD. Gut bacterial endotoxin: Influence on gut-associated lymphoreticular tissue and host immune function. Surv Immunol Res. 1984;3(4):241–52. [PubMed: 6438750]
270.
Nowotny A. Review of the molecular requirements of endotoxic actions. Rev Infect Dis. 1987;9(Suppl 5):S503–11. [PubMed: 3317746]
271.
Nowotny A, Moore ME, Nejman G. et al. Time dependency of endotoxin-induced resistance to transplantable tumors in mice. Cancer Invest. 1987a;5(3):195–203. [PubMed: 3308018]
272.
Nowotny A, Blanchard DK, Newton C. et al. Interferon induction by endotoxin-derived nontoxic polysaccharides. J Interferon Res. 1987b;7(4):371–8. [PubMed: 2444655]
273.
Rietschel ET, Brade H, Brade L. et al. Lipid A, the endotoxic center of bacterial lipopolysaccharides: Relation of chemical structure to biological activity. Detection of bacterial endotoxins with the limulus amebocyte lysate test. Prog Clin Biol Res. 1987;231:25–53. [PubMed: 3588622]
274.
Rietschel ET, Brade H, Holst O. et al. Bacterial endotoxin: Chemical constitution, biological recognition, host response, and immunological detoxification. Curr Topics Microbiol Immunol. 1996;216:39–81. [PubMed: 8791735]
275.
Rietschel ET, Brade H. Bacterial endotoxins. Sci Am. 1992;267(2):54–61. [PubMed: 1641625]
276.
Dabbert CB, Lochmiller RL, Zhang JR. et al. High in vitro endotoxin responsiveness of macrophages from an endotoxin-resistant wild rodent species, Sigmodon hispidus. Dev Comp Immunol. 1994;18(2):147–53. [PubMed: 8082816]
277.
Galanos C, Freudenberg MA, Luederitz O. et al. Chemical, physicochemical and biological properties of bacterial lipopolysaccharides. Prog Clin Biol Res. 1979a;29:321–332. [PubMed: 504265]
278.
Abel U. Die antineoplastische Wirkung pyrogener Bakterientoxine. In: Hager ED, Abel U, eds. Biomodulation und Biotherapie des Krebses. II. Endogene Fiebertherapie und exogene Hyperthermie in der Onkologie. Heidelberg: Verlag für Medizin Dr. E. Fischer. 1987:21–85.
279.
Chun M, Hoffmann MK. Combination immunotherapy of cancer in a mouse model: Synergism between tumor necrosis factor and other defence systems. Cancer Res. 1987;47:115–118. [PubMed: 3791198]
280.
Giese M, Kirchner H. Interferons and their effects. Onkologie. 1988;11:151–154. [PubMed: 2460811]
281.
Engelhardt R, Mackensen A, Galanos C. et al. Biological response to intravenously administered endotoxin in patients with advanced cancer. J Biol Response Mod. 1990;9:480–491. [PubMed: 2254760]
282.
Engelhardt R, Mackensen A, Galanos C. Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in Cancer patients. Cancer Res. 1991;51:2524–2530. [PubMed: 2021932]
283.
Engelhardt R, Otto F, Mackensen A. et al. Endotoxin (Salmonella abortus equi) in cancer patients. Clinical and immunological findings. Prog Clin Biol Res. 1995;392:253–61. [PubMed: 8524930]
284.
Mackensen A, Galanos C, Engelhardt R. Modulating activity of Interferon-γ on endotoxin-induced cytokine production in cancer patients. Blood. 1991a;78:3254–3258. [PubMed: 1720701]
285.
Mackensen A, Galanos C, Engelhardt R. Treatment of cancer patients with endotoxin induces release of endogenous cytokines. Pathobiology. 1991b;59:264–267. [PubMed: 1715715]
286.
Mackensen A, Galanos C, Wehr U. et al. Endotoxin tolerance: Regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients. Eur Cytokine Netw. 1992;3:571–579. [PubMed: 1284277]
287.
Knopf HP, Otto F, Engelhardt R. et al. Discordant adaptation of human peritoneal macrophages to stimulation by lipopolysaccharide and the synthetic lipid A analogue SDZ MRL 953. Down-regulation of TNF-alpha and IL-6 is paralleled by an up-regulation of IL-1 beta and granulocyte colony-stimulating factor expression. J Immunol. 1994;153:287–299. [PubMed: 7515924]
288.
Conti P, Reale M, Nicolai M. et al. Bacillus Calmette-Guerin potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients. Cancer Immunol Immunother. 1994;38(6):365–71. [PubMed: 8205557]
289.
Otto F, Schmid P, Mackensen A. et al. Phase II trial of intravenous endotoxin in patients with colorectal and nonsmall cell lung cancer. Eur J Cancer. 1996;32A:1712–1718. [PubMed: 8983279]
290.
Moore MA, Gabrilove J, Sheridan AP. Therapeutic implications of serum factors inhibiting proliferation and inducing differentiation of myeloid leukemic cells. Blood Cells. 1983;9(1):125–44. [PubMed: 6602636]
291.
Enterline PE, Sykora JL, Keleti G. et al. Endotoxins, cotton dust, and cancer. Lancet. 1985;2(8461):934–5. [PubMed: 2865429]
292.
Kearney R, Harrop P. Potentiation of tumour growth by endotoxin in serum from syngeneic tumour-bearing mice. Br J Cancer. 1980;42(4):559–67. [PMC free article: PMC2010436] [PubMed: 7002195]
293.
Kearney R, Harrop P. Modulation of anti-tumour immunity and the effect of bacterial endotoxin on the growth of different syngeneic tumours from small inocula in mice. Br J Exp Pathol. 1986;67(3):371–81. [PMC free article: PMC2013034] [PubMed: 3521708]
294.
DerHagopian RP, Sugarbaker EV, Ketcham A. Inflammatory oncotaxis. JAMA. 1978;240(4):374–5. [PubMed: 660874]
295.
DerHagopian RP. Inflammatory oncotaxis (letter) JAMA. 1979;241(21):2264. [PubMed: 439291]
296.
Sataline L, Pelliccia O. Inflammatory oncotaxis (letter) JAMA. 1978;240(22):243. [PubMed: 712933]
297.
Shine T, Wallack MK. Inflammatory oncotaxis after testing the skin of the cancer patient. Cancer. 1981;47(6):1325–8. [PubMed: 7226055]
298.
Ben-Baruch A. Host microenvironment in breast cancer development: Inflammatory cells, cytokines and chemokines in breast cancer progression: Reciprocal tumor-microenvironment interactions. Breast Cancer Res. 2003;5(1):31–6 (Epub 2002 Oct 28). [PMC free article: PMC154133] [PubMed: 12559043]
299.
Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis Nat Rev Cancer 20044(1):71–8. (Review) [PubMed: 14708027]
300.
Morita S, Yamamoto M, Kamigaki T. et al. Synthetic lipid A produces antitumor effect in a hamster pancreatic carcinoma model through production of tumor necrosis factor from activated macrophages. Kobe J Med Sci. 1996;42(4):219–31. [PubMed: 9023454]
301.
Vosika GJ. Phase-I study of intravenous modified lipid A. Cancer Immunol Immunother. 1984;18:107–112. [PubMed: 6391653]
302.
Goto S, Sakai S, Kera J. et al. Intradermal administration of lipopolysaccharide in treatment of human cancer. Cancer Immunol Immunother. 1996;42(4):255–61. [PubMed: 8665574]
303.
Jimbo T, Akimoto T, Tohgo A. Systemic administration of a synthetic lipid A derivative, DT-5461a, reduces tumor blood flow through endogenous TNF production in hepatic cancer model of VX2 carcinoma in rabbits. Anticancer Res. 1996;16(1):359–64. [PubMed: 8615636]
304.
Nowicki A, Ostrowska G, Aukerman SL. et al. Effect of macrophage-modulating agents on in vivo growth of transplantable Lewis lung cancer in mice. Arch Immunol Ther Exp (Warsz) 1994;42(4):313–7. [PubMed: 7487373]
305.
Freudenberg N, Joh K, Westphal O. et al. Haemorrhagic tumour necrosis following endotoxin administration. I. Communication: Morphological investigation on endotoxin-induced necrosis of the methylcholanthrene (Meth A) tumour in the mouse. Virchows Arch A Pathol Anat Histopathol. 1984;403:377–389. [PubMed: 6429940]
306.
Boon T, Coulie P, Marchand M. et al. Genes coding for tumor rejection antigens: Perspectives for specific immunotherapy. Important Adv Oncol. 1994:53–69. [PubMed: 8206495]
307.
Boon T, van der Bruggen P. Human tumor antigens recognized by T-lymphocytes. J Exp Med. 1996;183:725–729. [PMC free article: PMC2192342] [PubMed: 8642276]
308.
Gidlof C, Dohlsten M, Lando P. et al. A superantigen-antibody fusion protein for T-cell immunotherapy of human B-lineage malignancies. Blood. 1997;89(6):2089–97. [PubMed: 9058731]
309.
Hansson J, Ohlsson L, Persson R. et al. Genetically engineered superantigens as tolerable antitumor agents. Proc Natl Acad Sci USA. 1997;94(6):2489–94. [PMC free article: PMC20115] [PubMed: 9122222]
310.
Litton MJ, Dohlsten M, Hansson J. et al. Tumor therapy with an antibody-targeted superantigen generates a dichotomy between local and systemic immune responses. Am J Pathol. 1997;150(5):1607–18. [PMC free article: PMC1858206] [PubMed: 9137087]
311.
Jackson AM, Alexandroff AB, McIntyre M. et al. Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy. J Clin Path. 1994;47:309–312. [PMC free article: PMC501932] [PubMed: 7913098]
312.
Jackson AM, Alexandroff AB, Kelly RW. et al. Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guerin (BCG) immunotherapy. Clin Exp Immunol. 1995a;99(3):369–75. [PMC free article: PMC1534215] [PubMed: 7882559]
313.
Sung PK-L, Saldivar E, Phillips L. Interleukin -1β induces differential adhesiveness on human endothelial cell surfaces. Biochem Biophys Res Com. 1994;202:866–872. [PubMed: 7519425]
314.
Schumann RR, Pfeil D, Lamping N. et al. Lipopolysaccharides induces the rapid tyrosine phosphorylation of the mitogen-activated protein kinases erk-1 and p38 in cultured human vascular endothelial cells requiring the presence of soluble CD14. Blood. 1996;87:2805–2824. [PubMed: 8639898]
315.
Puri RK, Rosenberg SA. Combined effects of interferon alpha and interleukin 2 on the induction of a vascular leak syndrome in mice. Cancer Immunol Immunother. 1989;28(4):267–74. [PubMed: 2495179]
316.
Economou JS, Hoban M, Lee JD. et al. Production of tumor necrosis factor alpha and interferon gamma in interleukin-2-treated melanoma patients: Correlation with clinical toxicity. Cancer Immunol Immunother. 1991;34(1):49–52. [PubMed: 1760811]
317.
Edwards MJ, Abney DL, Heniford BT. et al. Passive immunization against tumor necrosis factor inhibits interleukin-2-induced microvascular alterations and reduces toxicity. Surgery. 1992;112(2):480–6. [PubMed: 1641784]
318.
Tutor JD, Mason CM, Dobard E. et al. Loss of compartmentalization of alveolar tumor necrosis factor after lung injury. Am J Respir Crit Care Med. 1994;149(5):1107–11. [PubMed: 8173748]
319.
Carswell EA, Old LJ, Kassel RJ. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci. 1975;72:3666–3670. [PMC free article: PMC433057] [PubMed: 1103152]
320.
Green S, Dobrjansky A, Chiasson M. et al. Corynebacterium parvum as the priming agent in the production of tumor necrosis factor in the mouse. J Natl Cancer Inst. 1977;59:1519. [PubMed: 333124]
321.
In: HommaJY Kanegasaki S Luederitz O Shiba T WestphalO eds. Bacterial endotoxin: Chemical, biological and clinical aspects. Weinheim, Basel: Verlag Chemie. 1984
322.
Nowotny A, Behling UH, Chang HL. Relation of structure to function in bacterial endotoxins. III. Biological activities in a polysaccharide-rich fraction. J Immunol. 1975;115(1):199–203. [PubMed: 239055]
323.
Mikolasek J. Direct evidence for rejection of tumour allografts in Str. pyogenes toxins-treated mice correlated with antistreptolysine O level in serum. Neoplasma. 1972;19(5):507–18. [PubMed: 4118595]
324.
Nativ O, Medalia O, Mor Y. et al. Treatment of experimental mouse bladder tumour by LPS-induced epithelial cell shedding. Br J Cancer. 1996;74(4):603–5. [PMC free article: PMC2074659] [PubMed: 8761377]
325.
Behling UH, Nowotny A. Immune adjuvancy of lipopolysaccharide and a nontoxic hydrolytic product demonstrating oscillating effects with time. J Immunol. 1977;118(5):1905–7. [PubMed: 858920]
326.
Grohsman J, Nowotny A. The immune recognition of TA3 tumors, its facilitation by endotoxin, and abrogation by ascites fluid. J Immunol. 1972;109(5):1090–5. [PubMed: 4562425]
327.
Fidler IJ, Gersten DM, Riggs CW. Relationship of host immune status to tumor cell arrest, distribution, and survival in experimental metastasis. Cancer (Phila) 1977;40:46–55. [PubMed: 880570]
328.
Ray PK. Immunosuppressor control as a modality of cancer treatment: Effect of plasma adsorption with Staphylococcus aureus protein A. Contemp Top Immunobiol. 1985;15:147–211. [PubMed: 3161699]
329.
Chasseing NA, Eugui EM, Borda ES. et al. Effects of sarcoma 180 growth on interleukin-1 and circulating immune complexes. Cancer Invest. 1994;12(4):390–4. [PubMed: 8032958]
330.
Das TK, Aziz M, Rattan A. et al. Prognostic significance of circulating immune complexes in malignant tumours of head and neck. J Indian Med Assoc. 1995;93(1):3–7. [PubMed: 7759908]
331.
von Mensdorff-Pouilly S, Gourevitch MM, Kenemans P. et al. Humoral immune response to polymorphic epithelial mucin (MUC-1) in patients with benign and malignant breast tumours. Eur J Cancer. 1996;32A(8):1325–31. [PubMed: 8869094]
332.
Zhang K, Sikut R, Hansson GC. A MUC1 mucin secreted from a colon carcinoma cell line inhibits target cell lysis by natural killer cells. Cell Immunol. 1997;176(2):158–65. [PubMed: 9073389]
333.
Jager E, Ringhoffer M, Karbach J. et al. Inverse relationship of melanocyte differentiation antigen expression in melanoma tissues and CD8+ cytotoxic-T-cell responses: Evidence for immunoselection of antigen-loss variants in vivo. Int J Cancer. 1996;66(4):470–6. [PubMed: 8635862]
334.
Gonzalez FM, Vargas JA, Gea-Banacloche JC. et al. Study of spontaneous cytotoxic activity in laryngeal carcinoma: Prognostic value. Acta Otorrinolaringol Esp. 1995;46(6):431–6. [PubMed: 8554823]
335.
Gupta SC, Agarwal J, Singh PA. et al. A sequential study of humoral factors in ovarian neoplasms. Indian J Pathol Microbiol. 1994;37(3):319–26. [PubMed: 7814065]
336.
Kuhl JS, Krajewski S, Duran GE. et al. Spontaneous overexpression of the long form of the Bcl-X protein in a highly resistant P388 leukaemia. Br J Cancer. 1997;75(2):268–74. [PMC free article: PMC2063280] [PubMed: 9010037]
337.
Yang X, Page M. P-glycoprotein expression in ovarian cancer cell line following treatment with cisplatin. Oncol Res. 1995;7(12):619–24. [PubMed: 8704279]
338.
Hamre MR, Clark SH, Mirkin BL. Resistance to inhibitors of S-adenosyl-L-homocysteine hydrolase in C1300 murine neuroblastoma tumor cells is associated with increased methionine adenosyltransferase activity. Oncol Res. 1995;7(10-11):487–92. [PubMed: 8866660]
339.
Binaschi M, Supino R, Gambetta RA. et al. MRP gene overexpression in a human doxorubicin-resistant SCLC cell line: Alterations in cellular pharmacokinetics and in pattern of cross-resistance. Int J Cancer. 1995;62(1):84–9. [PubMed: 7601572]
340.
Graham CH, Kobayashi H, Stankiewicz KS. et al. Rapid acquisition of multicellular drug resistance after a single exposure of mammary tumor cells to antitumor alkylating agents (see comments) J Natl Cancer Inst. 1994;86(13):975–82. [PubMed: 8007019]
341.
Shoulders HS. Observations on the results of combined fever and x-ray therapy on the treatment of malignancy. Southern Med J. 1942;35:966–970.
342.
Zweifach BW, Kivy-Rosenberg E, Nagler AL. Resistance to whole body x-irradiation in rats made tolerant to bacterial endotoxins. Am J Physiol. 1959;197:1364–1370. [PubMed: 13847963]
343.
Donaldson SS, Cooper Jr RA, Fletcher WS. Effect of Coley's Toxins and irradiation on the A. melanoma # 3 tumor in the golden hamster. Cancer. 1968;21:805–11. [PubMed: 4870091]
344.
Chandler JJ, Stark DB, Allen CV. et al. Treatment of cancer by bacterial toxins. Am Surg. 1965;31:443–449. [PubMed: 14321153]
345.
Nowotny A, Behling UH. Studies of host defenses enhanced by Endotoxins: A brief review. Klin Wochenschr. 1987;14:735–739. [PubMed: 6750227]
346.
Tang ZY, Zhou HY, Zhao G. et al. Preliminary results of mixed bacterial vaccine as adjuvant treatment of hepatocellular carcinoma. Med Oncol Tumour Pharmacoth. 1991;8:23–29. [PubMed: 1645825]
347.
Morales A. From the 19th to the 21st centuries: BCG in the treatment of superficial bladder cancer. Eur Urol. 1992a;21(Suppl 2):2–6. [PubMed: 1396943]
348.
Hellstrom I, Hellstrom KE, Siegall CB. et al. Immunoconjugates and immunotoxins for therapy of carcinomas. Adv Pharmacol. 1995;33:349–88. [PubMed: 7495675]
349.
Clark JI, Weiner LM. Biologic treatment of human cancer. Curr Probl Cancer. 1995;19(4):185–262. [PubMed: 7489640]
350.
Vitetta ES, Thorpe PE, Uhr JW. Immunotoxins: Magic bullets or misguided missiles? Trends Pharmacol Sci. 1993;14(5):148–54. [PubMed: 8212309]
351.
Cobb PW, LeMaistre CF. Therapeutic use of immunotoxins. Semin Hematol. 1995;29(3 Suppl 2):6–13. [PubMed: 1509295]
352.
Subira ML, Brugarolas A. Biotherapy of cancer. Rev Clin Esp. 1992;191(2):102–8. [PubMed: 1380172]
353.
Grossbard ML, Fidias P. Prospects for immunotoxin therapy of nonHodgkin's lymphoma. Clin Immunol Immunopathol. 1995;76(2):107–14. [PubMed: 7614729]
354.
Ozaki S, Okazaki T, Nakao K. Biological response modifiers (BRM) as antigens. III. T cell lines specific for BRM kill tumor cells in a BRM-specific manner. Cancer Immunol Immunother. 1995;40(4):219–27. [PubMed: 7538449]
355.
Old LJ, Clarke DA, Benacerraf B. Effect of Bacillus Calmette-Gúerin on transplanted tumors in the mouse. Nature. 1959;184:191–191. [PubMed: 14428599]
356.
Howard JG, Biozzi G, Halpern BN. et al. The effect of mycobacterium tuberculosis (BCG) infection on the resistance of mice to bacterial endotoxin and salmonella enteritidis infection. Br J Exp Pathol. 1959;40:281–290. [PMC free article: PMC2083463] [PubMed: 13662534]
357.
Ruddle NH, Waksman BH. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. J Exp Med. 1968;128:1267–1279. [PMC free article: PMC2138574] [PubMed: 5693925]
358.
Mastrangelo MJ, Kim YH, Bornstein RS. et al. Clinical and histologic correlation of melanoma regression after intralesional BCG therapy: A case report. J Natl Cancer Inst. 1974;52(1):19–24. [PubMed: 4590009]
359.
Hakim AA. Cyclic adenosine-3',5'-monophosphate in cellular immunity. Naturwissenschaften. 1974;61(5):222–3. [PubMed: 4367414]
360.
Hakim AA, Grand NG. Mechanism of action of BCG vaccine on neoplastic proliferation and host immune responses. J Pharm Sci. 1976;65(3):339–43. [PubMed: 1263078]
361.
Vosika GJ. Clinical Immunotherapy trials of bacterial components derived from Mycobacteria and Nocardia. Review Article. J Biol Response Mod. 1983;2:321–342. [PubMed: 6358421]
362.
Morales A, Nickel JC. Immunotherapy for superficial bladder cancer. A developmental and clinical overview. Urol Clin North Am. 1992b;19:549–556. [PubMed: 1378982]
363.
Jurincic-Winkler C, Metz KA, Beuth J. et al. Effect of keyhole limpet hemocyanin (KLH) and bacillus Calmette-Guerin (BCG) instillation on carcinoma in situ of the urinary bladder. Anticancer Res. 1995;15(6B):2771–6. [PubMed: 8669862]
364.
Comeri GC, Belvisi P, Conti G. et al. Role of BCG in T1G3 bladder transitional cell carcinoma (TCC): Our experience. Arch Ital Urol Androl. 1996;68(1):55–9. [PubMed: 8664924]
365.
Jackson AM, Alexandrov AB, Prescott S. et al. Production of urinary tumour necrosis factors and soluble tumour necrosis factor receptors in bladder cancer patients after bacillus Calmette-Guerin immunotherapy. Cancer Immunol Immunother. 1995b;40(2):119–24. [PubMed: 7882382]
366.
Zhang Y, Broser M, Cohen H. et al. Enhanced interleukin-8 release and gene expression in macrophages after exposure to Mycobacterium tuberculosis and its components. J Clin Invest. 1995;95(2):586–92. [PMC free article: PMC295520] [PubMed: 7860742]
367.
Roszkowski W, Roszkowski K, Ko HL. et al. Immunomodulation by propionibacteria. Zentralbl Bakteriol. 1990;274(3):289–98. [PubMed: 2090145]
368.
Turler A, Walter M, Schmitz-Rixen T. Current treatment strategy in malignant pleural effusion. Wien Klin Wochenschr. 1996;108(9):255–61. [PubMed: 8686317]
369.
Isenberg J, Stoffel B, Wolters U. et al. Immunostimulation by propionibacteria-effects on immune status and antineoplastic treatment. Anticancer Res. 1995;15(5B):2363–8. [PubMed: 8572653]
370.
Chen MF, Suzuki H, Yano S. Induction of murine lymphokine-activated killer-like cells by Corynebacterium parvum (C. parvum) in vitro: Lysis of tumor cells and macrophages by C. parvum-induced killer cells. Anticancer Res. 1992;12(2):451–6. [PubMed: 1580562]
371.
Bursuker I, Petty BA, Neddermann KM. et al. Immunomodulation in an apparently nonimmunogenic murine tumor. Int J Cancer. 1991;49(3):414–420. [PubMed: 1833344]
372.
Keller R, Keist R, Leist TP. et al. Resistance to a nonimmunogenic tumor, induced by Corynebacterium parvum or Listeria monocytogenes, is abrogated by anti-interferon gamma. Int J Cancer. 1990a;46(4):687–90. [PubMed: 2120139]
373.
Karashima A, Taniguchi K, Yoshikai Y. et al. Alteration in natural defense activity against NK-susceptible B16 melanoma cells after treatment with Corynebacterium parvum. Immunobiology. 1991;182(5):414–24. [PubMed: 1916884]
374.
Ko HL, Winkler C, Beuth J. et al. Influence of propionibacterium avidum KP-40 on the proliferation, maturation, emigration and activity of thymocytes and monocytes. J Med Microbiol Virol Parasitol Infect Dis. 1995;282(1):86–91. [PubMed: 7734834]
375.
Pulverer G, Buss G, Ko HL. et al. Propionibacterium acnes-metabolites inhibit experimental lung metastasis of murine sarcoma L-1 in BALB/c-mice. Int J Med Microbiol Virol Parasitol Infect Dis. 1992;277(3):364–70. [PubMed: 1486236]
376.
Pulverer G, Ko HL, Tunggal L. et al. Combined immunomodulation (Propionibacterium avidum KP-40) and lectin blocking (D-galactose) prevents liver tumor colonization in BALB/c-mice. Int J Med Microbiol Virol Parasitol Infect Dis. 1994;281(4):491–4. [PubMed: 7727896]
377.
Lipton A, Harvey HA, Balch CM. et al. Corynebacterium parvum versus bacille Calmette-Guerin adjuvant immunotherapy of stage II malignant melanoma (see comments) J Clin Oncol. 1991;9(7):1151–6. [PubMed: 2045856]
378.
Foresti V. Intrapleural Corynebacterium parvum for recurrent malignant pleural effusions. Respiration. 1995;62(1):21–6. [PubMed: 7716350]
379.
Isenberg J, Ko H, Pulverer G. et al. Preoperative immunostimulation by Propionibacterium granulosum KP-45 in colorectal cancer. Anticancer Res. 1994;14(3B):1399–404. [PubMed: 8067712]
380.
Raica M. Effects of intravesical Corynebacterium parvum on recurrences of superficial tumors of the urinary bladder. Anticancer Drugs. 1992;3(1):39–42. [PubMed: 1623214]
381.
Oettgen HF, Old LJ, Hoffmann MK. et al. Antitumor effects of Endotoxin: Possible mechanism of action. In: Homma Y, Kanegasaki S, Luederitz O, Shiba T, Westphal O (Hrsg.), eds. Bacterial Endotoxin. Weinheim, S: Verlag Chemie. 1984:205–221.
382.
Galanos C, Luederitz O, Westphal O. Preparation and properties of a standardized lipopolysaccharide from Salmonella abortus equi (Novo-Pyrexal) Zbl Bakt Hyg, 1. Abt Org A. 1979b;243:226–244. [PubMed: 452765]
383.
Galanos C, Lehmann V, Luderitz O. et al. Endotoxic properties of chemically synthesized lipid A part structures. Comparison of synthetic lipid A precursor and synthetic analogues with biosynthetic lipid A precursor and free lipid A. Eur J Biochem. 1984;140:221–227. [PubMed: 6714230]
384.
Yamamoto A, Nagamuta M, Usami H. et al. Release of tumor necrosis factor (TNF) into mouse peritoneal fluids by OK-432, a streptococcal preparation. Immunparmacol. 1986;11:79–86. [PubMed: 3710767]
385.
Furukawa H, Hiratsuka M, Iwanaga T. et al. Adjuvant chemotherapy for advanced gastric cancer. Nippon Geka Gakkai Zasshi. 1996;97(4):312–6. [PubMed: 8692150]
386.
Tsukuda M. Immunotherapy of patients with head and neck carcinomas. Gan To Kagaku Ryoho. 1996;23(3):283–90. [PubMed: 8712820]
387.
Kim JP, Kim YW, Yang HK. et al. Significant prognostic factors by multivariate analysis of 3926 gastric cancer patients World J Surg 199418(6):872–7. (discussion 877-8) [PubMed: 7846911]
388.
Kim JP, Kwon OJ, Oh ST. et al. Results of surgery on 6589 gastric cancer patients and immunochemosurgery as the best treatment of advanced gastric cancer Ann Surg 1992216(3):269–78. (discussion 278-9) [PMC free article: PMC1242606] [PubMed: 1417176]
389.
Abel U. Gutachten zum Stand des Nachweises der Wirksamkeit der aktiven Fiebertherapie bei malignen Erkrankungen. In: Buehring M, Kemper FH, Matthiessen PF, eds. Naturheilverfahren und unkonventionelle medizinische Richtungen. Springer: LoseblattSysteme. 1996:1–17.
390.
Torisu M, Uchiyama A, Goya T. et al. Eighteen-year experience of cancer immunotherapies— evaluation of their therapeutic benefits and future. Nippon Geka Gakkai Zasshi. 1991;92(9):1212–6. [PubMed: 1944189]
391.
Clark JW. Biological response modifiers. Cancer Chemother Biol Response Modif. 1991;12:193–212. [PubMed: 1931443]
392.
Juranic Z, Tomin R, Spuzic I. et al. The cytotoxic action of OK-432 from Streptococcus pyogenes. Med Hypotheses. 1990;33(2):73–4. [PubMed: 2147977]
393.
Cervical Cancer Immunotherapy StudyGroup. Immunotherapy using the streptococcal preparation OK-432 for the treatment of uterine cervical cancer. Cancer. 1987;60(10):2394–402. [PubMed: 2889522]
394.
Kikkawa F, Kawai M, Oguchi H. et al. Randomised study of immunotherapy with OK-432 in uterine cervical carcinoma. Eur J Cancer. 1993;29A(11):1542–6. [PubMed: 8217359]
395.
Okamura K, Hamazaki Y, Yajima A. et al. Adjuvant immunotherapy: Two randomized controlled studies of patients with cervical cancer. Biomed Pharmacother. 1989;43(3):177–81. [PubMed: 2528386]
396.
Fujita K. The role of adjunctive immunotherapy in superficial bladder cancer. Cancer. 1987;59(12):2027–30. [PubMed: 3567865]
397.
Marumo K. Immunotherapy and urological malignancy. Nippon Hinyokika Gakkai Zasshi. 1991;82(3):361–71. [PubMed: 1712869]
398.
Hanaue H, Kim DY, Machimura T. et al. Hemolytic streptococcus preparation OK-432; beneficial adjuvant therapy in recurrent gastric carcinoma. Tokai J Exp Clin Med. 1987a;12(4):209–14. [PubMed: 3503390]
399.
Hanaue H, Kim DY, Kubota M. et al. Effects of biological response modifier on thoracic duct lymphocytes in recurrent gastric cancer. Evaluation of OK-432, a hemolytic streptococcus preparation. Tokai J Exp Clin Med. 1987b;12(2):97–102. [PubMed: 3502432]
400.
Nakazawa S, Yoshino J, Okamura S. et al. Clinical efficacy of endoscopic injections of OK-432 in the treatment of gastric cancer. Scand J Gastroenterol. 1988;23(5):539–45. [PubMed: 3041555]
401.
Hattori T, Nakajima T, Nakazato H. et al. Postoperative adjuvant immunochemotherapy with mitomycin C, tegafur, PSK and/or OK-432 for gastric cancer, with special reference to the change in stimulation index after gastrectomy. Jpn J Surg. 1990;20(2):127–36. [PubMed: 2111414]
402.
Kyoto Research Group for Digestive Organ Surgery. A comprehensive multi-institutional study on postoperative adjuvant immunotherapy with oral streptococcal preparation OK-432 for patients after gastric cancer surgery. Ann Surg. 1992;216(1):44–54. [PMC free article: PMC1242545] [PubMed: 1632701]
403.
Maehara Y, Okuyama T, Kakeji Y. et al. Postoperative immunochemotherapy including streptococcal lysate OK-432 is effective for patients with gastric cancer and serosal invasion. Am J Surg. 1994;168(1):36–40. [PubMed: 8024097]
404.
Sugimachi K, Maehara Y, Akazawa K. et al. Postoperative chemotherapy including intraperitoneal and intradermal administration of the streptococcal preparation OK-432 for patients with gastric cancer and peritoneal dissemination: A prospective randomized study. Cancer Chemother Pharmacol. 1994;33(5):366–70. [PubMed: 8306409]
405.
Fukushima M. Adjuvant therapy of gastric cancer: The Japanese experience. Semin Oncol. 1996;23(3):369–78. [PubMed: 8658221]
406.
Watanabe Y, Iwa T. Clinical value of immunotherapy for lung cancer by the streptococcal preparation OK-432. Cancer. 1984;53(2):248–53. [PubMed: 6690008]
407.
Watanabe Y, Iwa T. Clinical value of immunotherapy with the streptococcal preparation OK-432 in nonsmall cell lung cancer. J Biol Response Mod. 1987;6(2):169–80. [PubMed: 3585412]
408.
Watanabe Y, Shimizu J, Oda M. et al. Clinical significance of immunotherapy for lung cancer— present and future. Nippon Geka Gakkai Zasshi. 1991;92(9):1217–20. [PubMed: 1944190]
409.
Luh KT, Yang PC, Kuo SH. et al. Comparison of OK-432 and mitomycin C pleurodesis for malignant pleural effusion caused by lung cancer. A randomized trial. Cancer. 1992;69(3):674–9. [PubMed: 1309678]
410.
Lee YC, Luh SP, Wu RM. et al. Adjuvant immunotherapy with intrapleural Streptococcus pyogenes (OK-432) in lung cancer patients after resection. Cancer Immunol Immunother. 1994;39(4):269–74. [PubMed: 7954529]
411.
Sakata Y, Komatsu Y, Takagi S. et al. Randomized controlled study of mitomycin C/carboquone/ 5-fluorouracil/OK-432 (MQ-F-OK) therapy and mitomycin C/5-fluorouracil/doxorubicin (FAM) therapy against advanced liver cancer. Cancer Chemother Pharmacol. 1989;23(Suppl):S9–12. [PubMed: 2647315]
412.
Suto T, Fukuda S, Moriya N. et al. Clinical study of biological response modifiers as maintenance therapy for hepatocellular carcinoma. Cancer Chemother Pharmacol. 1994;33(Suppl):S145–8. [PubMed: 8137477]
413.
Shibata S, Mori K, Moriyama T. et al. Randomized controlled study of the effect of adjuvant immunotherapy with Picibanil on 51 malignant gliomas. Surg Neurol. 1987;27(3):259–63. [PubMed: 3544286]
414.
Nakano A, Kato M, Watanabe T. et al. OK-432 chemical pleurodesis for the treatment of persistent chylothorax. Hepatogastroenterology. 1994;41(6):568–70. [PubMed: 7721246]
415.
Nio Y, Shiraishi T, Tsuchitani T. et al. Antitumor activity of orally administered streptococcal preparation, OK-432 on murine solid tumors and its absorption from the gut. In Vivo. 1989;3(5):307–13. [PubMed: 2519870]
416.
Noda T, Asano M, Yoshie O. et al. Interferon-gamma induction in human peripheral blood mononuclear cells by OK-432, a killed preparation of Streptococcus pyogenes. Microbiol Immunol. 1986;30(1):81–8. [PubMed: 3084924]
417.
Sekimoto M, Kokunai I, Shimano T. et al. Production of tumor necrosis factor (TNF) by monocytes from cancer patients and healthy subjects induced by OK-432 in vitro, and its augmentation by human interferon gamma. J Clin Lab Immunol. 1988;27(3):115–20. [PubMed: 3150012]
418.
Tabuchi K, Shiraishi T, Toda K. et al. Expression of apoptosis-related gene products in human brain tumors and apoptosis-inducing therapy. Nippon Rinsho. 1996;54(7):1922–8. [PubMed: 8741689]
419.
Hoshino T, Uchida A. Effective mechanisms of BRM, with special reference to induction of autologous tumor cell-killing (ATK) activity by OK-432. Gan To Kagaku Ryoho. 1986;13(4 Pt 2):1277–84. [PubMed: 3488024]
420.
Uchida A, Micksche M, Hoshino T. Intrapleural administration of OK432 in cancer patients: Augmentation of autologous tumor killing activity of tumor-associated large granular lymphocytes. Cancer Immunol Immunother. 1984;18(1):5–12. [PubMed: 6333269]
421.
Uchida A, Hoshino T. Reduction of suppressor cells in cancer patients treated with OK-432 immunotherapy. Int J Cancer. 1980;26(4):401–4. [PubMed: 6454666]
422.
Lewis JG, Pizzo SV, Adams DO. Simple and sensitive assay employing stable reagents for quantification of plasminogen activator. Am J Clin Pathol. 1981;76(4):403–9. [PubMed: 7197461]
423.
Goldberg DM. Enzymes as agents for the treatment of disease. Clin Chim Acta. 1992;206(1-2):45–76. [PubMed: 1572079]
424.
Taussig SJ, Szekerezes J, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas Comosus) and its clinical application. An update J Ethnopharmacol. 1988;22:191–203. [PubMed: 3287010]
425.
In: GardnerMLG Steffen C-J eds. Absorption of orally administered enzymes. Berlin, Heidelberg, New York: Springer. 1995:ISBN 3–540-58747-0.
426.
O'Meara RA, Jackson RD. Cytological observations on carcinoma. Ir J Med Sci. 1958;6:327–328. [PubMed: 13562961]
427.
Musser DA, Wagner JM, Weber FJ. et al. The binding of tumor localizing porphyrins to a fibrin matrix and their effects following photoirradiation. Res Commun Chem Pathol Pharmacol. 1980;28(3):505–25. [PubMed: 7403664]
428.
Smith CE. Microbial enzymes in clinical investigation, diagnosis and therapy. J Gen Microbiol. 1971;65(3):x. [PubMed: 5556685]
429.
Lehmann PV. Immunomodulation by proteolytic enzymes (editorial) Nephrol Dial Transplant. 1996;11(6):952–5. [PubMed: 8671947]
430.
Caspary WF. Physiology and pathophysiology of intestinal absorption. Am J Clin Nutr. 1992;55:299S–308S. [PubMed: 1728844]
431.
Lake-Bakaar G, Rubio CE, McKavanagh S. et al. Metabolism of 125I-labelled trypsin in man: Evidence for recirculation. Gut. 1980;21:580. [PMC free article: PMC1419902] [PubMed: 7429320]
432.
Steffen C, Menzel J, Smolen J. Intestinal resorption with 3H labeled enzyme mixture (wobenzyme) Acta Med Austriaca. 1979a;6(1):13–8. [PubMed: 506656]
433.
Mikolasek J. Inhibitory effect of varidase on in vitro tumoricidal activity of human serum. Neoplasma. 1974;21(4):483–5. [PubMed: 4431545]
434.
Holland PD, Browne O, Thornes RD. The enhancing influence of proteolysis on E rosette forming lymphocytes (T cells) in vivo and in vitro. Br J Cancer. 1975;31(2):164–9. [PMC free article: PMC2009370] [PubMed: 1080669]
435.
Thornes RD. Unblocking or activation of the cellular immune mechanism by induced proteolysis in patients with cancer. Lancet. 1974;2(877):382–4. [PubMed: 4137344]
436.
Tomar RH, John PA, Lapham C. Activation of natural killer cells in vitro by a product of beta-hemolytic streptococci. Cell Immunol. 1982;69(2):388–94. [PubMed: 6179637]
437.
Klein E, Di Renzo L, Yefenof E. Contribution of CR3, CD11b/CD18 to cytolysis by human NK cells. Mol Immunol. 1990;27(12):1343–7. [PubMed: 1980339]
438.
Hale LP, Haynes BF. Bromelain treatment of human T cells removes CD44, CD45RA, E2/MIC2, CD6, CD7, CD8, and Leu 8/LAM1 surface molecules and markedly enhances CD2-mediated T cell activation. J Immunol. 1992;149:3809–3816. [PubMed: 1281188]
439.
Munzig E, Eckert K, Harrach T. et al. Bromelain protease F9 reduces the CD44 mediated adhesion of human peripheral blood lymphocytes to human umbilical vein endothelial cells. FEBS Letters. 1994;351:215–218. [PubMed: 7521849]
440.
Kleef R, Delohery TM, Bovberg DH. Selective modulation of cell adhesion molecules on lymphocyres by bromelain protease 5. Pathobiology. 1996;63(6):339–46. [PubMed: 9159029]
441.
Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of bromelain with or without its proteolytic and anticoagulant activity. J Cancer Res Clin Oncol. 1988a;114:507–508. [PubMed: 3182910]
442.
Batkin S, Taussig SJ, Szekerezes J. Modulation of Pulmonary metastasis (Lewis Lung Carcinoma) by bromelain, an extract of the pineapple stem (Ananas Comosus) Cancer Invest. 1988b;6:241–242. [PubMed: 3378194]
443.
Rokitansky OV, Stauder G, Streichhan P. Enzymtherapie als prae- und postoperatives Adjuvans bei der Brustkrebsbehandlung. Deutsch Zschr Onkol / J Oncol. 1993;25:130–136.
444.
Uster S, Rimpler M. Influence of proteolytic treatment on the lectin-binding capacity of tumor cells. Forsch Komplementärmed. 1995;2:190–195.
445.
Timonen T, Gahmberg CG, Patarrayo M. Participation of CD11a-c/CD18, CD2 and RGD-binding receptors in endogenous and interleukin-2-stimulated NK activity of CD3-negative large granular lymphocytes. Int J Cancer. 1990;46:1035–1040. [PubMed: 1979068]
446.
Timonen T, Jääskeläinen J, Mäenpää A. et al. Growth requirements, binding and migration of human natural killer cells. Immunol Series. 1994;61:63–72. [PubMed: 8011757]
447.
Robertson MJ, Caligiuri MA, Manley TJ. et al. Human natural killer cell adhesion molecules - Differential expression after activation and participation in cytolysis. J Immunol. 1990;145:3194–3201. [PubMed: 1700001]
448.
Werfel T, Witter W, Gotze O. CD11b and CD11c antigens are rapidly increased on human natural killer cells upon activation. J Immunol. 1991;147(7):2423–7. [PubMed: 1680915]
449.
Ferrini S, Sforzini S, Cambiaggi A. et al. The LFA-1/ICAM cell adhesion pathway is involved in tumor-cell lysis mediated by bispecific monoclonal-antibody-targeted T lymphocytes. Int J Cancer. 1994;56(6):846–52. [PubMed: 7907079]
450.
Liu RH, Hotchkiss JH. Potential genotoxicity of chronically elevated nitric oxide: A review. Mutat Res. 1995;339(2):73–89. [PubMed: 7791803]
451.
Morisaki T, Torisu M. Enhanced adherence activity of OK-432-induced peritoneal neutrophils to tumor cells correlates to their increased expression of CD11b/CD18. Clin Immunol Immunopathol. 1991;59:474–486. [PubMed: 1674240]
452.
Stamenkovic I, Amiot M, Pesando JM. et al. A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell. 1989;46:1057–1062. [PubMed: 2466575]
453.
Gunthert U, Hofmann M, Rudy W. et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991;65:13–24. [PubMed: 1707342]
454.
Brown DC, Purushotham AD, George WD. Inhibition of pulmonary tumor seeding by antiplatelet and fibrinolytic therapy in an animal experimental model. J Surg Oncol. 1994;55(3):154–9. [PubMed: 8176924]
455.
Purushotham AD, Brown DC, McCulloch P. et al. Streptokinase inhibits pulmonary tumor seeding in an animal experimental model. J Surg Oncol. 1994;57(1):3–7. [PubMed: 8065148]
456.
Emeis JJ, Brouwer A, Barelds RJ. et al. On the fibrinolytic system in aged rats, and its reactivity to endotoxin and cytokines. Thromb Haemost. 1992;67(6):697–701. [PubMed: 1509412]
457.
Murthy MS, Summaria LJ, Miller RJ. et al. Inhibition of tumor implantation at sites of trauma by plasminogen activators. Cancer. 1991;68(8):1724–30. [PubMed: 1913515]
458.
Maruyama H, Nakajima J, Yamamoto I. A study on the anticoagulant and fibrinolytic activities of a crude fucoidan from the edible brown seaweed Laminaria religiosa, with special reference to its inhibitory effect on the growth of sarcoma-180 ascites cells subcutaneously implanted into mice. Kitasato Arch Exp Med. 1987;60(3):105–21. [PubMed: 2455094]
459.
Thornes RD. Adjuvant therapy of cancer via the cellular immune mechanism or fibrin by induced fibrinolysis and oral anticoagulants. Cancer. 1975;35(1):91–7. [PubMed: 1172718]
460.
Szreder W. Effect of artificial abacterial erysipelas and prolonged sterile abscess on neoplastic diseases in man and animals. Przegl Lek. 1968a;24(4):425–8. [PubMed: 5671740]
461.
Szreder W. Effect of artificially induced abacterial erysipelas and of chronic aseptic abscess on human and experimental neoplasms. Pol Med J. 1968b;7(5):1122–9. [PubMed: 5720424]
462.
Bykowska K, Janczarski M, Wegrzynowicz Z. et al. Plasma fibronectin in acute leukaemias and during streptokinase therapy. Mater Med Pol. 1988;20(2):114–8. [PubMed: 3221728]
463.
DeWys WD, Kwaan HC, Bathina S. Effect of defibrination on tumor growth and response to chemotherapy. Cancer Res. 1976;36(10):3584–7. [PubMed: 953985]
464.
Holt JA. Alternative therapy for recurrent Hodgkin's disease. Radiotherapy combined with hyperthermia by electromagnetic radiation to create complete remission in 11 patients without morbidity. Br J Radiol. 1980;53(635):1061–7. [PubMed: 7426932]
465.
Teuscher E, Pester E. A possible explanation of mechanisms inducing inhibition of vascularization of tumours by antifibrinolytic drugs—the influence of migratory behaviour of endothelial cells. Biomed Biochim Acta. 1984;43(4):447–56. [PubMed: 6207812]
466.
Sugimura M, Tsubakimoto, Kashibayashi Y. et al. Effect of human serum plus streptokinase on spontaneous pulmonary metastases of Vx2 carcinomas transplanted in the maxillary sinus of the rabbit. Int J Oral Surg. 1975;4(3):112–20. [PubMed: 808504]
467.
McKinna JA, Rowbotham HD. Experimental studies of factors causing blood-borne dissemination in cancer of the colon and rectum. Proc R Soc Med. 1971;64(5):569–70. [PMC free article: PMC1812547] [PubMed: 5576922]
468.
Ciavarella D. The use of protein A columns in the treatment of cancer and allied diseases. Int J Clin Lab Res. 1992;21(3):210–3. [PubMed: 1591370]
469.
Nand S, Molokie R. Therapeutic plasmapheresis and protein A immunoabsorption in malignancy: a brief review. J Clin Apheresis. 1990;5(4):206–12. [PubMed: 2229001]
470.
Dwivedi PD, Verma AS, Ray PK. Induction of immune rejection of tumors by protein A in mice bearing transplantable solid tissue Dalton's lymphoma tumors (published erratum appears in Immunopharmacol Immunotoxicol 1992;14(4):981) Immunopharmacol Immunotoxicol. 1992;14(1-2):105–28. [PubMed: 1597651]
471.
Prasad AK, Singh KP, Saxena AK. et al. Increased macrophage activity in protein A treated tumor regressed animals. Immunopharmacol Immunotoxicol. 1987;9(4):541–61. [PubMed: 3437106]
472.
Ray PK, Mohammed J, Allen P. et al. Effect of frequency of plasma adsorption over protein A-containing Staphylococcus aureus on regression of rat mammary adenocarcinomas: Modification of antitumor immune response and tumor histopathology. J Biol Response Mod. 1984a;3(1):39–59. [PubMed: 6707699]
473.
Ray PK, Idiculla A, Mark R. et al. Extracorporeal immunoadsorption of plasma from a metastatic colon carcinoma patient by protein A-containing nonviable Staphylococcus aureus: clinical, biochemical, serologic, and histologic evaluation of the patient's response. Cancer. 1982;49(9):1800–9. [PubMed: 7074582]
474.
Bandyopadhyay SK, Ray PK. Introduction of bacterial components in postadsorbed plasma during adsorption with Staphylococcus aureus. Cancer. 1985;56(2):266–72. [PubMed: 4005799]
475.
Ray PK, Bandyopadhyay S, Dohadwala M. et al. Antitumor activity with nontoxic doses of protein A. Cancer Immunol Immunother. 1984b;18(1):29–34. [PubMed: 6567477]
476.
Ray PK, Bandyopadhyay SK. Inhibition of rat mammary tumor growth by purified protein A—a potential anti-tumor agent. Immunol Commun. 1983;12(5):453–64. [PubMed: 6417005]
477.
Shukla Y, Verma AS, Mehrotra NK. et al. Antitumour activity of protein A in a mouse skin model of two-stage carcinogenesis. Cancer Lett. 1996;103(1):41–7. [PubMed: 8616807]
478.
Kumar S, Shukla Y, Prasad AK. et al. Protection against 7,12-dimethylbenzanthracene-induced tumour initiation by protein A in mouse skin (published erratum appears in Cancer Lett 1992 Oct 21;66(3):255) Cancer Lett. 1992;61(2):105–10. [PubMed: 1730133]
479.
Zaidi SI, Singh KP, Raisuddin S. et al. Modulation of primary antibody response by protein A in tumor bearing mice. Immunopharmacol Immunotoxicol. 1995;17(4):759–73. [PubMed: 8537611]
480.
Singh KP, Shau H, Gupta RK. et al. Protein A potentiates lymphokine-activated killer cell induction in normal and melanoma patient lymphocytes. Immunopharmacol Immunotoxicol. 1992a;14(1-2):73–103. [PubMed: 1597662]
481.
Guojun Wu. et al. Intravesical instillation of highly agglutinative staphylococcin for preventing postoperative recurrence of bladder transitional cell carcinoma. Chinese Journal of Clinical Oncology. 2003:P61–63.
482.
Leder L, Llera A, Lavoie PM. et al. A mutational analysis of the binding of staphylococcal enterotoxins B and C3 to the T cell receptor beta chain and major histocompatibility complex class II. J Exp Med. 1998;187(6):823–33. [PMC free article: PMC2212189] [PubMed: 9500785]
483.
Cho-Chung YS, Clair T, Shepeard C. et al. Arrest of hormone-dependent mammary cancer growth in vivo and in vitro by cholera toxin. Cancer Res. 1983;43:1473–1476. [PubMed: 6299521]
484.
Maroun JA, Pross HF, Stewart TH. et al. The effect of specific and nonspecific immunotherapy on natural killer cell activity in patients with nonsmall-cell lung cancer. J Clin Oncol. 1984;2(11):1209–14. [PubMed: 6491701]
485.
Livingston PO. Approaches to augmenting the immunogenicity of melanoma gangliosides: From whole melanoma cells to ganglioside-KLH conjugate vaccines. Immunol Rev. 1995;145:147–66. [PubMed: 7590824]
486.
Kalble T, Otto T. Unconventional therapeutic methods in superficial bladder cancer. Urologe A. 1994;33(6):553–6. [PubMed: 7817456]
487.
Shapiro A, Kadmon D, Catalona WJ. et al. Immunotherapy of superficial bladder cancer. J Urol. 1982;128(5):891–4. [PubMed: 6184490]
488.
Lamm DL, DeHaven JI, Riggs DR. et al. Immunotherapy of murine bladder cancer with keyhole limpet hemocyanin (KLH) J Urol. 1993;149(3):648–52. [PubMed: 8437283]
489.
Schmitz-Drager BJ, Schattka SO, Ebert T. Immunotherapy of superficial bladder cancer. Urologe A. 1993;32(5):374–81. [PubMed: 8212422]
490.
Sargent ER, Williams RD. Immunotherapeutic alternatives in superficial bladder cancer. Interferon, interleukin-2, and keyhole-limpet hemocyanin. Urol Clin North Am. 1992;19(3):581–9. [PubMed: 1378983]
491.
Olsson CA, Chute R, Rao CN. Immunologic reduction of bladder cancer recurrence rate. Trans Am Assoc Genitourin Surg. 1973;65:66–72. [PubMed: 4763514]
492.
Slingluff Jr CL. Tumor antigens and tumor vaccines: Peptides as immunogens. Semin Surg Oncol. 1996;12:446–453. [PubMed: 8914209]
493.
Haas C, Schirrmacher V. Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies. Cancer Immunol Immunother. 1996;43:190–194. [PubMed: 9001573]
494.
Schlom J, Kantor J, Abrams S. et al. Strategies for the development of recombinant vaccines for the immunotherapy of breast cancer. Breast Cancer Res Treat. 1996;38:27–39. [PubMed: 8825120]
495.
Baltz JK. Vaccines in the treatment of cancer. Am J Health Syst Pharm. 1995;52:2574–2585. [PubMed: 8590245]
496.
Shillitoe EJ, Kamath P, Chen Z. Papillomaviruses as targets for cancer gene therapy. Cancer Gene Ther. 1994;1(3):193–204. [PubMed: 7621251]
497.
Hu SL, Hellstrom I, Hellstrom KE. Recent advances in antitumor vaccines. Biotechnology. 1992;20:327–343. [PubMed: 1318138]
498.
Sinkovics JG. Viral oncolysates as human tumor vaccines. Int Rev Immunol. 1991;7(4):259–87. [PubMed: 1663989]
499.
Ioannides CG, Platsoucas CD, O'Brian CA. et al. Viral oncolysates in cancer treatment; immunological mechanisms of action (review) Anticancer Res. 1989;9:535–544. [PubMed: 2669619]
500.
Wheelock EF, Dingle JH. Observations on the repeated administration of viruses to a patient with acute leukemia. New Eng J Med. 1964;27:645–651. [PubMed: 14170843]
501.
Webb HE, Whetherley-Mein G, Gordon Smith CE. Leukemia and neoplastic processes treated with Langat and Kyasanur forest disease viruses: A clinical and labortory study of 28 patients. 1966 . [PMC free article: PMC1843446] [PubMed: 4285281]
502.
Csatary LK. Viruses in the treatment of cancer. The Lancet. 1971;7728:825. [PubMed: 4106650]
503.
Csatary LK, Eckhard S, Bukosza I. et al. Attenuated veterinary viruses vaccine for the treatment of cancer. Cancer Detection Prevention. 1993;17:619–627. [PubMed: 8275514]
504.
Hagmuller E, Beck N, Ockert D. et al. Adjuvant therapy of liver metastases: Active specific immunotherapy. Zentralbl Chir. 1995;120:780–785. [PubMed: 7502592]
505.
Schirrmacher V. Immunity and metastasis: in situ activation of protective T cells by virus modified cancer vaccines. Cancer Surv. 1992;13:129–154. [PubMed: 1423321]
506.
Hodge JW, McLaughlin JP, Abrams SI. et al. Admixture of a recombinant vaccinia virus containing the gene for the costimulatory molecule B7 and a recombinant vaccinia virus containing a tumor-associated antigen gene results in enhanced specific T-cell responses and antitumor immunity. Cancer Res. 1995;55(16):3598–603. [PubMed: 7543017]
507.
Restifo NP, Esquivel F, Asher AL. et al. Defective presentation of endogenous antigens by a murine sarcoma. J Immunol. 1991;147:1453–1459. [PMC free article: PMC1950464] [PubMed: 1907999]
508.
Piontek GE, Taniguchi K, Ljunggren HG. et al. YAC-1 MHC class I variants reveal an association between decreased NK sensitivity and increased H-2 expression after interferon treatment or in vivo passage. J Immunol. 1985;135(6):4281–8. [PubMed: 3905967]
509.
Karre K, Ljunggren HG, Piontek G. et al. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986;319(6055):675–8. [PubMed: 3951539]
510.
Ohlen C, Bejarano MT, Gronberg A. et al. Studies of sublines selected for loss of HLA expression from an EBV-transformed lymphoblastoid cell line. Changes in sensitivity to cytotoxic T cells activated by allostimulation and natural killer cells activated by IFN or IL-2. J Immunol. 1989;142(9):3336–41. [PubMed: 2468716]
511.
Ljunggren HG, Sturmhofel K, Wolpert E. et al. Transfection of beta 2-microglobulin restores IFN-mediated protection from natural killer cell lysis in YAC-1 lymphoma variants. J Immunol. 1990;145(1):380–6. [PubMed: 2113557]
512.
Ljunggren HG, Karre K. In search of the ‘missing self’: MHC molecules and NK cell recognition (see comments) Immunol Today. 1990;11(7):237–44. [PubMed: 2201309]
513.
Yamasaki T, Akiyama Y, Fukuda M. et al. Natural resistance against tumors grafted into the brain in association with histocompatibility-class-I-antigen expression. Int J Cancer. 1996;67(3):365–71. [PubMed: 8707410]
514.
Salcedo M, Diehl AD, Olsson-Alheim MY. et al. Altered expression of Ly49 inhibitory receptors on natural killer cells from MHC class I-deficient mice. J Immunol. 1997;158(7):3174–80. [PubMed: 9120271]
515.
Thomasson DL, Stewart CC. Macrophage tumoricidal activity: Activation and killing kinetics. In: CHIRIGOS MA, Mitchell M, Mastrangelo MJ, Krim M, eds. Mediation of cellular immunity in cancer by Immune modifiers. New York: Raven Press. 1981:1–7.
516.
Henkart P, Millard P, Reynolds C. et al. Cytolytic activity of purified cytoplasmic granule from cytolytic rat LGL tumors. J Exp Med. 1974;160:75. [PMC free article: PMC2187435] [PubMed: 6736872]
517.
Gifford GE, Flick DA. Natural production and release of tumour necrosis factor. Ciba Found Symp. 1987b;131:3–20. [PubMed: 3131075]
518.
Morrison DC, Lei MG, Kirikae T. et al. Endotoxin receptors on mammalian cells. Immunobiology. 1993;187(3-5):212–26. [PubMed: 7687233]
519.
Morrison DC, Ryan JL. Bacterial endotoxins and host immune responses. Adv Immunol. 1979;28:293–450. [PubMed: 396770]
520.
Takayama K, Qureshi N, Beutler B. et al. Diphosphoryl lipid A from Rhodopseudomonas sphaeroides ATCC 17023 blocks induction of cachectin in macrophages by lipopolysaccharide. Infect Immun. 1989;57(4):1336–8. [PMC free article: PMC313273] [PubMed: 2784418]
521.
Qureshi N, Honovich JP, Hara H. et al. Location of fatty acids in lipid A obtained from lipopolysaccharide of Rhodopseudomonas sphaeroides ATCC 17023. J Biol Chem. 1988;263(12):5502–4. [PubMed: 3258599]
522.
Nathan CF. Secretory products of macrophages. J Clin Invest. 1987;79(2):319–26. [PMC free article: PMC424063] [PubMed: 3543052]
523.
Wright SD, Jong MT. Adhesion-promoting receptors on human macrophages recognize Escherichia coli by binding to lipopolysaccharide. J Exp Med. 1986;164(6):1876–88. [PMC free article: PMC2188477] [PubMed: 3537192]
524.
Wright SD, Ramos RA, Tobias PS. et al. CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein (see comments) Science. 1990;249(4975):1431–3. [PubMed: 1698311]
525.
Ulevitch RJ, Mathison JC, Schumann RR. et al. A new model of macrophage stimulation by bacterial lipopolysaccharide. J Trauma. 1990;30(12 Suppl):S189–92. [PubMed: 2254981]
526.
Schumann RR, Leong SR, Flaggs GW. et al. Structure and function of lipopolysaccharide binding protein. Science. 1990;249(4975):1429–31. [PubMed: 2402637]
527.
Schumann RR, Rietschel ET, Loppnow H. The role of CD14 and lipopolysaccharide-binding protein (LPB) in the activation of different cell types by endotoxin. Med Microbiol Immunol. 1994;183:279–297. [PubMed: 7541105]
528.
Schuett C. Role of CD14 in cellular activation by endotoxins. Chemoth J. 1991;4:169–179.
529.
Morrison DC, Kirikae T, Kirikae F. et al. The receptor(s) for endotoxin on mammalian cells. Prog Clin Biol Res. 1994;388:3–15. [PubMed: 7530368]
530.
Hailman E, Lichenstein HS, Wurfel MM. et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med. 1994;179(1):269–77. [PMC free article: PMC2191344] [PubMed: 7505800]
531.
Carrithers SL, Parkinson SJ, Goldstein SD. et al. Escherichia coli heat-stable enterotoxin receptors. A novel marker for colorectal tumors. Dis Colon Rectum. 1996a;39(2):171–81. [PubMed: 8620784]
532.
Carrithers SL, Barber MT, Biswas S. et al. Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues. Proc Natl Acad Sci USA. 1996b;93(25):14827–32. [PMC free article: PMC26221] [PubMed: 8962140]
533.
Carrithers SL, Parkinson SJ, Goldstein S. et al. Escherichia coli heat-stable toxin receptors in human colonic tumors. Gastroenterology. 1994;107(6):1653–61. [PubMed: 7958675]
534.
Ding A, Sanchez E, Tancinco M. et al. Interactions of bacterial lipopolysaccharide with microtubule proteins. J Immunol. 1992;148(9):2853–8. [PubMed: 1573273]
535.
Ding A, Sanchez E, Nathan CF. Taxol shares the ability of bacterial lipopolysaccharide to induce tyrosine phosphorylation of microtubule-associated protein kinase. J Immunol. 1993;151(10):5596–602. [PubMed: 7901279]
536.
Vale RD. Intracellular transport using microtubule-based motors. Annu Rev Cell Biol. 1987;3:347–78. [PubMed: 3120763]
537.
Mitchison TJ, Kirschner MW. Some thoughts on the partitioning of tubulin between monomer and polymer under conditions of dynamic instability. Cell Biophys. 1987;11:35–55. [PubMed: 2450668]
538.
Harlan JM. Leukocyte-endothelial interactions. Blood. 1985;65:513–525. [PubMed: 3918593]
539.
Dustin ML, Rothlein R, Bhan AK. et al. Induction by IL-1 and interferon-gamma: Tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1) J Immunol. 1986;137(1):245–54. [PubMed: 3086451]
540.
Detmar M, Tenorio S, Hettmannsperger U. et al. Cytokine regulation of proliferation and ICAM-1 expression of human dermal microvascular endothelial cells in vitro. J Invest Dermatol. 1992;98(2):147–53. [PubMed: 1346267]
541.
Ishii T, Walsh LJ, Seymour GJ. et al. Modulation of Langerhans cell surface antigen expression by recombinant cytokines. J Oral Pathol Med. 1990;19(8):355–9. [PubMed: 1701195]
542.
Lindsley HB, Smith DD, Cohick CB. et al. Proinflammatory cytokines enhance human synoviocyte expression of functional intercellular adhesion molecule-1 (ICAM-1) Clin Immunol Immunopathol. 1993;68(3):311–20. [PubMed: 8103722]
543.
Wedi B, Elsner J, Czech W. et al. Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on the human mast-cell line (HMC)-1 by inflammatory mediators. Allergy. 1996;51(10):676–84. [PubMed: 8904994]
544.
Czech W, Krutmann J, Budnik A. et al. Induction of intercellular adhesion molecule 1 (ICAM-1) expression in normal human eosinophils by inflammatory cytokines. J Invest Dermatol. 1993;100(4):417–23. [PubMed: 8095960]
545.
Piela-Smith TH, Broketa G, Hand A. et al. Regulation of ICAM-1 expression and function in human dermal fibroblasts by IL-4. J Immunol. 1992;148(5):1375–81. [PubMed: 1347050]
546.
Hogg N, Berlin C. Structure and function of adhesion receptors in leukocyte trafficking. Immunol Today. 1995;16(7):327–30. [PubMed: 7576066]
547.
Chong AFS, Aleksijevic A, Scuderi P. et al. Phenotypical and functional analysis of lymphokine-activated killer (LAK) cell clones. Ability of CD3+, LAK cell clones to produce interferon γ and tumor necrosis factor upon stimulation with tumor targets. Cancer Immunol Immunother. 1989a;29:270–278. [PubMed: 2502310]
548.
Chong AFS, Scuderi P, Grimes WJ. et al. Tumor targets stimulate IL-2 activated killer cells to produce interferon-γ and tumor necrosis factor. J Immunol. 1989b;142:2133–2139. [PubMed: 2493506]
549.
Pober JS, Gimbrone MA, Cotran RS. et al. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma-interferon. J Exp Med. 1983;157:1339–1353. [PMC free article: PMC2186979] [PubMed: 6403654]
550.
Yu CL, Haskard DO, Cavender D. et al. Human gamma-interferon increases the binding of T lymphocytes to endothelial cells. Clin Exp Immunol. 1985;62:554–560. [PMC free article: PMC1577468] [PubMed: 2935340]
551.
Kimber I, Sparshott SM, Bell EB. et al. The effects of interferon on the recirculation of lymphocytes in the rat. Immunology. 1987;60:585–591. [PMC free article: PMC1453287] [PubMed: 3583313]
552.
Schleimer RP, Rutledge BK. Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin-1, endotoxin and tumor-promoting phorbol diesters. J Immunol. 1986;136:649–654. [PubMed: 2416819]
553.
Yu CL, Haskard DO, Cavender D. et al. Effects of bacterial lipopolysaccharide on the binding of lymphocytes to endothelial cell monolayers. J Immunol. 1986;136:569–573. [PubMed: 3484495]
554.
Schlievert PM, Watson DW. Group A streptococcal pyrogenic exotoxin: Pyrogenicity alteration of blood-brain barrier, and separation of sites for pyrogenicity and enhancement of lethal endotoxin shock. Infect Immun. 1978;21:753–763. [PMC free article: PMC422062] [PubMed: 361577]
555.
Schlievert PM, Bettkin KM, Watson DW. Production of pyrogenic exotoxin by groups of Streptococci association with group A. J Infect Dis. 1979;140:676–681. [PubMed: 393776]
556.
Jones M, Hoover R, Meyrick B. Endotoxin enhancement of lymphocyte adherence to cultured sheep lung microvascular endothelial cells. Am J Respir Cell Mol Biol. 1992;7(1):81–9. [PubMed: 1378287]
557.
Carratelli CR, Nuzzo I, Bentivoglio C. et al. CD11a/CD18 and CD11b/18 modulation by lipoteichoic acid, N-acetyl-muramyl-alpha-alanyl-D-isoglutamine, muramic acid and protein A from Staphylococcus aureus. FEMS Immunol Med Microbiol. 1996;16(3-4):309–15. [PubMed: 9116650]
558.
Henriques GM, Miotla JM, Cordeiro SB. et al. Selectins mediate eosinophil recruitment in vivo: A comparison with their role in neutrophil influx. Blood. 1996;87(12):5297–304. [PubMed: 8652845]
559.
Heinzelmann M, Mercer-Jones MA, Gardner SA. et al. Bacterial cell wall products increase monocyte HLA-DR and ICAM-1 without affecting lymphocyte CD18 expression. Cell Immunol. 1997;176(2):127–34. [PubMed: 9073385]
560.
Picker L, Butcher E. Annu Rev Immunol. 1992;10:561–591. [PubMed: 1590996]
561.
Ottaway CA. In: Husband AJ, ed. Migration and Homing of Lymphoid Cells (Vol. II) CRC Press. 1988:167–194.
562.
Springer TA. Adhesion receptors of the immune system. Nature. 1990;34:425–434. [PubMed: 1974032]
563.
Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: The multistep paradigm. Cell. 1994;76(2):301–14. [PubMed: 7507411]
564.
Pohlman TH, Stannes KA, Beatty PG. et al. An endothelial cell surface factor(s) induced in vitro by lipopolysaccharide, interleukin-1, and tumor necrosis factor alpha increases neutrophil adherence by a CDw18-dependednt mechanism. J Immunol. 1986;136:4548–4553. [PubMed: 3486903]
565.
Hynes RO, Lander AD. Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell. 1992;68(2):303–22. [PubMed: 1733501]
566.
Mackay CR, Imhof BA. Cell adhesion in the immune system. Immunol Today. 1993;14:99–102. [PubMed: 8466633]
567.
Dinarello CA, Mier JW. Lymphokines. N Engl J Med. 1987;317:940–945. [PubMed: 2442611]
568.
Patarroyo M, Prieto J, Rincon J. et al. Leukocyte-cell adhesion: A molecular process fundamental in leukocyte physiology. Immunol Rev. 1990;114:67–108. [PubMed: 1973408]
569.
Patarroyo M. Adhesion molecules mediating recruitment of monocytes to inflamed tissue. Immunobiology. 1994;191(4-5):474–7. [PubMed: 7713561]
570.
Munro JM. Endothelial-leukocyte adhesive interactions in inflammatory diseases. Eur Heart J. 1993;14(Suppl K):72–7. [PubMed: 7510638]
571.
Magnuson DK, Maier RV, Pohlman TH. Protein kinase C: A potential pathway of endothelial cell activation by endotoxin, tumor necrosis factor, and interleukin-1 Surgery 1989106(2):216–22. (discussion 222-3) [PubMed: 2669197]
572.
Miura S, Tsuzuki Y, Kurose I. et al. Endotoxin stimulates lymphocyte-endothelial interactions in rat intestinal Peyer's patches and villus mucosa. Am J Physiol. 1996;271(2 Pt 1):G282–92. [PubMed: 8770044]
573.
Briscoe DM, Cotran RS, Pober JS. Effects of tumor necrosis factor, lipopolysaccharide, and IL-4 on the expression of vascular cell adhesion molecule-1 in vivo. Correlation with CD3+ T cell infiltration. J Immunol. 1992;149(9):2954–60. [PubMed: 1383333]
574.
Dohlsten M, Hedlund G, Lando PA. et al. Role of the adhesion molecule ICAM-1 (CD54) in staphylococcal enterotoxin-mediated cytotoxicity. Eur J Immunol. 1991;21(1):131–5. [PubMed: 1671356]
575.
Jarousseau AC, Thibault G, Reverdiau P. et al. Adhesive properties of choriocarcinoma cells toward lymphocytes activated or not by interleukin-2. Cell Immunol. 1994;157(1):38–47. [PubMed: 8039251]
576.
Piali L, Fichtel A, Terpe HJ. et al. Endothelial vascular cell adhesion molecule 1 expression is suppressed by melanoma and carcinoma. J Exp Med. 1995;181:811–816. [PMC free article: PMC2191895] [PubMed: 7530765]
577.
Sligh Jr JE, Ballantyne CM, Rich SS. et al. Inflammatory and are in intercellular adhesion molecule 1. Proc Natl Acad Sci USA. 1993;90(18):8529–33. [PMC free article: PMC47390] [PubMed: 8104338]
578.
Schmittel A, Scheibenbogen C, Keilholz U. Lipopolysaccharide effectively up-regulates B7-1 (CD80) expression and costimulatory function of human monocytes. Scand J Immunol. 1995;42(6):701–4. [PubMed: 8552995]
579.
Zaitseva M, Golding H, Manischewitz J. et al. Brucella abortus as a potential vaccine candidate: Induction of interleukin-12 secretion and enhanced B7.1 and B7.2 and intercellular adhesion molecule 1 surface expression in elutriated human monocytes stimulated by heat-inactivated B. abortus. Infect Immun. 1996;64(8):3109–17. [PMC free article: PMC174195] [PubMed: 8757841]
580.
Pohlman TH, Harlan JM. Human endothelial cell response to lipopolysaccharide, interleukin-1, and tumor necrosis factor is regulated by protein synthesis. Cell Immunol. 1989;119:41–52. [PubMed: 2784080]
581.
Haverstick DM, Gray LS. Lymphocyte adhesion mediated by lymphocyte function-associated antigen- 1. I. Long term augmentation by transient increases in intracellular cAMP. J Immunol. 1992a;149(2):389–96. [PubMed: 1352527]
582.
Galea P, Thibault G, Lacord M. et al. IL-4, but not tumor necrosis factor-a, increases endothelial cell adhesiveness for lymphocytes by activating a cAMP-dependent pathway. J Immunol. 1993;151:588–596. [PubMed: 7687617]
583.
Haverstick DM, Gray LS. Lymphocyte adhesion mediated by lymphocyte function-associated antigen- 1. II. Interaction between phorbol ester- and cAMP-sensitive pathways. J Immunol. 1992b;149(2):397–402. [PubMed: 1352528]
584.
Eissner G, Kolch W, Mischak H. et al. Differential role of protein kinase C in cytokine induced lymphocyte-endothelium interaction in vitro. Scand J Immunol. 1994;40(4):395–402. [PubMed: 7939411]
585.
Lanier LL. Distribution and function of lymphocyte surface antigens. Molecules costimulating T lymphocyte activation and effector function. Ann NY Acad Sci. 1993;677:86–93. [PubMed: 8494250]
586.
Li GC, Mivechi NF, Weitzel G. Heat shock proteins, thermotolerance, and their relevance to clinical hyperthermia. Int J Hyperthermia. 1995;11(4):459–88. [PubMed: 7594802]
587.
Kobayashi T, Shiozaki H, Shimano T. et al. Analysis of cytotoxic activity of the CD4+ T lymphocytes generated by local immunotherapy. Br J Cancer. 1996;73(1):110–6. [PMC free article: PMC2074300] [PubMed: 8554971]
588.
Itoh Y, Koshita Y, Takahashi M. et al. Characterization of tumor-necrosis-factor-gene-transduced tumor-infiltrating lymphocytes from ascitic fluid of cancer patients: Analysis of cytolytic activity, growth rate, adhesion molecule expression and cytokine production. Cancer Immunol Immunother. 1995;40(2):95–102. [PubMed: 7882388]
589.
Li R, Nortamo P, Kantor C. et al. A leukocyte integrin binding peptide from intercellular adhesion molecule-2 stimulates T cell adhesion and natural killer cell activity. J Biol Chem. 1993;268(29):21474–7. [PubMed: 8104939]
590.
Somersalo K, Carpen O, Saksela E. et al. Activation of natural killer cell migration by leukocyte integrin-binding peptide from intracellular adhesion molecule-2 (ICAM-2) J Biol Chem. 1995;270(15):8629–36. [PubMed: 7721764]
591.
Scott CF, Bolender S, McIntyre GD. et al. Activation of human cytolytic cells through CD2/T11. Comparison of the requirements for the induction and direction of lysis of tumor targets by T cells and NK cells. J Immunol. 1989;142:4105–4112. [PubMed: 2565930]
592.
Saito H, Kurose I, Ebinuma H. et al. Kupffer cell-mediated cytotoxicity against hepatoma cells occurs through production of nitric oxide and adhesion via ICAM-1/CD18. Int Immunol. 1996;8(7):1165–72. [PubMed: 8757962]
593.
Todd IIIrd RF, Arnaout MA, Rosin RE. et al. Subcellular localization of the large subunit of Mo1 (Mo1 alpha; formerly gp 110), a surface glycoprotein associated with neutrophil adhesion. J Clin Invest. 1984;74(4):1280–90. [PMC free article: PMC425295] [PubMed: 6480827]
594.
Diamond MS, Springer TA. The dynamic regulation of integrin adhesiveness. Curr Biol. 1994;4(6):506–17. [PubMed: 7922371]
595.
Hershkoviz R, Alon R, Mekori YA. et al. Heat-stressed CD4+ T lymphocytes: Differential modulations of adhesiveness to extracellular matrix glycoproteins, proliferative responses and tumour necrosis factor-α secretion. Immunol. 1993;79:241–247. [PMC free article: PMC1421855] [PubMed: 8102119]
596.
Schadendorf D, Diehl S, Zuberbier T. et al. Quantitative detection of soluble adhesion molecules in sera of melanoma patients correlates with clinical stage. Dermatology. 1996;192(2):89–93. [PubMed: 8829517]
597.
Endo S, Inada K, Kasai T. et al. Levels of soluble adhesion molecules and cytokines in patients with septic multiple organ failure. J Inflamm. 1995-96;46(4):212–9. [PubMed: 8878795]
598.
Musiani P, Modesti A, Giovarelli M. et al. Cytokines, tumour-cell death and immunogenicity: A question of choice. Immunol Today. 1997;18(1):32–6. [PubMed: 9018972]
599.
Duff GW, Oppenheim JJ. Comparative aspects of host-parasite and host-tumor relationships. Cytokine. 1992;4:331–339. [PubMed: 1420993]
600.
Blankenstein T, Rowley DA, Schreiber H. Cytokines and cancer: Experimental systems. Curr Opinion Immunol. 1991;3:694–698. [PubMed: 1755987]
601.
Haas GP, Redman BG, Rao VK. et al. Immunotherapy for metastatic renal cell cancer: Effect on the primary tumor. J Immunother. 1993;13:130–135. [PubMed: 8318498]
602.
Hock H, Dorsch M, Kunzendorf U. et al. Mechanisms of rejection induced by tumor cell-targeted gene transfer of Interleukin 2, Interleukin 4, Interleukin 7, tumor necrosis factor, or interferon gamma. Proc Natl Acad Sci USA. 1993;90:2774–2778. [PMC free article: PMC46178] [PubMed: 8464888]
603.
van der Schelling GP, Ijzermans JN, Marquet RL. et al. Cytokines as immunotherapy in cancer. Ned Tijdschr Geneeskd. 1992;136(14):681–5. [PubMed: 1373229]
604.
Hill AD, Redmond HP, Croke DT. et al. Cytokines in tumor therapy. Br J Surg. 1992;79(10):990–7. [PubMed: 1384923]
605.
Holmlund JT. Cytokines. Cancer Chemother Biol Response Modif. 1993;14:150–206. [PubMed: 7508728]
606.
Kershaw MH, Trapani JA, Smyth MJ. Cytotoxic lymphocytes: Redirecting the cell-mediated immune response for the therapy of cancer. Ther Immunol. 1995;2(3):173–81. [PubMed: 8885135]
607.
Goey SH, Verweij J, Stoter G. Immunotherapy of metastatic renal cell cancer. Ann Oncol. 1996;7(9):887–900. [PubMed: 9006738]
608.
Kruit WH, Stoter G. The role of adoptive immunotherapy in solid cancers. Neth J Med. 1997;50(2):47–68. [PubMed: 9050332]
609.
Bubenik J. Cytokine gene-modified vaccines in the therapy of cancer. Pharmacol Ther. 1996;69(1):1–14. [PubMed: 8857300]
610.
Shieh JH, Peterson RH, Moore MA. Bacterial endotoxin regulation of cytokine receptors on murine bone marrow cells: In vivo and in vitro study. J Immunol. 1994;152(2):859–66. [PubMed: 8283056]
611.
Pace JL, Taffet SM, Russell SW. The effect of endotoxin in eliciting agents on the activation of mouse macrophages for tumor cell killing. J Reticuloendothel Soc. 1981;30(1):15–21. [PubMed: 7021820]
612.
Pace JL, Russell SW, LeBlanc PA. et al. Comparative effects of various classes of mouse interferons on macrophage activation for tumor cell killing. J Immunol. 1985;134(2):977–81. [PubMed: 2578167]
613.
Björk L, Andersson J, Ceska M. et al. Endotoxin and Staphylococcus aureus enterotoxin A induce different patterns of cytokines. Cytokine. 1992;4(6):513–9. [PubMed: 1292633]
614.
Schlievert PM, Bohach GA, Ohlendorf DH. et al. Molecular structure of staphylococcus and streptococcus superantigens. J Clin Immunol. 1995;15(6 Suppl):4S–10S. [PubMed: 8613491]
615.
Fast DJ, Schlievert PM, Nelson RD. Toxic shock syndrome-associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumor necrosis factor production. Infection Immunity. 1989;57:291–294. [PMC free article: PMC313091] [PubMed: 2642470]
616.
Fields BA, Malchiodi EL, Li H. et al. Crystal structure of a T-cell receptor beta-chain complexed with a superantigen. Nature. 1996;384:188–192 (See also comment Nature 1996 384109-110). [PubMed: 8906797]
617.
Shimizu M, Yamamoto A, Nakano H. et al. Augmentation of antitumor immunity with bacterial superantigen, staphylococcal enterotoxin B-bound tumor cells. Cancer Res. 1996;56(16):3731–6. [PubMed: 8706016]
618.
Riesenfeld-Orn I, Wolpe S, Garcia-Bustos JF. et al. Production of interleukin-1 but not tumor necrosis factor by human monocytes stimulated with pneumococcal cell surface components. Infect Immun. 1989;57(7):1890–3. [PMC free article: PMC313816] [PubMed: 2786503]
619.
Beeson PB. Tolerance to bacterial pyrogens. I. Factors influencing its development. J Exp Med. 1947;86:29–38. [PMC free article: PMC2135744] [PubMed: 19871652]
620.
Thomas L. The physiological disturbances produced by endotoxins. Ann Rev Physiol. 1954;16:467–490. [PubMed: 13171836]
621.
Greisman SE, DuBuy B. Mechanisms of endotoxin tolerance. IX. Effect of exchange transfusion. Proc Soc Exp Biol Med. 1975;148(3):675–8. [PubMed: 1093191]
622.
Greisman SE, Hornick RB. The nature of endotoxin tolerance. Trans Am Clin Climatol Assoc. 1975;86:43–50. [PMC free article: PMC2441361] [PubMed: 1179593]
623.
Greisman SE, Hornick RB. Endotoxin tolerance In: Beers Jr RF, Basset E, eds. The role of immunological factors in infectious, allergic, and autoimmune processes. New York: Raven Press 197643–50. (W3 MI543 no8)
624.
Mengozzi M, Ghezzi P. Cytokine down-regulation in endotoxin tolerance. Eur Cytokine Netw. 1993;4(2):89–98. [PubMed: 8318675]
625.
Lindberg AA, Greisman SE, Svenson SB. Induction of endotoxin tolerance with nonpyrogenic O-antigenic oligosaccharide-protein conjugates. Infect Immun. 1983;41(3):888–95. [PMC free article: PMC264584] [PubMed: 6193067]
626.
Johnson CA, Greisman SE. Mechanisms of endotoxin tolerance. In: Hinshaw LB, ed. Handbook of Endotoxin. Vol 2: Pathophysiology of Endotoxin. Amsterdam: Elsevier Science Publishers BV. 1985:359–401.
627.
Williams JF. Induction of tolerance in mice and rats to the effect of endotoxin to decrease the hepatic microsomal mixed-function oxidase system. Evidence for a possible macrophage-derived factor in the endotoxin effect. Int J Immunopharmacol. 1985;7(4):501–9. [PubMed: 3840129]
628.
Madonna GS, Vogel SN. Induction of early-phase endotoxin tolerance in athymic (nude) mice, B-cell-deficient (xid) mice, and splenectomized mice. Infect Immun. 1986;53(3):707–10. [PMC free article: PMC260853] [PubMed: 3488965]
629.
Freudenberg MA, Galanos C. Induction of tolerance to lipopolysaccharide (LPS)-D-galactosamine lethality by pretreatment with LPS is mediated by macrophages. Infect Immun. 1988;56(5):1352–7. [PMC free article: PMC259829] [PubMed: 3356468]
630.
Haas JG, Thiel C, Blomer K. et al. Downregulation of tumor necrosis factor expression in the human Mono-Mac-6 cell line by lipopolysaccharide. J Leukoc Biol. 1989;46(1):11–4. [PubMed: 2732625]
631.
Zuckerman SH, Evans GF, Butler LD. Endotoxin tolerance: Independent regulation of interleukin-1 and tumor necrosis factor expression. Infect Immun. 1991;59(8):2774–80. [PMC free article: PMC258086] [PubMed: 1855993]
632.
Roth J, McClellan JL, Kluger MJ. et al. Attenuation of fever and release of cytokines after repeated injections of lipopolysaccharide in guinea-pigs. J Physiol (Lond) 1994;477(Pt 1):177–85. [PMC free article: PMC1155585] [PubMed: 8071885]
633.
Takasuka N, Tokunaga T, Akagawa KS. Preexposure of macrophages to low doses of lipopolysaccharide inhibits the expression of tumor necrosis factor-alpha mRNA but not of IL-1 beta mRNA. J Immunol. 1991;146(11):3824–30. [PubMed: 1903414]
634.
Ziegler-Heitbrock HW, Blumenstein M, Kafferlein E. et al. In vitro desensitization to lipopolysaccharide suppresses tumour necrosis factor, interleukin-1 and interleukin-6 gene expression in a similar fashion. Immunology. 1992;75(2):264–8. [PMC free article: PMC1384704] [PubMed: 1551689]
635.
Zhang X, Morrison DC. Lipopolysaccharide-induced selective priming effects on tumor necrosis factor alpha and nitric oxide production in mouse peritoneal macrophages. J Exp Med. 1993a;177(2):511–6. [PMC free article: PMC2190891] [PubMed: 8426119]
636.
Mathison JC, Virca GD, Wolfson E. et al. Adaptation to bacterial lipopolysaccharide controls lipopolysaccharide-induced tumor necrosis factor production in rabbit macrophages. J Clin Invest. 1990;85(4):1108–18. [PMC free article: PMC296541] [PubMed: 2318968]
637.
LaRue KEA, McCall CE. A labile transcriptional repressor modulates endotoxin tolerance. J Exp Med. 1994;180:2269–2275. [PMC free article: PMC2191765] [PubMed: 7964499]
638.
Deitch EA, Specian RD, Berg RD. Induction of early-phase tolerance to endotoxin-induced mucosal injury, xanthine oxidase activation and bacterial translocation by pretreatment with endotoxin. Circulatory Shock. 1992;36:208–216. [PubMed: 1535293]
639.
Patton JS, Peters PM, McCabe J. et al. Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor necrosis factor-a in rodents. J Clin Invest. 1987;80:1587–1596. [PMC free article: PMC442427] [PubMed: 3500186]
640.
Vogel SN, Kaufman EN, Tate MD. et al. Recombinant interleukin-1 alpha and recombinant tumor necrosis factor alpha synergize in vivo to induce early endotoxin tolerance and associated hematopoietic changes. Infect Immun. 1988;56(10):2650–7. [PMC free article: PMC259625] [PubMed: 3262089]
641.
Gorgen I, Hartung T, Leist M. et al. Granulocyte colony-stimulating factor treatment protects rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor-alpha. J Immunol. 1992;149(3):918–24. [PubMed: 1378868]
642.
Erroi A, Fantuzzi G, Mengozzi M. et al. Differential regulation of cytokine production in lipopolysaccharide tolerance in mice. Infect Immun. 1993;61(10):4356–9. [PMC free article: PMC281166] [PubMed: 8406825]
643.
Mengozzi M, Fantuzzi G, Sironi M. et al. Early down-regulation of TNF production by LPS tolerance in human monocytes: Comparison with IL-1 beta, IL-6, and IL-8. Lymphokine Cytokine Res. 1993;12(4):231–6. [PubMed: 7692988]
644.
Wakabayashi G, Cannon JG, Gelfand JA. et al. Altered interleukin-1 and tumor necrosis factor production and secretion during pyrogenic tolerance to LPS in rabbits. Am J Physiol. 1994;267(1 Pt 2):R329–36. [PubMed: 8048640]
645.
Takahashi N, Fiers W, Brouckaert P. Anti-tumor activity of tumor necrosis factor in combination with interferon-gamma is not affected by prior tolerization. Int J Cancer. 1995a;63(6):846–54. [PubMed: 8847144]
646.
Takahashi N, Brouckaert P, Fiers W. Mechanism of tolerance to tumor necrosis factor: Receptor-specific pathway and selectivity. Am J Physiol. 1995b;269(2 Pt 2):R398–405. [PubMed: 7653662]
647.
Zhang X, Morrison DC. Lipopolysaccharide structurefunction relationship in activation versus reprogramming of mouse peritoneal macrophages. J Leukoc Biol. 1993b;54(5):444–50. [PubMed: 8228623]
648.
Hirohashi N, Morrison DC. Low-dose lipopolysaccharide (LPS) pretreatment of mouse macrophages modulates LPS-dependent interleukin-6 production in vitro. Infect Immun. 1996;64(3):1011–5. [PMC free article: PMC173871] [PubMed: 8641750]
649.
Zhang X, Morrison DC. Pertussis toxin-sensitive factor differentially regulates lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production in mouse peritoneal macrophages. J Immunol. 1993c;150(3):1011–8. [PubMed: 8423328]
650.
Evans GF, Zuckerman SH. Glucocorticoid-dependent and -independent mechanisms involved in lipopolysaccharide tolerance. Eur J Immunol. 1991;21(9):1973–9. [PubMed: 1716205]
651.
Lazar G, Agarwal MK. The influence of a novel glucocorticoid antagonist on endotoxin lethality in mice strains. Biochem Med Metab Biol. 1986;36(1):70–4. [PubMed: 3741703]
652.
Bertini R, Bianchi M, Ghezzi P. Adrenalectomy sensitizes mice to the lethal effects of interleukin 1 and tumor necrosis factor. J Exp Med. 1988;167(5):1708–12. [PMC free article: PMC2188949] [PubMed: 3259257]
653.
Beutler B, Krochin N, Milsark IW. et al. Control of cachectin (tumor necrosis factor) synthesis: Mechanisms of endotoxin resistance. Science. 1986;232(4753):977–80. [PubMed: 3754653]
654.
Waage A, Slupphaug G, Shalaby R. Glucocorticoids inhibit the production of IL6 from monocytes, endothelial cells and fibroblasts. Eur J Immunol. 1990;20(11):2439–43. [PubMed: 2253684]
655.
Parente L, Di Rosea M, Flower RJ. et al. Relationship between the anti-phospholipase and anti-inflammatory effects of glucocorticoid-induced proteins. Eur J Pharmacol. 1984;99(2-3):233–9. [PubMed: 6428924]
656.
Radomski MW, Palmer RM, Moncada S. Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA. 1990;87(24):10043–7. [PMC free article: PMC55311] [PubMed: 1702214]
657.
Fish RE, Spitzer JA. Continuous infusion of endotoxin from an osmotic pump in the conscious, unrestrained rat: A unique model of chronic endotoxemia. Circ Shock. 1984;12(2):135–49. [PubMed: 6368040]
658.
Demling RH, Lalonde CC, Jin LJ. et al. The pulmonary and systemic response to recurrent endotoxemia in the adult sheep. Surgery. 1986;100(5):876–83. [PubMed: 3535147]
659.
Schlievert PM, Bettin KM, Watson DW. Inhibition of ribonucleic acid synthesis by group A streptococcal pyrogenic exotoxin. Infect Immun. 1980;27(2):542–8. [PMC free article: PMC550799] [PubMed: 6155335]
660.
Deitch EA, Berg R, Specian R. Endotoxin promotes the translocation of bacteria from the gut. Arch Surg. 1987;122(2):185–90. [PubMed: 3545142]
661.
O'Dwyer ST, Michie HR, Ziegler TR. et al. A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg. 1988;123:1459–1464. [PubMed: 3142442]
662.
Deitch EA, Ma L, Ma WJ. et al. Inhibition of endotoxin-induced bacterial translocation in mice. J Clin Invest. 1989;84(1):36–42. [PMC free article: PMC303949] [PubMed: 2661590]
663.
Deitch EA. The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure. Arch Surg. 1990;125(3):403–4. [PubMed: 2407230]
664.
Walker RI. The contribution of intestinal endotoxin to mortality in hosts with compromised resistance: A review. Exp Hematol. 1978;6(2):172–84. [PubMed: 23952]
665.
Lundqvist C, Melgar S, Yeung MM. et al. Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions. J Immunol. 1996;157(5):1926–34. [PubMed: 8757311]
666.
Winchurch RA, Thupari JN, Munster AM. Endotoxemia in burn patients: Levels of circulating endotoxins are related to burn size. Surgery. 1987;102(5):808–12. [PubMed: 3672321]
667.
Woodruff PW, O'Carroll DI, Koizumi S. et al. Role of the intestinal flora in major trauma. J Infect Dis. 1973;128(Suppl):290–4. [PubMed: 4541677]
668.
Bahrami S, Redl H, Yao YM. et al. Involvement of bacteria/endotoxin translocation in the development of multiple organ failure. Curr Top Microbiol Immunol. 1996;216:239–58. [PubMed: 8791743]
669.
Carrico CJ, Meakins JL, Marshall JC. et al. Multiple-organ-failure syndrome. Arch Surg. 1986;121(2):196–208. [PubMed: 3484944]
670.
In: KosakaM Suguhara T Schmidt KL Simon E eds. Thermotherapy for Neoplasia Inflammation and Pain. Tokyo: Springer. 2001
671.
Burd, Dziedzic, Yan Xu. et al. Tumor cell apoptosis, lymphocyte recruitment and tumor vascular changes are induced by low temperature, long duration (fever-like) whole body hyperthermia. J Cell Pysiol. 1998;177:137–147. [PubMed: 9731754]
672.
Ardenne von M. Spontaneous remission of tumors following hyperthermia - a feedback process? Naturwissenschaften. 1965;52(23):645. [PubMed: 5873900]
673.
Ardenne von M, Chaplain RA, Reitnauer PG. In vivo studies on cancer multiple-step therapy using the attack combination of optimum tumor overacidification, hyperthermia and weak X-irradiation. Dtsch Gesundheitsw. 1969;24(20):924–35. [PubMed: 5375903]
674.
Ardenne von M, Reitnauer PG. Measurements on selective damage to cancer cells in vitro by attack-combination with hyperacidification plus 40 degree C hyperthermia and various bile acids with favorable pH. Arzneimittelforschung. 1970;20(3):323–9. [PubMed: 5467505]
675.
Ardenne von M, Rieger F. On the present state of extreme total-body hyperthermia as element in the cancer therapy Z Krebsforsch Klin Onkol Cancer Res Clin Oncol 196769(4):341–4. (Ardenne MV Synergic therapeutic effect of selective local hyperthermia and selective optimized hyperacidity against tumors Theoretical and experimental bases Ther Ggw 1977 Jul116(7)1299-316) [PubMed: 4233419]
676.
Kirsch R, Schmidt D, Fichler J. et al. Problems of multiple step-therapy of carcinoma. II. Effect of hyperthermia on cancer tissue. Dtsch Gesundheitsw. 1967a;22(16):732–5. [PubMed: 5587080]
677.
Kirsch R, Schmidt D, Schmidt H. Problems of multiple step-therapy of carcinoma. I. On the history of hyperthermic treatment Dtsch Gesundheitsw 1967b22(15):678–81. (contd) [PubMed: 5590967]
678.
Pritchard MT, Ostberg JR, Evans SS. et al. Protocols for simulating the thermal component of fever: Preclinical and clinical experience. Methods. 2004;32(1):54–62. [PubMed: 14624878]
679.
Yonezawa M, Otsuka T, Matsui N. et al. Hyperthermia induces apoptosis in malignant fibrous histiocytoma cells in vitro. Int J Cancer. 1996;66(3):347–51. [PubMed: 8621256]
680.
Ensor JE, Wiener SM, McCrea KA. et al. Differential effects of hyperthermia on macrophage interleukin-6 and tumor necrosis factor-alpha expression. Am J Physiol. 1994;266(4 Pt 1):C967–74. [PubMed: 8178969]
681.
Shen RN, Lu L, Young P. et al. Influence of elevated temperature on natural killer cell activity, lymphokine-activated killer cell activity and lectin-dependent cytotoxicity of human umbilical cord blood and adult blood cells. Int J Radiat Oncol Biol Phys. 1994;29(4):821–6. [PubMed: 8040029]
682.
Zanker KS, Lange J. Whole body hyperthermia and natural killer cell activity (letter) Lancet. 1982;1(8280):1079–80. [PubMed: 6122886]
683.
Park MM, Hornback NB, Endres S. et al. The effect of whole body hyperthermia on the immune cell activity of cancer patients. Lymphokine Res. 1990(Summer);9(2):213–23. [PubMed: 2110991]
684.
Haranaka K, Sakurai A, Satomi N. Antitumor activity of recombinant human tumor necrosis factor in combination with hyperthermia, chemotherapy, or immunotherapy. J Biol Response Mod. 1987a;6:379–391. [PubMed: 3625230]
685.
Haranaka K, Satomi N, Sakurai A. et al. Antitumour effects of tumour necrosis factor: Cytotoxic or necrotizing activity and its mechanism. Ciba Found Symp. 1987b;131:140–53. [PubMed: 3450479]
686.
van der Zee J, van den Aardweg GJ, van Rhoon GC. Br J Cancer. 1995. pp. 1158–62. [PMC free article: PMC2033841] [PubMed: 7779705]
687.
Strauch ED, Fabian DF, Turner J. et al. Combined hyperthermia and immunotherapy treatment of multiple pulmonary metastases in mice. Surg Oncol. 1994;3(1):45–52. [PubMed: 8186870]
688.
Kappel M, Tvede N, Hansen MB. et al. Cytokine production ex vivo: Effect of raised body temperature. Int J Hyperthermia. 1995;11(3):329–35. [PubMed: 7636320]
689.
Robins HI, Kutz M, Wiedemann GJ. et al. Cytokine induction by 41.8 degrees C whole body hyperthermia. Cancer Lett. 1995b;97(2):195–201. [PubMed: 7497463]
690.
Blake D, Bessey P, Karl I. et al. Hyperthermia induces IL-1 alpha but does not decrease release of IL-1 alpha or TNF-alpha after endotoxin. Lymphokine Cytokine Res. 1994;13(5):271–5. [PubMed: 7858059]
691.
Multhoff G, Botzler C, Meier T. et al. Proceedings of the fourth International Meeting of Heat Shock Response. Biology of Heat Shock Proteins and Molecular Chaperones. Cold Spring Harbor. 1994:330.
692.
Parsell DA, Lindquist S. Heat shock proteins and stress tolerance. The biology of heat shock proteins and molecular chaperones. Cold Spring Harbor Laboratory Press. 1994a
693.
Benndorf R, Bielka H. Cellular stress response: Stress proteins—physiology and implications for cancer. Recent Results Cancer Res. 1997;143:129–44. [PubMed: 8912416]
694.
Fuller KJ, Issels RD, Slosman DO. et al. Cancer and the heat shock response. Eur J Cancer. 1994;30A(12):1884–91. [PubMed: 7880622]
695.
Ferrarini M, Heltai S, Zocchi MR. et al. Unusual expression and localization of heat-shock proteins in human tumor cells. Int J Cancer. 1992;51(4):613–9. [PubMed: 1601523]
696.
Zhang YH, Takahashi K, Jiang GZ. et al. In vivo production of heat shock protein in mouse peritoneal macrophages by administration of lipopolysaccharide. Infect Immun. 1994b;62(10):4140–4. [PMC free article: PMC303088] [PubMed: 7927668]
697.
Hirvonen MR, Brune B, Lapetina EG. Heat shock proteins and macrophage resistance to the toxic effects of nitric oxide. Biochem J. 1996;315(Pt 3):845–9. [PMC free article: PMC1217283] [PubMed: 8645166]
698.
Seitz CS, Kleindienst R, Xu Q. et al. Coexpression of heat-shock protein 60 and intercellular-adhesion molecule-1 is related to increased adhesion of monocytes and T cells to aortic endothelium of rats in response to endotoxin. Lab Invest. 1996;74(1):241–52. [PubMed: 8569188]
699.
Deitch EA, Beck SC, Cruz NC. et al. Induction of heat shock gene expression in colonic epithelial cells after incubation with Escherichia coli or endotoxin. Crit Care Med. 1995;23(8):1371–6. [PubMed: 7634807]
700.
Dressel R, Heine L, Elsner L. et al. Induction of heat shock protein 70 genes in human lymphocytes during fever therapy. Eur J Clin Invest. 1996;26(6):499–505. [PubMed: 8817165]
701.
Jindal S. Heat shock proteins: Applications in health and disease. Trends Biotechnol. 1996;14(1):17–20. [PubMed: 8579818]
702.
Fracella F, Rensing L. Stress proteins: their growing significance in medicine. Naturwissenschaften. 1995;82(7):303–9. [PubMed: 7643907]
703.
Parsell DA, Kowal AS, Singer MA. et al. Protein disaggregation mediated by heat-shock protein Hsp104. Nature. 1994b;372(6505):475–8. [PubMed: 7984243]
704.
Srivastava PK. Protein tumor antigens. Curr Opin Immunol. 1991;3(5):654–8. [PubMed: 1755984]
705.
Blachere NE, Udono H, Janetzki S. et al. Heat shock protein vaccines against cancer. J Immunother. 1993;14(4):352–6. [PubMed: 8280719]
706.
Suto R, Srivastava PK. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science. 1995;269(5230):1585–8. [PubMed: 7545313]
707.
Burdon RH. The heat shock proteins. Endeavour. 1988;12(3):133–8. [PubMed: 2460330]
708.
Zimarino V, Wu C. Induction of sequence-specific binding of Drosophila heat shock activator protein without protein synthesis. Nature. 1987;327(6124):727–30. [PubMed: 3600771]
709.
Wiederrecht G, Shuey DJ, Kibbe WA. et al. The Saccharomyces and Drosophila heat shock transcription factors are identical in size and DNA binding properties. Cell. 1987;48(3):507–15. [PubMed: 3100052]
710.
Giaccia AJ, Auger EA, Koong A. et al. Activation of the heat shock transcription factor by hypoxia in normal and tumor cell lines in vivo and in vitro. Int J Radiat Oncol Biol Phys. 1992;23(4):891–7. [PubMed: 1618682]
711.
Hauser GJ, Dayao EK, Wasserloos K. et al. HSP induction inhibits iNOS mRNA expression and attenuates hypotension in endotoxin-challenged rats. Am J Physiol. 1996;271(6 Pt 2):H2529–35. [PubMed: 8997314]
712.
de Vera ME, Wong JM, Zhou JY. et al. Cytokine-induced nitric oxide synthase gene transcription is blocked by the heat shock response in human liver cells. Surgery. 1996;120(2):144–9. [PubMed: 8751576]
713.
Feinstein DL, Galea E, Aquino DA. et al. Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFkappaB activation. J Biol Chem. 1996;271(30):17724–32. [PubMed: 8663604]
714.
Wong HR, Mannix RJ, Rusnak JM. et al. The heat-shock response attenuates lipopolysaccharide-mediated apoptosis in cultured sheep pulmonary artery endothelial cells. Am J Respir Cell Mol Biol. 1996;15(6):745–51. [PubMed: 8969269]
715.
Chi SH, Mestril R. Stable expression of a human HSP70 gene in a rat myogenic cell line confers protection against endotoxin. Am J Physiol. 1996;270(4 Pt 1):C1017–21. [PubMed: 8928728]
716.
Snyder YM, Guthrie L, Evans GF. et al. Transcriptional inhibition of endotoxin-induced monokine synthesis following heat shock in murine peritoneal macrophages. J Leukoc Biol. 1992;51(2):181–7. [PubMed: 1431555]
717.
Ribeiro SP, Villar J, Downey GP. et al. Effects of the stress response in septic rats and LPS-stimulated alveolar macrophages: Evidence for TNF-alpha posttranslational regulation. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1843–50. [PubMed: 8970379]
718.
Yoshida K, Maaieh MM, Shipley JB. et al. Monophosphoryl lipid A induces pharmacologic ‘preconditioning’ in rabbit hearts without concomitant expression of 70-kDa heat shock protein. Mol Cell Biochem. 1996;159(1):73–80. [PubMed: 8813712]
719.
Sliutz G, Karlseder J, Tempfer C. et al. Drug resistance against gemcitabine and topotecan mediated by constitutive hsp70 overexpression in vitro: Implication of quercetin as sensitiser in chemotherapy. Br J Cancer. 1996;74(2):172–7. [PMC free article: PMC2074570] [PubMed: 8688318]
720.
Hotchkiss R, Nunnally I, Lindquist S. et al. Hyperthermia protects mice against the lethal effects of endotoxin. Am J Physiol. 1993;265(6 Pt 2):R1447–57. [PubMed: 8285289]
721.
Maeda H, Molla A, Oda T. et al. Internalization of serratial protease into cells as an enzyme-inhibitor complex with alpha 2-macroglobulin and regeneration of protease activity and cytotoxicity. J Biol Chem. 1987;262(23):10946–50. [PubMed: 2440880]
722.
Oda T, Kojima Y, Akaike T. et al. Inactivation of chemotactic activity of C5a by the serratial 56-kilodalton protease. Infect Immun. 1990;58(5):1269–72. [PMC free article: PMC258619] [PubMed: 1691142]
723.
Legres LG, Pochon F, Barray M. et al. Evidence for the binding of a biologically active interleukin-2 to human alpha 2-macroglobulin. J Biol Chem. 1995;270(15):8381–4. [PubMed: 7536736]
724.
Heumann D, Vischer TL. Immunomodulation by alpha 2-macroglobulin and alpha 2-macroglobulin-proteinase complexes: The effect on the human T lymphocyte response. Eur J Immunol. 1988;18(5):755–60. [PubMed: 2454194]
725.
Petersen CM, Ejlersen E, Moestrup SK. et al. Immunosuppressive properties of electrophoretically “slow” and “fast” form alpha 2-macroglobulin. Effects on cell-mediated cytotoxicity and (allo-) antigen-induced T cell proliferation. J Immunol. 1989;142(2):629–35. [PubMed: 2463311]
726.
Borth W, Teodorescu M. Inactivation of human interleukin-2 (IL-2) by alpha 2-macroglobulin-trypsin complexes. Immunology. 1986;57(3):367–71. [PMC free article: PMC1453844] [PubMed: 2420701]
727.
Wollenberg GK, LaMarre J, Rosendal S. et al. Binding of tumor necrosis factor alpha to activated forms of human plasma alpha 2 macroglobulin. Am J Pathol. 1991a;138(2):265–72. [PMC free article: PMC1886187] [PubMed: 1704186]
728.
O'Connor-McCourt MD, Wakefield LM. Latent transforming growth factor-beta in serum. A specific complex with alpha 2-macroglobulin. J Biol Chem. 1987;262(29):14090–9. [PubMed: 2443501]
729.
Danielpour D, Sporn MB. Differential inhibition of transforming growth factor beta 1 and beta 2 activity by alpha 2-macroglobulin. J Biol Chem. 1990;265(12):6973–7. [PubMed: 1691181]
730.
LaMarre J, Wollenberg GK, Gauldie J. et al. Alpha 2-macroglobulin and serum preferentially counteract the mitoinhibitory effect of transforming growth factor-beta 2 in rat hepatocytes. Lab Invest. 1990;62(5):545–51. [PubMed: 1692923]
731.
Hall SW, LaMarre J, Marshall LB. et al. Binding of transforming growth factor-beta 1 to methylamine-modified alpha 2-macroglobulin and to binary and ternary alpha 2-macroglobulin-proteinase complexes. Biochem J. 1992;281(Pt 2):569–75. [PMC free article: PMC1130723] [PubMed: 1371050]
732.
Huang JS, Huang SS, Deuel TF. Human platelet-derived growth factor: Radioimmunoassay and discovery of a specific plasma-binding protein. J Cell Biol. 1983;97(2):383–8. [PMC free article: PMC2112520] [PubMed: 6885904]
733.
Huang JS, Huang SS, Deuel TF. Specific covalent binding of platelet-derived growth factor to human plasma alpha 2-macroglobulin. Proc Natl Acad Sci USA. 1984;81(2):342–6. [PMC free article: PMC344672] [PubMed: 6198647]
734.
Borth W, Luger TA. Identification of alpha 2-macroglobulin as a cytokine binding plasma protein. Binding of interleukin-1 beta to “F” alpha 2-macroglobulin. J Biol Chem 1989; 264. (10):5818–25. [PubMed: 2466831]
735.
Legres LG, Pochon F, Barray M. et al. Human alpha 2-macroglobulin as a cytokine-binding plasma protein. A study with rh-interleukin-1 beta and rh-interleukin-6. Ann NY Acad Sci. 1994;737:439–43. [PubMed: 7524417]
736.
Matsuda T, Hirano T, Nagasawa S. et al. Identification of alpha 2-macroglobulin as a carrier protein for IL-6. J Immunol. 1989;142(1):148–52. [PubMed: 2462586]
737.
James K. Interactions between cytokines and alpha 2-macroglobulin (see comments) Immunol Today. 1990;11(5):163–6. [PubMed: 1692465]
738.
Borth W. Alpha 2-macroglobulin. A multifunctional binding and targeting protein with possible roles in immunity and autoimmunity. Ann NY Acad Sci. 1994;737:267–72. [PubMed: 7524401]
739.
James K, van den Haan J, Lens S. et al. Preliminary studies on the interaction of TNF alpha and IFN gamma with alpha 2-macroglobulin. Immunol Lett. 1992;32(1):49–57. [PubMed: 1379978]
740.
Barrett AJ, Starkey PM. The interaction of alpha 2-macroglobulin with proteinases. Characteristics and specificity of the reaction, and a hypothesis concerning its molecular mechanism. Biochem J. 1973;133(4):709–24. [PMC free article: PMC1177761] [PubMed: 4201304]
741.
Starkey PM, Barrett AJ. Inhibition by alpha-macroglobulin and other serum proteins. Biochem J. 1973;131(4):823–31. [PMC free article: PMC1177542] [PubMed: 4198623]
742.
Rinderknecht H, Carmack C, Geokas MC. Effect of specific antibodies and a2-macroglobulin on emzymatic activity of trypsin and chymotrypsin. Immunochemistry. 1975;12(1):1–8. [PubMed: 49290]
743.
Delain E, Barray M, Tapon-Bretaudiere J. et al. The molecular organization of human alpha 2-macroglobulin. An immunoelectron microscopic study with monoclonal antibodies. J Biol Chem. 1988;263(6):2981–9. [PubMed: 2449433]
744.
LaMarre J, Wollenberg GK, Gonias SL. et al. Cytokine binding and clearance properties of proteinase-activated alpha 2-macroglobulins. Lab Invest. 1991a;65(1):3–14. [PubMed: 1712874]
745.
Feldman SR, Rosenberg MR, Ney KA. et al. Binding of alpha 2-macroglobulin to hepatocytes: Mechanism of in vivo clearance. Biochem Biophys Res Commun. 1985;128(2):795–802. [PubMed: 2581569]
746.
Kaplan J, Nielsen ML. Analysis of macrophage surface receptors. II. Internalization of alpha-macroglobulin trypsin complexes by rabbit alveolar macrophages. J Biol Chem. 1979a;254(15):7329–35. [PubMed: 88450]
747.
Kaplan J, Nielsen ML. Analysis of macrophage surface receptors. I. Binding of alpha-macroglobulin protease complexes to rabbit alveolar macrophages. J Biol Chem. 1979b;254(15):7323–8. [PubMed: 88449]
748.
Imber MJ, Pizzo SV. Clearance and binding of two electrophoretic “fast” forms of human alpha 2-macroglobulin. J Biol Chem. 1981;256(15):8134–9. [PubMed: 6167573]
749.
Van Leuven F, Cassiman JJ, Van Den Berghe H. Demonstration of an alpha2-macroglobulin receptor in human fibroblasts, absent in tumor-derived cell lines. J Biol Chem. 1979;254(12):5155–60. [PubMed: 87392]
750.
Dickson RB, Willingham MC, Pastan I. Binding and internalization of 125I-alpha 2-macroglobulin by cultured fibroblasts. J Biol Chem. 1981;256(7):3454–9. [PubMed: 6162847]
751.
Niemuller CA, Randall KJ, Webb DJ. et al. Alpha 2-macroglobulin conformation determines binding affinity for activin A and plasma clearance of activin A/alpha 2-macroglobulin complex. Endocrinology. 1995;136(12):5343–9. [PubMed: 7588280]
752.
Gonias SL, LaMarre J, Crookston KP. et al. Alpha 2-macroglobulin and the alpha 2-macroglobulin receptor/ LRP. A growth regulatory axis. Ann NY Acad Sci. 1994;737:273–90. [PubMed: 7524402]
753.
Van Leuven F, Marynen P, Sottrup-Jensen L. et al. The receptor-binding domain of human alpha 2-macroglobulin. Isolation after limited proteolysis with a bacterial proteinase. J Biol Chem. 1986;261(24):11369–73. [PubMed: 2426272]
754.
Cunningham AJ, Elliott SF, Black JR. et al. A simple method for isolating alpha 2 macroglobulin-cytokine complexes. J Immunol Methods. 1994;169(2):287–92. [PubMed: 7510763]
755.
LaMarre J, Wolf BB, Kittler EL. et al. Regulation of macrophage alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-gamma. J Clin Invest. 1993;91(3):1219–24. [PMC free article: PMC288080] [PubMed: 7680664]
756.
Taveira Da Silva AM, Kaulbach HC, Chuidian FS. et al. Brief report: Shock and multiple-organ dysfunction after self-administration of salmonella endotoxin. N Engl J Med. 1993;328:1457–1460. [PubMed: 8479465]
757.
Hager ED. Mikrobielle immunmodulatoren: Aktive fiebertherapie mit bakterientoxinen. In: Buehring M, Kemper FH, Matthiessen PF, eds. Naturheilverfahren und unkonventionelle medizinische Richtungen. Springer LoseblattSysteme. 1996
758.
Nowotny A, Behling UH. Studies on host defenses enhanced by endotoxins: A brief review. Klin Wochenschr. 1982;60(14):735–9. [PubMed: 6750227]
759.
Cooper KE. Some responses of the cardiovascular system to heat and fever. Can J Cardiol. 1994;10(4):444–8. [PubMed: 8193989]
760.
Miller AB, Hoogstraten B, Staquet M. et al. Reporting results of cancer treatment. Cancer. 1981;47:207–214. [PubMed: 7459811]
761.
Parr I, Wheeler EA, Alexander P. Similarities of the antitumor actions of endotoxin, lipid A and double-stranded RNA. Br J Cancer. 1973;27:370–389. [PMC free article: PMC2008799] [PubMed: 4713170]
762.
Brouckaert P, Fiers W. Tumor necrosis factor and the systemic inflammatory response Syndrome. Curr Topics Microbiol Immunol. 1996;216:167–187. [PubMed: 8791740]
763.
Libert C, Van Molle W, Brouckaert P. et al. alpha1-Antitrypsin inhibits the lethal response to TNF in mice. J Immunol. 1996;157(11):5126–9. [PubMed: 8943423]
764.
Alexander HR, Doherty GM, Buresh CM. et al. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med. 1991a;173(4):1029–32. [PMC free article: PMC2190820] [PubMed: 1826127]
765.
Alexander HR, Doherty GM, Block MI. et al. Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats. Infect Immun. 1991b;59(11):3889–94. [PMC free article: PMC258973] [PubMed: 1937748]
766.
Everaerdt B, Brouckaert P, Fiers W. Recombinant IL-1 receptor antagonist protects against TNF-induced lethality in mice. J Immunol. 1994;152:5041–5049. [PubMed: 8176222]
767.
Fukumura D, Miura S, Kurose I. et al. IL-1 is an important mediator for microcirculatory changes in endotoxin-induced intestinal mucosal damage. Dig Dis Sci. 1996;41(12):2482–92. [PubMed: 9011462]
768.
Maeda H, Akaike T, Wu J. et al. Bradykinin and nitric oxide in infectious disease and cancer. Immunopharmacology. 1996;33(1-3):222–30. [PubMed: 8856154]
769.
Kaplanski G, Teysseire N, Farnarier C. et al. IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway. J Clin Invest. 1995;96(6):2839–44. [PMC free article: PMC185994] [PubMed: 8675654]
770.
Smith PD, Suffredini AF, Allen JB. et al. Endotoxin administration to humans primes alveolar macrophages for increased production of inflammatory mediators. J Clin Immunol. 1994;14(2):141–8. [PubMed: 8195316]
771.
Friedman H, Butler RC, Specter S. et al. Nontoxic endotoxin polysaccharide induces soluble mediators which potentiate antibody production by murine retrovirus-suppressed splenocytes. Int J Immunopharmacol. 1988;10(3):283–92. [PubMed: 3053470]
772.
Friedman H, Klein T, Specter S. et al. Immunoadjuvanticity of endotoxins and nontoxic derivatives for normal and leukemic immunocytes. Adv Exp Med Biol. 1990;256:525–35. [PubMed: 2183563]
773.
Nowotny A, Keler T, Pham PH. et al. Isolation of a nonendotoxic antitumor preparation from Serratia marcescens. J Biol Response Mod. 1988;7(3):296–308. [PubMed: 3292707]
774.
Parant M, Le Contel C, Parant F. et al. Influence of endogenous glucocorticoid on endotoxin-induced production of circulating TNF-alpha. Lymphokine Cytokine Res. 1991;10(4):265–71. [PubMed: 1932370]
775.
Mengozzi M, Fantuzzi G, Faggioni R. et al. Chlorpromazine specifically inhibits peripheral and brain TNF production, and up-regulates IL-10 production, in mice. Immunology. 1994;82:207–210. [PMC free article: PMC1414809] [PubMed: 7927490]
776.
LeMay LG, Vander AJ, Kluger MJ. The effects of pentoxifylline on lipopolysaccharide (LPS) fever, plasma interleukin 6 (IL-6), and tumor necrosis factor (TNF) in the rat. Cytokine. 1990c;2(4):300–6. [PubMed: 2104230]
777.
Elsner J, Sach M, Knopf HP. et al. Synthesis and surface expression of ICAM-1 in polymorphonuclear neutrophilic leukocytes in normal subjects and during inflammatory disease. Immunobiology. 1995;193(5):456–64. [PubMed: 8522360]
778.
Scher RL, Carras A, Schwab D. et al. Interferon gamma enhances lymphokine-activated killer cell adhesion but not lysis of head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 1995;121(11):1271–5. [PubMed: 7576474]
779.
Koyama S. Immunosuppressive effect of shedding intercellular adhesion molecule 1 antigen on cell-mediated cytotoxicity against tumor cells. Jpn J Cancer Res. 1994;85(2):131–4. [PubMed: 7908284]
Copyright © 2000-2013, Landes Bioscience.
Bookshelf ID: NBK6084

Views

  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...