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Influence of Tumor Microenvironment on Thermoresponse: Biologic and Clinical Implications

,* , , and .

Corresponding Author: Family Medicine Area, ASL-01 Legnano; Radiotherapy Unit Policlinico di Monza, Via Amati 11, 20052 Monza (Mi), Italy. Office address: P.O.B. 5, 20029 Turbigo (Mi), Italy. Email:

Solid tumours tend to have a more acidic and hypoxic microenvironment than normal tissue. This hostile microenvironment results from a disparity between oxygen supply and demand of the tumor tissue. Overcoming hypoxia tumor induces a new vascular supply. This new vasculature is however inefficient and chaotic. It perpetuates the factors that have stimulated its induction. This review focuses on these processes and peculiarly on angiogenesis, tumor vascular morphology, hypoxia, pH, and the metabolic-vascular events induced or following tumour tissue heating. The various mechanisms that either modulate tumor microenvironments or blood perfusion during hyperthermia are described, providing also the many clinical modalities that may enhance or sensitize cancer cells to heat.

Introduction: Tumor Microenvironment

Human solid neoplasia should be regarded as an intricate, yet poorly organized “organoid”, whose function is maintained by a dynamic interplay between neoplastic and host cells.1-3 This interplay constitutes the tumour metabolic microenvironment, defined by Vaupel4 as a complex pathophysiological entity resulting by the interactions of self-influencing factors, which go hand in hand: tumor perfusion, tumor oxygenation status, pH distribution and metabolic-bioenergetic status.

Hypoxia, HIF-1 and Angiogenesis

Hypoxia, HIF-1

The growth of tumours beyond a critical mass >1-2 mm3 (106 cells) is dependent on adequate blood supply.4,5

Up to a distance from host vessel of 100-200 μm the initial foci of neoplastic cells receive their nutrients and oxygen by diffusion. Beyond this distance, hypoxia occurs and the need of adequate blood supply is crucial.5-7 However, the establishment of this neovascular supply in the attempt to overcome hypoxia is inefficient and irregular. It may not occur at the same rate as the proliferation of the tumour. The result is the persistence within the tumour mass of heterogeneous microregions of nonproliferating hypoxic cells, which are surrounded by vital well nourished and proliferating cells (fig. 1).4,5,7

Figure 1. Photomicrograph of a section of mammary tumor, developed by a 5 month old female transgenic MMTV-neu (erbB2) mouse.

Figure 1

Photomicrograph of a section of mammary tumor, developed by a 5 month old female transgenic MMTV-neu (erbB2) mouse. T = tumor cord; N = necrosis; Hyp = hypoxic, perinecrotic, rim of tumor cells; C = capillary. Hematoxylin and Eosin. 40x objective.

Several methods to measure hypoxia are currently available and have demonstrated the presence of hypoxic cells both in experimental and in human tumours.8

The hypoxic microenvironments are characterized by low oxygen tension, low extracellular pHe, high interstitial fluid pressure, glucose deficiency, multidrug resistance, increased extracellular lactate concentration and tendency to metastasization.4

The forming of new blood vessels depends on a balance between angiogenesis inhibitors and promoters.6,8 Tumor regional hypoxia and hypoglycaemia are the principal stimulators for the expression of local proangiogenic cytokines, especially vascular endothelial growth factor (VEGF) (fig. 2).9-11 The early response gene that produces hypoxia inducible factor-1 (HIF-1) and its subunits (HIF-1α and -1β) regulate VEGF expression. HIF-1 is a protein of 120 KDa, member of the basic helix-loop-helix superfamily transcription factors, and its expression is very sensitive to oxygen concentration (1% O2).11-13

Figure 2. In this figure the structural and functional effects of Hypoxia, HIF-1 and VEGF on tumor microcirculation, cancer metabolism and therapies are illustrated.

Figure 2

In this figure the structural and functional effects of Hypoxia, HIF-1 and VEGF on tumor microcirculation, cancer metabolism and therapies are illustrated. The vicious circles that occur are also shown. (Modified with permission from: Baronzio et al. (more...)

The adaptation to hypoxia by earlier proliferating neoplastic cells results in the induction of genes that regulate the anaerobic metabolism, nitric oxide synthase and the angiogenesis process.9,12 Recent studies have shown that HIF-1and VEGF transcripts are overexpressed by several human neoplastic cells including breast, prostate, gastric, colon, lung, bladder and endometrium and they are more active in hypoxic and necrotic areas.14-17 VEGF is correlated to vascular density, especially in brain tumors and it is associated with bad prognosis.15 VEGF or vascular permeability factor (VPF), is a 32 to 44-KDa multifunctional potent stimulator of endothelial cells.13,18 It becomes active by binding to three high affinity tyrosine kinase receptors [VEGFR-1(flt-1), VEGFR-2(KDR/Flk-1) and VEGFR-3(Flt-4)], that are highly expressed on endothelial tumour vessels but not on mature vessels. They exert different effects on endothelial cells (ECs). VEGFR-1 mediates cell motility of ECs, whereas VEGFR-2 regulates vascular permeability and VEGFR-3 lymphoangiogenesis.13,14,19

Hypoxia appears to be the principal stimulus for the production and the stabilization of VEGF and VEGF mRNA, but recent evidences suggest that VEGF expression has increased in many tumours, as well in absence of hypoxia. This increase results from at least three factors: (A) loss of function of some tumour suppressor genes (such as the von Hippel-Lindau (VHL), p53, p16); (B) activation of oncogenes (including raf, ras,HER2/erb2 (neu) and src15,20-22) (C) excessive quantity of growth factors, produced by tumour cells and their supporting network (fig. 2).14,16

Tumor Neovascularization

The acquisition of new in-growing vessels may occur by different mechanisms. ECs are normally quiescent and tightly regulated by a delicate balance between proangiogenic and antiangiogenic molecules.14,15 In presence of an excessive secretion of angiogenic molecules by tumours, ECs are stimulated and they organize themselves in vessel structure through multistep sequential and distinct processes, depending on tumour type and anatomic localization. These processes include vessel Cooption, vasculogenesis and angiogenesis.


It is the process in which tumours take up preexisting normal blood vessels and use them for their initial growth. As just described, this is a limiting process and irrelevant in the great majority of solid tumours; in fact, cancer cells grow until oxygen demand exceeds supply and the distance from host vessels is lower than 100-200 μm.14


It is the mechanism in which precursors endothelial ECs from bone marrow are recruited by the tumor and aggregate to form new blood vessels. Recent studies have demonstrated this process in experimental animal tumours, but its relevance in human neoplasia is not fully elucidated.23-25


Upon adequate stimulus, endothelial cells begin to sprout from preexisting capillaries and after the degradation of the extracellular matrix (ECM) by matrix metalloproteases, and the expression of adhesion molecules such as αvβ3 integrin, migrate and organize themselves in capillary tube formation and ultimately in a vascular network.6,16

Tumor Vascular Morphology-Perfusion and Hypoxia

Blood vessels associated with the tumor tend to be significantly different in architecture from the surrounding normal tissue (see Table 1)26-28 and they show, in presence of VEGF and other cytokines, a decreased expression of leukocyte-endothelial cell adhesion molecules (ICAM-1,VCAM-1, E-selectin ) and an enhanced expression of CD 44.29-31 The decreased expression of adhesion molecules reduce significantly leukocytes and natural killer cells (NKs) recruitment, partially contributing to the phenomenon of immune-evasion,30,32 whereas the enhanced expression of CD44 may confer a growth advantage on many neoplastic cells.15

Table 1. Structural and functional abnormalities of tumor vasculature.

Table 1

Structural and functional abnormalities of tumor vasculature.

Moreover, VEGF induces tumor neovessels to become leakier and to lose a large quantity of fluids (proteins and other circulating macromolecules) towards the interstitium.33-36 Fluid accumulated inside the tumor interstitium, known as tumor interstitial fluid (TIF), occupies from 30% to 60% of the tumour volume and compared to normal fluids it has a different biochemical nature.36,37 TIF retention causes an increase in tumor interstitial pressure (TIFP) (fig. 2).37-39 TIFP increase goes from tumour centre towards periphery, reaching the value of 50 mm Hg, as Jain and coworkers measured in human and experimental tumours on colon, breast, head-neck carcinomas and metastases specimens from lung, liver and lymph nodes.40-42

Tumor blood flow (TBF) is determined by arteriovenous pressure difference (Δ Pa-v) divided by a factor η for Z, where η expresses the flow resistance or blood viscosity and Z the geometric resistance.34

TBF = Δ Pa-v/ η Z (1)

Normally in tumors, Δ Pa-v is lower than in normal microcirculation. This is caused by the increased number of arteriovenous fistulae present at tumor periphery, that creates a low resistance pathway at tumour surface and diverts blood from entering the tumour mass. Indicator dilution methods, angiography and experimental studies have confirmed this anomalous behaviour.34,35 Associated to low perfusional tumour supply, Sevick and Jain have found that viscosity parameters Z and η were abnormally high on tissue isolated mammary Adenocarcinoma (R3230AC) and on 22 carcinosarcoma. The geometric resistance Z is a complex function of vascular morphology (i.e., number of blood vessels, branching pattern, diameter, length and volume), and increases according to tumor size, length and vessel tortuosity.42 Tumor neovessels are tortuous, heterogeneous, inefficient and devoid of hierarchisation, as confirmed by different Authors using biochemical, corrosion cast and electronic microscopic studies.27,28

Tumor blood viscosity η has been found elevated and correlated with the shear rate, hematocrit and circulating blood cells deformability.34,43

Normally capillary diameter ranges from 3.5 to 20 μm, so at some point along their travel in the capillaries, red blood cells (RBCs) as well as white cells (WBCs) have to undergo deformation to pass through. By contrast in the tumor microvasculature, various factors can modify RBCs and WBCs deformability. Particularly the low oxygen partial pressure, the acidic pH, and the increased concentration of fibrinogen tend to make red blood cells and leucocytes less deformable, and more sticky, thus easily trapped intravascularly and blocking TBF.34

A further modifier factor of viscosity is the local increase of the hematocrit. Several authors34,36,44,45 have demonstrated that this phenomenon is to be ascribed to the fluid loss operating in tumor capillaries with a consequent local hemoconcentration and further worsening of blood flow.

Blood flow measurements in human cancer show heterogeneous values going from highly vascularized organs, such as brain, and poorly vascularized, such as adipose tissue. Perfusion flow at tumour level is higher or lower than in the tissue of origin, depending on the physiological state of the latter.34,45 It is higher at the tumour periphery than in the central zone and generally primary tumours are better supplied than metastatic lesions. In most studies, perfusion on rodent tumours decreases with tumour size when compared to normal tissue. However, in the minority of experiments the decreased flow was not confirmed even in a similar tumor type. Several pathophysiological mechanisms have been proposed to explain this difference such as transplantation site, stage of tumor growth, flow registration and recording methods.5

TBF is not regulated according to metabolic demand as in the case of normal tissues.4 This decreased metabolic adaptability to cells associated to an irregular blood availability (perfusion) produce a clusters of cells, lacking nutrients and oxygen (hypoxic cells).46

Two kinds of hypoxic or clusters of cells in situation of low energy state have been recognized: (A) Diffusion-limited or chronic hypoxic cells; (B) Transient or acute hypoxic cells. The two types of hypoxia have different origin and coexist together in a well-perfused zone of the tumour mass too, causing a functional disturbance of macro and microflow.4,5 A more realistic vision shows that these two situations change continuously, because tumour blood flow is time fluctuating.45-47

Chronic hypoxia is the result of availability of nutrients and oxygen towards the tumoral tissue, the diffusion in the extracellular space and the respiration rate of cancer cells.4,5 It has been calculated and observed that when cancer cells are >100-200 μm away from functional blood supply become hypoxic and suffering (fig. 1, fig. 3).

Figure 3. Photomicrograph of a section of mammary tumor, developed by a 5 month old female transgenic MMTV-neu (erbB2) mouse.

Figure 3

Photomicrograph of a section of mammary tumor, developed by a 5 month old female transgenic MMTV-neu (erbB2) mouse. T = tumor cord; N = necrosis; L = lymphatic vessel; C = capillary. Hematoxylin and Eosin. 20x objective.

Cells adjacent to capillaries displayed a mean oxygen concentration of 2%, located at 200 μm displayed a mean oxygen concentration of 0.2%.47 The distance from the nutritive vessels, the haemoglobin concentration and the blood flow crossing that tumour area are the only parameters responsible for chronic hypoxia. In fact, the removal of O2 by tumour cells, has been calculated to be efficient or better than the one of normal tissues, revealing that neoplastic cells in vivo do not have impaired ability to utilize oxygen as proposed in the past.45

Acute hypoxia is the result of intermittent opening and reopening of tumor blood vessels. Among the various factors responsible for this temporarily blood flow stop, two of them seem the most plausible:

  1. TIFP combined with the irregular expansion of tumour mass, whose three dimensional growth is subjected to a continuous remodelling in a confined space and it causes a temporary compression or occlusion of some tumour capillaries.5,37-39
  2. transient stop of tumor blood flow or supply by platelets plug (see fig. 4).5,47
Figure 4. Photomicrograph of a platelet thrombus in a peripheral blood smear of a mouse bearing an Ehrlich carcinoma implanted on the hind leg.

Figure 4

Photomicrograph of a platelet thrombus in a peripheral blood smear of a mouse bearing an Ehrlich carcinoma implanted on the hind leg. MGG staining. X 63 objective. Differential interference contrast.

In our opinion, this intravascular thrombosis deserves to be taken into much higher account than usually done.47 In fact, the majority of cancer patients have coagulation abnormalities associated to hypoxia.48 Recently, it has been demonstrated that hypoxia not only induces VEGF but also stimulates endothelial cells to over express tissue factor (TF) and Plasminogen activator inhibitor (PAI-I). These factors induce endothelium to become prothrombotic and cause fibrin formation and platelet activation.49 Furthermore, VEGF binds to fibrinogen and fibrin by stimulating endothelial cell proliferation.50 Fibrin has been demonstrated to be essential for supporting endothelial cells spreading and migration.6 The haemostatic system, in a certain sense, becomes a regulator of angiogenesis and it can partially explain acute hypoxia and its regional appearance and disappearance.5,47,48,51 Concluding hypoxia becomes a self-perpetuating mechanism able to trigger angiogenesis, intratumoral fluid accumulation and thrombosis (fig. 2, fig. 4).48

Tumor Bioenergetic Status, Hypoxia, pH

Normally cancer cells display many altered metabolic abnormalities including an increased capacity to metabolise carbohydrates mainly by anaerobic glycolysis even under aerobic conditions. This metabolic behaviour results from the induction of many enzymes* involved in the intermediate reactions of glycolysis by HIF-1 genes.52-54 The relevance of these alterations is that oxidation of glucose stops at the stage of pyruvic acid and proceeds anaerobically producing for the same ATP amount six times more lactic acid and H+ than normal cells. The excessive lactic acid and H+ accumulation in tumour milieu, matched with the compromised interstitial fluid transport, causes the decrease of the external tumor pH (pHe).55-58 Recently studies indicate that both local glucose-glutamine and oxygen availabilities affect tumour acidity independently. In the authors' opinion these findings have significant implications for cancer treatment.59

Most pH estimations in tumour tissues were obtained by the insertion of microelectrodes.58,60 They demonstrated the value of pHe in a range between 5.6 to 7.6 (normal tissue pHe is 6.8) and they pointed out that tumors grow in an acidic environment. However for many years microelectrodes measurements were inaccurate and the calculated pHi was thought to be acidic. Recently the advent of31 P magnetic resonance spectroscopy, noninvasive method of measurement, has permitted to measure pHi and pHe simultaneously more accurately. Associated to these measures other parameters of interest can be obtained and are: tissue perfusion and vessel permeability. These studies have shown that in a majority of animal and human tumors pHe is lower than pHi. In fact, the tumor pHi resulted, similar to that normal tissue or near neutrality (i.e ± 0.1 to 0.2 pH units) whereas pHe obtained from different human tumors were 0.41 ± 0.27 units lower than the normal tissue one.60,61 The neutral pHi and pH gradient with the acidification of tumor milieu can be explained by the following factors:

  1. In normal tissue the lactic acid, accumulated in the interstitial fluid, is rapidly removed through lymphatic drainage, whereas in TIF is not so easily removed (due to a compromised vasculature and an absent lymphatic drainage).56
  2. Cancer cells, as normal cells, express a number of pH regulatory mechanisms to maintain a cytosol pH near neutrality (pHi = 7.4). The mechanisms underlying regulation of intracellular pH have been identified as their inhibitors and are illustrated and listed in Table 2 and Figure 5.62 A brief description of the most important exchanger mechanisms active in cancer cells and their inhibitors is reported:
Table 2. pH regulators and inhibitors.

Table 2

pH regulators and inhibitors.

  1. Vacuolar-type H+ ATP-ase is a ion transporter regulated by ATP dependent mechanism.
  2. H+-lactate cotransport Na +/H * exchanger [MCT],is an exchanger mechanism reversibly blocked by Amiloride and quercetin.
  3. Na+dependent Cl-/HCO3- exchanger [BCT], is blocked by disulfonic stilbene derivative 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid [DIDS]
  4. Sodium-proton exchanger [NHE]. The NHE family of ion exchangers includes six isoforms (NHE1—NHE6) that function in an electroneutral exchange of intracellular H+ for extracellular Na+ They are blocked by Amiloride and its derivative Cariporide. 5,6) electrogenic Na+-HCO3- cotransport

The lactate efflux and formation can be also blocked by metabolic inhibitors such as: lonidamine or by meta-Iodio-benzylguanidine (MIBG) or alpha-cyano-4-hydroxy-cinnamic acid (CNCn). These drugs are active on mitochondrial generation of lactic acid by blocking Krebs cycle) (Table 2 and fig. 5).

Figure 5. In this diagram the pH regulatory mechanisms and the inhibitors used to acidify in a acute way the intracellular environment are illustrated.

Figure 5

In this diagram the pH regulatory mechanisms and the inhibitors used to acidify in a acute way the intracellular environment are illustrated. 1) vacuolar -type H+ ATP-ase ; 2) H+- lactate cotransport Na+/H* exchanger [MCT], 3) Na+ dependent Cl-/HCO3- (more...)

Effects of Hyperthermia on Metabolism

Recent studies have emphasized that metabolic alterations often follow hyperthermia.63 Mueller-Klieser et al,64 using bioluminescence and photon counting methods for imaging in situ the metabolites used by tumour tissues, have shown an enhanced glycolytic activity followed by an increase in lactate levels upon heating application.65 The higher glucose and lactate concentrations may be the result of a temporarily increase in blood flow and an expansion of interstitial tumour compartment.66 Furthermore, the intensified acidosis with the enlargement of hypoxic tumor areas that follows the transient decrease in tumor perfusion application sensitize and facilitate tumor cell destruction by hyperthermia (fig. 6).67,68

Figure 6. In this figure the effects of HT on hypoxic cells, on tumor microcirculation and on surrounding normal tissue are illustrated.

Figure 6

In this figure the effects of HT on hypoxic cells, on tumor microcirculation and on surrounding normal tissue are illustrated. In bold black are shown the direct effects of HT, whereas the indirect effects are shown in gray. (Modified with permission (more...)

Effects of pH on Hyperthermia

Since Gray's studies in the fifties (1955),69 it has been demonstrated that hypoxic and acidic regions in solid human tumors are common. These cells, chronically exposed to low extracellular pH, are relatively resistant to ionizing radiation but they tend to be markedly sensitive to the thermal damage.68,70 Earlier studies, in vitro conditions, ascribed this effect to the low pH of tumor milieu (pHe) and showed that thermosensitization was more evident at mild temperatures (e.g., <42°C) rather than at higher temperatures. Gerweck and coll have demonstrated that environmental parameters such as hypoxia and acidosis, can strongly modify the cellular hyperthermic response. The Chinese Hamster Ovary (CHO) cancer cells survival curves in vitro have clearly evidenced that the oxygen enhancement ratio (OER) for hyperthermic cell kill is ≈ 1 in contrast with 2.5 to 3.0 for radiation inactivation (fig. 7).70 From these studies the authors concluded that hypoxic cells appeared to be slightly more sensitive to hyperthermia than oxygenated cells. As hypoxic cells live in acidic environments, these authors studied the same CHO cells in vitro at different pH of medium (see fig. 7). They concluded, in accordance with other authors, that exposure of tumor cells to hyperthermia at conditions of pH below 7.4 enhanced cell lethality. Such increased cell sensitivity, often larger by a factor of 102 at some dose level, continued even during the development of thermotolerance.69,70 For clinical purposes, Gerweck and Richards71 have introduced the concept of “pH enhancement ratio” that is the ratio of the inactivation rates at pHe 6.7 vs. pH 7.4. This pH range has been calculated in vitro on different tumor cell lines and according to these authors, it is the only value among which pH sensitisation takes place.71 These authors refer that the pH sensitising effect is manifest over a pH range which is observed in tumor tissue, i.e., pH 6.6 to 7.0 (fig. 8).68,70,71

Figure 7. OER curves of Chinese hamster ovary cells (CHO) treated with hyperthermia.

Figure 7

OER curves of Chinese hamster ovary cells (CHO) treated with hyperthermia. Hypoxia was induced 10-20 min prior to treatment. (Suit an Gerweck , Cancer Res 1979; 39:2290-2298. Reprinted form ref. with permission).

Figure 8. CHO cells cultured at different pH under aerobic conditions and heated during the midportion of pH exposure conditions.

Figure 8

CHO cells cultured at different pH under aerobic conditions and heated during the midportion of pH exposure conditions. (Suit an Gerweck , Cancer Res 1979; 39:2290-2298. Reprinted from ref. with permission).

However, heat sensitivity of cancer cells seems to be limited when they are exposed to a chronic low pHe.72 In fact, Hahn and Shiu,73 after studying CHO cells in vitro, maintained in acidic medium for different time before the exposition to heat treatment, have demonstrated that cells exposed to a low pH for prolonged periods were less sensitive to heat than cells exposed to an acidic medium shortly before heating. Other authors have confirmed these observations and have shown that cancer cells exposed for long period to low pH milieu, are less responsible to heat treatment and have a higher pHi compared to a brief period adapted one.69,70,74 Other experimental studies have demonstrated that it is sufficient an acute reduction of pHe below 7.0-7.2 to increase the hyperthermia damage and to decrease thermotolerance.69,70,75,76 These studies in vitro have been performed under conditions where pHe was rapidly altered, a condition that does not correspond to one in vivo conditions where low pHe is gradually achieved and the cells are exposed to an acidic environment for more prolonged periods, the so-called chronic hypoxic cells. These phenomena can explain the less dramatic effects on hypoxic cells obtained on patients after a treatment of hyperthermia as reported by van der Berg.77 Recent studies have tried to differentiate the pHe sensitising effect in vitro and in vivo. Rhee et al78 studied the effectiveness of low extracellular pH in sensitising cells to heat using SCK mammary carcinoma cells of A/J mice. They have demonstrated a different thermosensitivity and thermotolerance following hyperthermia, at different pH values (pH 7.2, 6.6, 5.5) on in vivo and in vitro derived cells. For any heating temperature tested the sensitising effects of pH was much smaller on in vivo derived cells that on in vitro derived cells. Furthermore, this reduction of pH effect was observed for cells derived from larger tumors as well as tumors at an early stage of growth in which the internal milieu was not acidic. This indicates that cellular adaptation to low intratumor pH was not the sensitising factor and might be related to other factors than pH, such as nutrients deprivation and decreased blood perfusion.78,79

Although recent experiments proved that thermosensitivity is more dependent upon pHi rather than pHe75,80 pHe value alone has demonstrated to be a useful prognostic indicator and that the reduction in pHe induces a decrease in the intracellular pH.81-85

Since that extracellular pHe is the result of lactic acid accumulation, von Ardenne86 tried to further lower the tumor milieu pH through the administration of supraphysiological levels of glucose. Earlier animal and human experiments indeed demonstrated that intraperitoneal or endovenous injection of glucose reduced intratumor pHe and increased the response to thermotherapy. 86-88 However, recent studies have evidenced that the change of pH is induced by tumor blood flow reduction or nutrition deprivation rather than by the increased glycolysis (fig. 9).79,83

Figure 9. In this diagram the direct effects of glucose administration (bold white) on Tumor Blood Flow (TBF) and on tumor extracellular/intracellular pH are illustrated.

Figure 9

In this diagram the direct effects of glucose administration (bold white) on Tumor Blood Flow (TBF) and on tumor extracellular/intracellular pH are illustrated. Associated are shown the indirect effect of hyperglycaemia on cardiac output (bold gray) with (more...)

Although the experimental evidence has demonstrated that hyperglycaemia is a useful method for enhancing the response to thermoradiotherapy, its clinical application is not yet of routine. This is partly due to a fear of inducing uncontrollable physiologic alterations and to an absence of a standardized protocol.89- 91 The clinical application and administration of hyperglycaemia will be discussed later.

Hyperthermia Effects on Tumor Blood Flow and Endothelium


Hyperthermia has as principal goal that of destroying tumor tissue (vasculature included) by achieving a temperature that exceeds the cytotoxic threshold (42.5°C) and induces cell death in tumor tissue with a selective sparing of normal surrounding tissue.92

Although cancer cells are destroyed by hyperthermia alone, many factors, including the cell type and blood perfusion, influence its success. In fact, it has been shown experimentally and theoretically that heat transferred away from a tissue is the result of the rate and the volume of blood flowing through that tissue (perfusion).93- 95 Since the importance of blood perfusion in heat dissipation, a brief description of heat effects on tumor blood flow [TBF] and on endothelium is useful.

Effects on Tumor Blood Flow (TBF) and on Normal Circulation

The relationship between temperature rise and perfusion has been demonstrated by Jain et al92 to be inversely correlated: as the perfusion rate decreases the tumor temperature increases. The gap in temperature obtainable between normal and tumor tissue is due to the differences in conduction and convection characteristics between the two tissues.96

Tumor blood flow and distribution are different from normal tissue and show regional variations in the same tumor itself as quantified by Gullino and Grantham.93 Blood flow in human cancer showed a greater variability as compared to animals, however a different flow between normal and tumor tissue exists.46 Tumor blood flow appears to be inferior than that of normal tissue and to have a decreased adaptability to metabolic demands and physical stress (heat).45 The reasons are to be ascribed to the absence of innervation.45,46 The vasodilatation that happens after heat application to normal tissues is not present at the same extent in tumor vasculature.96,97,98 This determines a decreased convection and permits to entrap heat in the tumor area, rising the temperature in that target area.97,98 In fact, different authors heating deep seated human tumors by radiofrequency (13.56 MHz) therapy, have reported that tumor temperature was higher than that of surrounding normal tissue.99-103

After heat exposition macroscopic blood flow measurements in normal tissue such as skin or muscle showed a rapid and a dynamic vasodilatation with increased permeability of the vascular wall (fig. 6). Song94,95 and Vaupel97 demonstrated that the degree of alteration was temperature and treatment duration dependent. The heating changes in the tumor were slightly absent or increased at the beginning of treatment, if the treatment time was prolonged a decrease with a stasis of blood flow took place.97,98 Similar conclusions on blood flow behaviour during hyperthermia have been reached by other authors using microscopic measurement such as RBC velocity, laser doppler flowmetry and hydrogen clearance methods.97,98 Jain et al68 studied RBC velocity and vessel lumen diameter in mature granulation tissue and in neoplastic tissue (VX2 carcinoma). They found and confirmed the above-mentioned observations, but noted that stasis occurred in normal and tumor tissue both. The difference in stasis was dependent on temperature. In fact, the stasis in normal tissue occurred later and at higher temperature (47°C) whereas stasis in tumor tissue was reached before and at a lower temperature (41.00°C).98 As for stasis, Li96 founded that the recovery kinetics of tumor blood flow after heating was temperature dependent, i.e., blood stasis occurred in the range 3-5 hr after heating, remaining low for 24 hr and partially recovering after 48 hr. Aside the vasodilatation a complexity of other events follow heat application. They are different biochemical and microcirculatory changes, such as: acidosis, RBC stiffening and aggregation, degenerative changes of endothelium, increased vascular permeability, platelet aggregation, leukocyte sticking and intravascular clotting (fig. 6).97,98 These phenomena worsen the tumor microenvironment further and explain why neoplastic cells are damaged more easily by temperature (42-45°C) than normal cells.95

Effects on Endothelium

Different in vivo and in vitro studies have shown that endothelial cells [ECs] and in particular those proliferating ones can be damaged by heat.104 The damages can regard the integrity of endothelium or its vulnerability to heat. Histological methods have revealed that after hyperthermia, a rapid reduction and rearrangement of F-actin stress fibers follows. These fibers maintain the junctional integrity among the cells. Their lack determines an increase in vascular permeability, a phenomenon usually observed after HT.103,104 The effects of hyperthermia are not however similar in all tumor types. This difference has been demonstrated by Nishimura105 and it is dependent on the quantity of connective tissues present in the vascular architecture. Furthermore Hyperthermia regulates positively different adhesion molecules on endothelium surfaces providing an increased recruitment of T cells to tumors.106 This effect, associated to the increased vascular permeability and extravasation, partially explains the escape of leukocytes from the vasculature and the peritumoral inflammatory reaction.

As described, tumor blood vessels are more vulnerable to heat than normal surrounding blood vessels, probably for their structurally immaturity.4,5,95 Furthermore, tumor vessels, as neoplastic cells have shown to acquire thermal adaptation (Thermotolerance) to reheating.94 This phenomenon, referred by Song as vascular Thermotolerance (VT), differs as regards neoplastic cells Thermotolerance (NT). NT refers generally to a resistance to heat induced cell killing through the production of Heat shock proteins (HSP), while VT is a thermal adaptation developed by tumor vessels that initially respond to the stress of reheating by increasing blood flow instead of reducing it. The reasons for this behaviour are not completely known and remain actually only speculative.94

Antiangiogenetic Effect of Hyperthermia

Hyperthermia has demonstrated to kill tumor cells by a direct and an indirect mechanisms. 97 The indirect killing mechanism has been recognized as an inhibitory effect on angiogenesis. In the 60s the inhibition of angiogenesis was ascribed to ischaemia with a consequent obstruction and destruction of tumor blood vessels followed by an inability to form new vessels.97,104 Recently a biochemical mechanism has been recognized.107 These Authors have clearly demonstrated that heat application can inhibit angiogenesis by activation of a Plasminogen Activator Inhibitor I-dependent mechanism (PAI-I). The effect has been investigated and found operating in vivo and in vitro with a reduction in the number of microvessels. Endothelial cells viability was not affected.107

Clinical Methods for Improving Thermoresponse


Tumor vascular supply is extremely important for maintaining tumor growth, progression and metastasization. Furthermore, tumor perfusion can affect related micro environmental parameters, such as oxygenation status, pH distribution, bioenergetic status, nutrient supply and sensitivity of cancer cells to anticancer treatments, hyperthermia included.95,96 Blood flow is the major determinant of heat dissipation and it is responsible for the selective and uniform heating increase in tumor target area respect the normal counterpart.92 The relationship between blood flow and the effective tumor conductivity has been studied by Jain et al,92 who found that temperature rise in tumor mass is inversely and linked to the effective thermal conductivity. Since hypoxic cells and preferentially cells exposed, to an acute acidification have shown an increased thermosensitivity (fig. 7), many investigators have developed different methodologies with the aim of increasing thermoresponse as the heat induced cell damage.95

Clinically, a modification of tumor thermoresponse could be obtained or modulating tumor blood flow, tumor microenvironment or trying to ameliorate the heat deposition into the tumour tissue (Table 3, and fig. 10).95,97,103,108 Otherwise expressed the clinical attempt to increase the heat response can be reached or by inducing hypoxia through blood flow manipulation or trying to render tumor cells more vulnerable to heat.

Table 3. Clinical methods for improving thermoresponse.

Table 3

Clinical methods for improving thermoresponse.

Figure 10. In this figure the interactions of Hyperthermia with the chemotherapy and radiotherapy are illustrated together the principal points of tumor microenvironment modification [TBF (Tumor Blood Flow); Micromilieu, Membranes, Metabolism] for improving the therapeutic response to heat.

Figure 10

In this figure the interactions of Hyperthermia with the chemotherapy and radiotherapy are illustrated together the principal points of tumor microenvironment modification [TBF (Tumor Blood Flow); Micromilieu, Membranes, Metabolism] for improving the (more...)

Tumor Blood Flow (TBF) Modulation

Blood Flow Reduction or Deprivation

Cutting off the tumor's blood supply by physical clamping produces 100% radiobiological hypoxia109 that increases cancer cells death by apoptosis. Field83 has demonstrated drastic changes in the isoeffect relationship when deprivation of blood supply by clamping was applied upon hyperthermia. Firstly, tumor tissue becomes more sensitive, equivalent to a factor near two in heating time; secondly the transition at 42.5°C is eliminated, showing a reduction or an abolishment of thermotolerance.

Clamping of Nutritive Vessels

Blood flow deprivation by clamping blood supply has been demonstrated in vivo to make tumor cells totally hypoxic and to enhance significantly thermal sensitivity on animals. Thermal enhancement had a ratio of 1.8-2.6 and was dependent on time. The proportion of tumor controlled by hyperthermia increased alone from 33% to 83%, depending on whether the clamp was applied immediately before heating or 60' before heating. No cures were observed for heat applied immediately before clamping, or immediately after the release of the clamp110 Other authors have demonstrated that vascular occlusion by clamping followed by glucose load can decrease tumor pH further and consequently enhance thermoresponse.83


Since blood flow reduction by clamping is not clinically attainable, embolization has been used as a method of blood flow stoppage.111 Embolization of liver tumors can be indicated for the treatment of colorectal metastases, hepatocellular carcinoma (HCC), and metastases from other parts of the body. Chemoembolization is a combination of two effective therapies with the aim of improving both. One is the high concentration drug delivery to tumor mass, the second is the production of hypoxia for inhibiting the active efflux of the administred drug.111 As previously reported hypoxia improves the response to heat.69 This does chemoembolization an efficient method of treatment in association with thermotherapy for treating liver. Liver has two main blood supplies which keeps it alive and functioning. The portal vein supplies 75% of the blood entering the liver and the hepatic arteries supply the remaining 25%, although they are the ones that provide nearly 100% of the blood that feeds primitive and secondary liver tumors.111 The seal of hepatic arteries concentrates the level of chemotherapy, 10 to 25 times higher, than that of standard chemotherapy. To underfed humans liver tumors hepatic arteries are blocked or embolized by different methods. The most used is an oil-based mixture associated to chemotherapy. This embolization consists in lipiodol (ethiodizedoil) or starch microspheres (DSM) alone or associated with chemotherapy. DSM (Spherex, Pharmacia, Sweden) are particles of cross-linked starch, measuring 20-70 μm, degraded by amylases, and able to block hepatic artery transiently and reversibly. Tanaka et al112 blocked the hepatic artery, injecting a mixture of Lipiodol/or DSM plus anticancer drugs [e.g., Mitomycin C (10-20 mg) or 5-FU (500-750 mg)]. Forty eight hours after this block they performed hyperthermia twice a week for a total of 4-6 treatments. Results of this HT schedule were evaluated by CT images and angiograms. The mean maximal temperature(TMAX) reached was of the order of 41.5°C and the response rate was of 40%.

Drugs Able to Modify Tumor Blood Flow95,96,103,108,113

The goal of TBF modulation by drugs is to make the tumor sufficiently hypoxic/or underfed and consequently more thermo sensible, similarly to clamping or Chemoembolization. Drugs, which are of course less cumbersome of the preceding methods of treatment, are of two types: vasodilatators and agents that attack vascular endothelium (VTA). Vasodilatators starves the tumor through a steal phenomenon, while VTA get tumor hypoxic by disrupting and decreasing the nutritive vessels.

  1. Vasodilatators: Hydralazine, Calcium blocking agents (verapamil, flunarizine), Serotonin and its Analogues.102,103,108
  2. Vascular Targeting Agents (VTA): FAA, DMXXA, CA4DP, TNF; IL-1.76,103,114,115

Microenvironment Modification

Hyperglycaemia and Drugs Acting on Tumor Metabolism

Hyperglycaemia and drugs act on tumor metabolism.76,75,,86,88,92 Several animal studies have demonstrated that hyperglycaemia can sensitise mammalian cells to heat.116,117,118 Initially the effect was thought to be metabolic induced (pH drop, due to excessive lactic acid production), but recent studies by Ward-Hartley and Jain have demonstrated that the hypoxia and pH reductions are secondary to the tumor blood flow reduction.103 Calderwood and Dickson reported that intraperitoneal injection of glucose reduced tumor blood flow by more than 90% for a few hours.116 Furthermore, these authors have demonstrated that blood flow inhibition and pH reduction are related to the serum concentration of glucose level.117 Nagata118 reported similar effects on 25 cancer patients who received intravenous injection of 500 ml of 10% glucose. Tanaka102 has clearly demonstrated that patients treated with hyperglycaemia were more responsive to thermoradiotherapy than a control group treated by thermoradiotherapy alone. The mechanisms responsible for blood flow reduction in tumors during hyperglycaemia are multiple and have been explained by Ward and Jain.92 The reduction is a consequence of systemic and local effects both. The systemic effects were ascribed to a significant cardiac output redistribution that consequently reduced tumour blood flow by steal phenomena (see fig. 9). The local mechanism that contributed to reduce tumor blood flow was linked to Red blood cell (RBC) deformability decrease. Initially this increase in rigidity was postulated to be pH dependent,95 but Crandall et al119 have demonstrated that it was necessary a long exposure time to a low pH for obtaining a RBC rigidity. Traykov and Jain questioned this lag period and demonstrated that RBC deformability followed almost immediately the infusion of glucose and galactose.120 This rapid local phenomena associated to the steal effect of cardiac output are responsible for the initial blood flow reduction. The metabolic interaction with pH decrease can perpetuate the reduction of blood flow for many hours after glucose administration. Studies by Hasegawa121 have shown that a difference in pH drop exists between tumor and normal tissue. In fact, 30-60 min after glucose administration the pH rapidly dropped of 0.3 to 0.6 units in tumor, as compared to a decrease by only 0.1 unit of normal tissue. The complete recovery to baseline was also different in the two tissues. Animal studies have demonstrated that the administration of glucose prior to hyperthermia can modify tumor regrowth and thermotolerance (i.e., fig. 11).122 Tumor regrowth delay was greater in the group treated with glucose as compared to the group not treated. Thermotolerance disappeared 12 h after heat treatment in the group with glucose administration, whereas in the untreated group thermotolerance disappeared only after 72 h.122 The majority of experimental studies have been performed in vitro and in animals. Recently, after the increased use of hyperthermia in association with radiotherapy, many human studies have been performed. Dickson Calderwood demonstrated that serum glucose levels in the range of 1000 mg/dl can cause a complete cessation of tumor blood flow.116 Similar levels of glucose in humans are however not attainable without side effects. Levels of 400mg/dl have been demonstrated by Lippmann et al123 the maximum attainable for long periods (24h) with no modifications of blood count and acid base equilibrium. Krag et al91 with the goal of achieving a steady level of 400 mg/dl for short periods of time (3h), intravenously administered a glucose loading dose of 77 mg/m2 to three patients with advanced metastatic cancer. After 20 minutes, levels over 400 mg/dl were obtained and maintained for 3 h with no apparent side effects and rebound hypoglycaemia. Levels beyond 700 mg/dl were attempted, but could not be maintained without side effects. Other authors have studied and compared the effects on tumor blood flow, pHe and the clinical response of human patients submitted to a glucose load.124-126 Nagata et al125 demonstrated that a glucose administration of 500 ml of 10% glucose by intravenous route reduced the tumour blood flow, measured by laser Doppler flowmetry, to 66% of the baseline level at 30 min after the beginning of infusion. A complete tumor response (CR) of 30% was obtained on glucose treated patients compared to a group treated only by Radiotherapy and hyperthermia.125 Leeper et al126 have determined whether intravenous (i.v.) or combined intravenous plus oral glucose administration were more effective in inducing acute tumor extracellular acidification. They concluded that the effects of hyperglycaemia induced by i.v. + oral administration were similar and i.v. exhibited an acidification of 0.14 ± 0.002 pH unit after 91 ± 7 min of infusion. Engin and coll.85 have evaluated the importance of extracellular pH as prognostic indicator of tumor response to thermoradiotherapy. The authors measured the tumor pHe of 26 human tumors with a needle microelectrode of 2.5 cm of length. They reported that the difference in pHe exhibited by complete responding (CR) patients and noncompletely responding (NCR) 6.88 ± 0.09 versus 7.24 ± 0.09 was statistically significant (p≥0.08). On these grounds, they suggest that extracellular pHe measurement may be a useful prognostic indicator of tumor response to thermotherapy. Although, a pHe reduction of ≈0.2 units is easily obtainable by glucose load,127 greater reduction ≥0.5 units are necessary for inducing acute intracellular acidosis.128 The degree of reduction of pHi that accompanies acute extracellular acidification is the critical factor for sensitizing cells to hyperthermia and for abrogating the heat shock proteins induction. Recently various Authors have demonstrated that for obtaining such pHe drop in melanoma, metabolic inhibitors such as meta-Iodio-benzylguanidine (MIBG) or alpha-cyano-4-hydroxy-cinnamic acid (CNCn) must be added.129 For understanding, the biochemical points of action of these inhibitors (see fig. 9). In conclusion, the concomitant administration of glucose together with MIBG increases the tumour magnitude and duration of acidification and the oxygen tension.130,131 This association has the potential to improve response to radiation therapy and to hyperthermia itself.

Figure 11. Growth curves of BT4 An tumors after ACNU 20 or 10 mg/kg combined with hyperthermia with or without hyupertonic glucose 6 g/Kg i.

Figure 11

Growth curves of BT4 An tumors after ACNU 20 or 10 mg/kg combined with hyperthermia with or without hyupertonic glucose 6 g/Kg i.p. 2 hours before treatment. It is interesting to note the decreased tumor regrowth after glucose-chemotherapy-HT administration. (more...)

The protocol used in our laboratory was similar to that used by Nagata (Table 4).125 Following these studies, we used 500 cc of Glucose at 10% obtaining blood glucose value of 300-400 mg/dl without side effects (unpublished observations). Recently, following the suggestions of Leeper group129-132 we have added to the hyperglycemia two metabolic inhibitors such as quercetin and Amiloride (Moduretic®) (Table 4).

Table 4. Treatment schedule clinically used by our group.

Table 4

Treatment schedule clinically used by our group.

Modifiers of Thermal Sensitivity

Lidocaine and anesthetics,133,134 Calcium antagonists,135 Polyunsaturated fatty Acids.136 Cycloxygenase inhibitors,137 Betulinic acid,138 aldehydes,139 Vitamins and bioflavonoids.139- 142

Heat Delivery Methods

Tumor cell killing curves by heat show a shape that it is both time and temperature dependent and not dissimilar from those obtained for x-rays. The data in vitro are consistent with results in vivo and show that relatively small changes in temperature can have a large effect on cell killing143,144 The critical temperature has been demonstrated to be between 42.5°C and 43°C. Unfortunately the hyperthermia devices now in use are not able to keep this range of temperature for enough time uniformly. This justifies the attempt done by different authors to change or to modify the treatment application.

Rapid Heating

Rapid heating is a method developed by Hasegawa group145 in the attempt to shorten hyperthermic treatment still reaching temperature sufficient to kill tumour cells and to change tumor blood perfusion. The experiments have been made on C3H mice inoculated with SCC-VII tumor in the thigh, heated with warm water bath and RF heating devices. C3H mice were divided in two treatment groups and compared, the former in which the heating temperature was increased to the target temperature in 1 min, and the latter group in which the heating temperature was gradually increased. The following parameters were studied: changes in blood flow in tumour and normal tissue, tumour growth rate, cancer cells apoptosis. Changes in blood flow were not observed in the slow heating group before or after the hyperthermic treatment, whereas in the rapid heating group a significant increase in blood flow was observed in the normal tissue followed by a significant decrease after heat treatment in the tumour tissue. Tumor growth delay was more evident in the RF rapid heating group compared with warm water heating group. Apoptosis and cytokinetic activity modifications were favorable to the rapid heating group, revealing that a vascular injury was effectively obtained with a shortage in treatment time in this group.145 Clinical studies on this methodology are warranted.

Mild Hyperthermia and Oxygenation

As previous described, solid tumors contain regions of low extracellular pH and oxygen that may affect treatment outcome. Laboratory and clinical data confirm that hyperthermia may enhance the therapeutic index of ionizing radiation.143 Several mechanisms have been found and are summarized in the recent reviews of Kampinga144 and Vujaskovic.146 Among these mechanisms, tumor oxygenation improvement after mild hyperthermia (HT with temperature between 39-42.5°C) is now considered to be of the utmost importance. As determined by Song et al,95 normal and tumor tissue show a different behavior following heat deposition. Blood tumor vessels respond markedly different to a second heat application showing a greater vulnerability and vasodilatation to heat than normal surrounding blood vessels. This phenomena, referred by Song as vascular Thermotolerance (VT), appears to account for the improvement in the tumour blood flow observed after the reheating at 42.5°C. As the blood flow increase, an improvement in tumor oxygenation follows which may last for as long as 24-48 h.94,95 Tumor oxygenation by mild HT has been found to be more effective than carbogen breathing in increasing the radiation response of experimental tumors.147 Clinical studies on 18 patients with locally advanced breast cancer treated with thermo-chemo-radiotherapy have confirmed these experimental results. Tumour oxygenation improvement appeared to be temperature dependent and associated with the lower thermal doses.148

Summary and Conclusions

Tumour hypoxia is a problem that makes tumors more resistant to ionizing radiation and chemotherapeutic drugs. Hyperthermia represents a possibility in its overcoming; overall in association with other therapies such as Radiotherapy and chemo — immunotherapy.149 Moreover the effect of Mild HT on oxygenation is of great relevance In fact, temperature of 39-39.5°C is more easily obtainable in clinic than killing temperature of 42.5°C.


We thank for her secretarial assistance N. Tortolone and L. Scappini (Novara university medical library).


Ruiter D, Bogenreider T, Herlyn M. Melanoma-stroma interactions: Structural and functional aspects. Lancet Oncol. 2002;3:35–42. [PubMed: 11905603]
Delpech B. Le stroma des cancers. Bull Cancer. 1991;78:869–900. [PubMed: 1768934]
Singh S, Ross SR, Acena M. et al. Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J Exp Med. 1992;175:139–146. [PMC free article: PMC2119086] [PubMed: 1309851]
Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply and metabolic microenvironment of human tumors, a review. Cancer Res. 1989;49:6449–6465. [PubMed: 2684393]
Freitas I, Baronzio GF. Tumor hypoxia, reoxygenation and oxygenation strategies: Possible role in photodynamic therapy. J Photochem Photobiol B Biol. 1991;11:3–30. [PubMed: 1791492]
Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med. 1971;285:1182–1186. [PubMed: 4938153]
Berges G, Benjamin L. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2002;3:401–410. [PubMed: 12778130]
Mc DonaldDM, Choyke PL. Imaging of angiogenesis: From microscope to clinic. Nat Med. 2003;9:713–725. [PubMed: 12778170]
Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia role of the HIF system. Nat Med. 2003;9:677–684. [PubMed: 12778166]
Semenza GL. HIF-1 and human disease: One highly involved factor. Gene Dev. 2000;14:1983–1991. [PubMed: 10950862]
Semenza GL. Homeostatic regulation by hypoxia-inducible factor 1. Science and Medicine. 2002;8:338–347.
Dachs GU, Tozer GM. Hypoxia modulated gene expression: Angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer. 2000;36:1649–1660. [PubMed: 10959051]
Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18:4–25. [PubMed: 9034784]
Papetti M, Herman I. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002;282:c947–c970. [PubMed: 11940508]
Griffioen AW, Molema G. Angiogenesis: Potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev. 2000;52:238–268. [PubMed: 10835101]
Kurebayashi J, Osuki T, Kunishe H. et al. Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res. 1999;90:977–981. [PubMed: 10551327]
Balbay MD, Pettaway CA, Kuniyasu H. et al. Highly metastatic human prostate cancer growing within prostate of athymic mice overexpresses vascular endothelial growth factor. Clin Cancer Res. 1999;5:783–789. [PubMed: 10213213]
L HlatkyP, Hahnfeldt C, Tsionou C. Coleman: Vascular endothelial growth factor: Environmental controls and effects in angiogenesis. Br J Cancer. 1996;(Suppl XII):s151–s156. [PMC free article: PMC2149987] [PubMed: 8763869]
Pepper MS. Lymphangiogenesis and tumor metastasis: Myth or reality? Clin Cancer Res. 2001;7:462–468. [PubMed: 11297234]
Polverini PJ. How the extracellular matrix and macrophages contribute to angiogenesis-dependent diseases. Eur J Cancer. 32A;14:2430–2437. [PubMed: 9059331]
Cliiford SC, Maher ER. Von Hippel-Lindau disease. Adv Cancer Res. 2001;82:85–105. [PubMed: 11447766]
Grugel S, Finkezeller G, Weindel K. et al. Both v-Ha-ras and v-raf stimulate expression of vascular endothelial growth factor in NIH 3T3 cells. J Biol Chem. 1995;270:25915–9. [PubMed: 7592779]
Takakura N, Watanabe T, Suenobu S. et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell. 2000;102:199–209. [PubMed: 10943840]
Lyden D, Hattori K, Dias S. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 2001;7(11):1194–1201. [PubMed: 11689883]
Abramsson A, Berlin O, Papayan H. et al. Analysis of mural cell recruitment to tumor vessels. Circulation. 2002;105:112–117. [PubMed: 11772885]
Dewirst MW, Tso CY, Oliver R. et al. Morphologic and hemodynamics comparison of tumor and healing normal tissue microvasculature. It J Radiat Oncol Biol Phys. 1989;17:91–99. [PubMed: 2745213]
Konerding MA, Malkusch W, Klaptor B. et al. Evidence for characteristic vascular patterns in solid tumors: Quantitative studies using corrosion casts. Br J cancer. 1999;80:724–32. [PMC free article: PMC2362271] [PubMed: 10360650]
Konerding MA, Steiberg F, van Ackern C. et al. Vascular patterns of tumors: Scanning and trasmission electron microscopic studies on humam xenografts. Strahlentherapie un Onkologie. 1992;168:444–452. [PubMed: 1519160]
Hirshi KK, D'Amore PA. Control of angiogenesis by pericytes: Molecular mechanism and significanceIn: Goldberg ID, Rosen EM, eds.Regulation of Angiogenesis: Birkhauser Press 1997419–428. [PubMed: 9002230]
Griffioen AW, Tromp SC, Hillen HFP. Angiogenesis modulates the tumor immune response. Int J Exp Path. 1998;79:363–368. [PMC free article: PMC3220368] [PubMed: 10319018]
Griffioen AW, Coenen MJH, Damen CA. et al. CD44 is involved in tumor angiogenesis; an activation antigen on human endothelial cells. Blood. 1997;90:1150–59. [PubMed: 9242547]
Carlos TM. Leucocyte recruitment at sites of tumor: Dissonant orchestration. J Leucoc Biol. 2001;70:171–184. [PubMed: 11493608]
Sevick EM, Jain RK. Measurement of capillary filtration coefficient in a solid tumor. Cancer Res. 1991;51:1352–1355. [PubMed: 1997172]
Jain RK. Determinants of tumor blood flow: A review. Cancer Res. 1988;48:2641–2658. [PubMed: 3282647]
Gullino PM. The internal Milieu of Tumors. Prog Exp Tum Res. 1966;8:1–25. [PubMed: 5330588]
Gullino PM. Extracellular compartments of solid tumorsIn: Beckert FB, ed.Cancer, a Comprehensive Treatise. Vol 3, Biology of Tumors: Cellular Biology and GrowthNew York: Plenum,1975327–354.
Freitas I, Baronzio GF, Bono B. et al. Tumor interstitial Fluid: Misconsidered component of internal milieu of a solid tumor. Anticancer Res. 1997;17:165–172. [PubMed: 9066647]
Nagy JA, Herzberg KT, Dvorak JM. et al. Pathogenesis of malignant ascites formation: Initiating events that lead to fluid accumulation. Cancer Res. 1991;53:2631–2643. [PubMed: 8495427]
Steen RG. Oedema and tumor perfusion: Characterization by quantitative 1H MR imaging. Am J Radiol. 1992;158:259–264. [PubMed: 1729777]
Boucher Y, Less JR, Posner MC. et al. Interstitial hypertension in human primary and metastatic tumorsIn: Chapman JD, Dewey WC, Withmore GF, eds.Radiation Research: A Twentieth Century Perspective. Vol 1San Diego: Academic Press,1991465.
Gutmann R, Leuning M, Feyh J. et al. Interstitial Hypertension in head and neck tumors inpatients. Correlation with tumor size. Cancer Res. 1992;52:1993–1995. [PubMed: 1551128]
Sevick EM, Jain RK. Geometric resistance to blood flow in solid tumours perfused ex vivo: Effects of tumor size and perfusion pressure. Cancer Res. 1989;49:3506–3512. [PubMed: 2731172]
Sevick EM, Jain RK. Viscous resistance to blood flow in solid tumors: Effect of hematocrit and intratumor viscosity. Cancer Res. 1989;49:3513–3519. [PubMed: 2731173]
Peterson HI. Modification of tumor blood flow, a review. Int J Radiat Biol. 1991;60:201–210. [PubMed: 1677972]
Vaupel P. Tumor blood flowIn: Molls M, Vaupel P, eds.Blood Perfusion and microenvironment of human tumorsBerlin Heidelberg, New York: SpringerVerlag,200041–46.
Durand RE. Intermittent blood flow in solid tumours an under appreciated source of “drug resistance” Cancer Metastasis Rev. 2001;20:57–61. [PubMed: 11831648]
Baronzio GF, Freitas I, Kwann H. Tumor microenvironment (hypoxia-interstitial Fluid) and haemorheologic abnormalities. Semin Thromb Hemost. 2003;29:489–497. [PubMed: 14631549]
Denko NC, Giaccia AJ. Tumor hypoxia, the physiological link between Trousseau's Syndrome (carcinoma —induced Coagulopaty) and metastasis. Cancer Res. 2001;61:795–798. [PubMed: 11221857]
Verheul HMW, Hoekman JK, Broxterman HJ. et al. Vascular endothelial factor-stimulated endothelial cells promote adhesion and activation of platelets. Blood. 2000;96:4216–4221. [PubMed: 11110694]
Sahni A, Francis CW. Vascular endothelial growth factor binds to fibrinogen and fibrin stimulates endothelial cell proliferation. Blood. 2000;96:3772–3778. [PubMed: 11090059]
Browder T, Folkman J, Pirie-Sheperd S. The hemostatic system as regulator of angiogenesis. J Biochem. 2000;275:1521–1524. [PubMed: 10636838]
Dang CV, Semenza GL. Oncogenic alterations of metabolism. TIBS. 1999;24:68–72. [PubMed: 10098401]
Shapot VS. Biochemical aspects of tumor growth. MIR Publishers. 1980
Behrooz A, Ismail-Beigi F. Stimulation of glucose transport by Hypoxia: Signals and mechanisms. New Physiol Sci. 1999;14(6):105–110. [PubMed: 11390832]
Younes M, Lechago LV, Somano JR. et al. Wide expression of the human erythrocyte glucose transporter Glut 1 in human cancers. Cancer Res. 1996;56:1164–1167. [PubMed: 8640778]
Gullino PM, Grantham FH, Smith SH. et al. Modification of the acid base status of the internal milieu of tumors. J Natl Cancer Inst. 1965;34:857–869. [PubMed: 4284033]
Asby BS, Cantab MB. pH studies in human malignant tumours. Lancet. 1996;2:312–315. [PubMed: 4161494]
Griffiths JR, McIntyre DJ, Howe FA. et al. Why are cancers acidic? A carrier mediated diffusion model for H+transport in the interstitial fluidIn: Goodie JA, Chadwick DJ, eds.The Tumor Microenvironment: Causes and Consequences of Hypoxia and Acidity. Novartis Foundation SymposiumChichester, New York: John Wiley,200146–67. [PubMed: 11727936]
Helmlinger G, Sckell A, Dellian M. et al. Acid production in glycolysis-impaired tumors provides new insights into tumour metabolism. Clin Cancer Res. 2002;8:1284–1291. [PubMed: 11948144]
Stubbs M, McSheehy PMJ, Griffiths JR. et al. Causes and consequences of tumor acidity and implications for treatment. Mol Med Today. 2000;6:15–19. [PubMed: 10637570]
Newell K, Tannock. Regulation of intracellular pH and viability of tumors cells. Funktionsanalyse Biologischer Systeme. 1991;20:219–234.
Izumi H, Torigoe T, Ishiguchi H. et al. Cellular pH regulators: Potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 2003;29:541–549. [PubMed: 14585264]
Vaupel P. Pathophysiological effects of hyperthermia in solid tumors and their clinical implicationIn: Georg H Omlor, Peter Vaupel, Cristof Alexander RG, eds.Isolated Hyperthermic Limb PerfusionGeorgetown: Landes Bioscience,19959–45.
Mueller-Klieser W, Walenta S, Paschen W. et al. Metabolic imaging in microregions of tumors and normal tissues with bioluminescence and photon counting. JNCI. 1988;80:842–848. [PubMed: 3392744]
Vaupel P. Pathophysiological mechanisms of hyperthermia in cancer therapyIn: Gautherie M, ed.Biological Basis of Oncologic ThermotherapyBerlin, Heidelberg, New York: Springer-Verlag,199073–134.
Gerweck LE. Tumor pH: Implication for treatment and novel drug design. Semin Radiat Oncol. 1998;8(3):176–182. [PubMed: 9634494]
Hetzel FW. Biological rationale for hyperthermia. Radiol Clin North Am. 1989;27:499–508. [PubMed: 2648455]
Dudar TE, Jain RK. Differential response of normal and tumor microenvironment to hyperthermia. Cancer Res. 1984;44:605–612. [PubMed: 6692365]
Hall EJ. HyperthermiaIn: Hall EJ, ed.Radiobiology for the RadiologistLippincott: Wilkins Williams,2000495–520.
Suit HD, Gerweck LE. Potential for hyperthermia and radiation therapy. Cancer Res. 1979;39:2290–2298. [PubMed: 36224]
Gerwek LE, Richards B. Influence of pH on thermal sensitivity of cultured human glioblastoma cells. Cancer Res. 1981;41:4019–4024. [PubMed: 7193512]
Gerwek LE. Modifiers of Thermal effectsIn: Urano M, Douple E, eds.Hyperthermia and Oncology. Vol 1The Netherlands: VSP,198883–98.
Hahn GM, Shiu E. Adaptation to low pH modifies thermal and thermochemical response of mammalian cells. Int J Hyperthermia. 1986;2:379–387. [PubMed: 2433369]
Gerwek LE, Richards B. Influence of pH on thermal sensitivity of cultured human glioblastoma cells. Cancer Res. 1981;41:4019–4024. [PubMed: 7193512]
Lyons JC, Kim G, Song CW. Modification of intracellular pH and Thermosensitivity. Radiation Research. 1992;129:79–87. [PubMed: 1728060]
Song CW, Park H, Griffin RJ. Theoretical and experimental basis of HyperthermiaIn: Kosaka M, Sugahara T, Schmidt KL, Simon E, eds.Thermotherapy for neoplasia, inflammation, and painTokyo: Springer Verlag,2001394–407.
Van der Berg A, Wike-Hooley JL, Broekmayer-Reurink et al. The relationship between the unmodified initial tissue pH of human tumors and the response to combined radiotherapy and local hyperthermia treatment. Eur J Cancer Clin Oncol. 1989;25:73–78. [PubMed: 2920770]
Rhee JC, Eddy HA, Salazar OM. et al. A differential low ph effect on tumour cells grown in vivo and in vitro when treated with hyperthermia. Int J Hyperthermia. 1991;7:75–84. [PubMed: 2051078]
Hall EJ. HyperthermiaIn: Hall EJ, ed.Radiobiology for the radiologistLippincott: Williams Wilkins,2000495–520.
Gerwek LE, Dahlberg WK, Greco B. Effect of pH on single or fractionated heat treatment at 42-43°C. Cancer Res. 1983;43:1163–1167. [PubMed: 6825089]
Nielsen OS, Overgaard J. Effect of extracellular pH on thermotolerance and recovery of hyperthermic damage in vitro. Cancer Res. 1979;38:2772–2778. [PubMed: 36226]
Han JS, Storck CW, Wachsberger PR. et al. Acute extracellular acidification increases nuclear associated protein levels in human melanoma cells during 42 degrees C hyperthermia and enhances cell killing. Int J Hyperthermia. 2002;18:404–415. [PubMed: 12227927]
Field SB. In vivo aspects of hyperthermic oncologyIn: Field SB, Hand JW, eds.An Introduction to the Practical Aspects of Clinical HyperthermiaLondon, New York, Philadelphia: Taylor & Francis,199055–68.
Van De Merwe SA, Van Den Berg Block E, Kroon BBR. et al. Temporary vascular occlusion and glucose: Effects on tumour and normal tissue PH in animal experiments. Int J Hyperthermia. 1995;11:829–839. [PubMed: 8586904]
Engin K, Leeper DB, Thistlethwaite AJ. et al. Tumor extracellular pH as a prognostic factor in thermoradiotherapy. Int J Radiation Oncology Biol Phys. 1994;29:125–132. [PubMed: 8175419]
Von Ardenne. Selective multiphase cancer therapy. Conceptual aspects and experimental basis. Adv Pharmacol Chemother. 1972;10:339–380. [PubMed: 4598606]
Dixon JA, Calderwood SK. Effect of hyperglycaemia and hyperthermia on the glycolsis, pH and respiration of the Yoshida sarcoma in vivo. J Natl Cancer Inst. 1979;63:1371–1381. [PubMed: 41958]
Muller—Klieser W, Walenta S, Kellher DK. et al. Tumour growth inhibition by induced hyperglycaemia/hyperlactatacidaemia and localized hyperthermia. Int J Hyperthermia. 1996;12:501–11. [PubMed: 8877474]
Lippmann HG, Graichen D. Glucose and K+ balance during high dosage intravenous glucose infusion. Infusionsther Klin Ernahr. 1977;4:166–178. [PubMed: 561030]
van Den Berg AP, van Den Berg AE, Kal HB. et al. A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model. II. Improved tumor control at clinically achievable temperatures. Int J Radiat Oncol Biol Phys. 2001;50:793–801. [PubMed: 11395249]
Krag DN, Storm FK, Morton DL. Induction of transient hyperglycaemia in cancer patients. Int J Hyperthermia. 1990;6:741–744. [PubMed: 2394924]
Ward KA, Jain RK. Response of tumours to hyperglycaemia: Characterization, significance and role in hyperthermia. Int J Hyperthermia. 1988;4:223–250. [PubMed: 3290346]
Gullino PM, Grantham FH. Studies on the exchange of fluids between host and tumor. II. The blood flow of hepatomas and other tumors in rats and mice. J Natl Cancer Inst. 1961;27:1465–1491. [PubMed: 13902916]
Song CW, Chelstrom LM, Sung JH. Effects of a second heating on tumor blood flow. Radiat Res. 1990;122:66–71. [PubMed: 2320726]
Song CW. Effect of local hyperthermia on blood flow and microenvironment: A review. Cancer Res. 1984;44(suppl):4721–4730. [PubMed: 6467226]
Li GC. Thermal biology and physiology in clinical hyperthermia: Current status and future needs. Cancer Res. 1984;44(suppl):4886s–4893s. [PubMed: 6467242]
Vaupel P, Kallinowski F. Physiological effects of hyperthermia. Recent Results in Cancer. 1987;104:71–109. [PubMed: 3296051]
Reinhold HS, Endrich B. Tumor microcirculation as a target for hyperthermia. Int J Hyperthermia. 1986;2:11–137. [PubMed: 3540146]
LeVeen HH, Wapnick S, Piccione V. et al. Tumor eradication by radiofrequency therapy. Response in 21 patients. J Am Med Assoc. 1976;235:2198–2200. [PubMed: 775137]
Kim JH, Hahn EW, Tokita N. et al. Local tumor Hyperthermia in combination with radiation therapy. 1. Malignant cutaneous lesions. Cancer. 1977;40:161–69. [PubMed: 880548]
Hiraoka M, Shiken JO, Keizo A. et al. Radiofrequency capacitive Hyperthermia for deep-seated tumors, 1. Studies on Thermometry. Cancer. 1987:121–127. [PubMed: 3581026]
Tanaka Y. Thermal response of microcirculation and modification of tumor blood flow in treating the tumorsIn: Kosaka M, Sugahara T, Schmidt KL, Simon E, eds.Theoretical and experimental basis of Hyperthermia. In Thermotherapy for neoplasia, inflammation, and painTokyo: Springer Verlag,2001408–419.
Jain RK, Ward-Hartley K. Tumor blood flow-Characterization, modifications and role in hyperthermia. IEEE Transactions on Sonics and Ultrasonic. 1984;31:504–526.
Fajardo LF, Prionas SD. Endothelial cells and hyperthermia. Int J Hyperthermia. 1994;3:347–353. [PubMed: 7930800]
Nishimura Y, Hiraoka M, Jo S. et al. Microangiographic and histologic analysis of the effects of hyperthermia on murine tumor vasculature. Int J Radiat Oncol Biol Phys. 1988;15:411–420. [PubMed: 3403322]
Evans SS, Frey M, Scheider DM. et al. Regulation of leukocyte-endothelial cell interaction in tumor immunityIn: Mihich and Croce, eds.Biology of TumorsPlenum Press,1998(Ch 20)273–286.
Roca C, Primo L, Valdembri D. et al. Hyperthermia inhbits angiogenesis by a Plasminogen Activator Inhibitor —I dependent mechanism. Cancer Res. 2003;63:1500–1507. [PubMed: 12670896]
Jirtle RL. Chemical modifications of tumor blood flow. Int J Hyperthermia. 1988;4:355–371. [PubMed: 3290350]
Suit H, Shalek RJ. Response of spontaneous mammary carcinoma of the C3H mouse to X-irradiation given under conditions of local tissue anoxia. J Nat Cancer Inst. 1963;31:497–509. [PubMed: 14058998]
Hill SA, Denekamp J. The effect of vascular occlusion on the thermal sensitisation of a mouse tumour. Br J Radiol. 1978;51:997–1002. [PubMed: 737414]
Stuart K. Chemoembolization in the management of liver tumors. The Oncologist. 2003;8:425–437. [PubMed: 14530495]
Tanaka Y, Yamamoto K, Nagata K. Effects of multimodal treatment and hyperthermia on hepatic tumors. Cancer Chemother Pharmacol Suppl. 1998;1:111–114. [PubMed: 1333897]
Hirst DG, Hirst VK, Shaffi KM. et al. The influence of vasoactive agents on the perfusion of tumors growing in three sites in the mouse. Int J Radiat Oncol Biol Phys. 1991;60:211–218. [PubMed: 1677973]
Baguley BC, Wilson WR. Potential of DMXAA combination therapy for solid tumors. Expert Rev Anticancer Ther. 2002;2:593–603. [PubMed: 12382527]
Horsman MR, Murata R. Combination of vascular targeting agents with thermal or radiation therapy. Int J Radiat Oncol Biol Phys. 2002;54:1518–1523. [PubMed: 12459380]
Calderwood SK, Dickson JA. Effect of hyperthermia on blood flow, pH and response to hyperthermia (42°C) of the Yoshida sarcoma in the rat. Anticancer Res. 1980;40:4728–4733. [PubMed: 7438104]
Dickson JA, Calderwood SK. Thermosensitivity of neoplastic tissues in vivoIn: Storm FK, ed.Hyperthermia in Cancer TherapyBoston, GK: Hall,198363–140.
Nagata K, Tanaka Y, Akagi K. et al. Enhancement of thermoradiotherapy by glucose administration for superficial malignant tumors. J Radiat Res. 1998;14:157–167. [PubMed: 9589321]
Crandall E, Crtz A, Osher A. et al. Influence of pH on elastic deformability of the human erythrocyte membrane. Am J Physiol. 1978;235:c269–c278. [PubMed: 31792]
Traykov TT, Jain RK. Effect of glucose and galactose on red blood cell membrane deformability. Int J Microcirc Clin Exp. 1987;6:35–44. [PubMed: 3583577]
Hasegawa T, Gu Y-H, Takahashi T. et al. Effects of hyperthermia-induced changes in pH value on tumor response and thermotoleranceIn: Kosaka M, Sugahara T, Schmidt KL, Simon E, eds.Thermotherapy for Neoplasia, Inflammation, and PainTokyo: Springer Verlag,2001431–438.
Shem BC, Dahl O. Thermal enhancement of ACNU and potentiation of thermochemotherapy with ACNU by hypertonic glucose in the BT4A rat glioma. J Neuroncol. 1991;10:247–252. [PubMed: 1895166]
Lippmann HG, Graichen D. Glucose and K+ balance during high dosage intravenous glucose infusion. Infusionsther Klin Ernahr. 1977;4:166–178. [PubMed: 561030]
Von ArdenneM. In vivo Theorie zum glykolytishen Stoffwechsel der Tumoren ihrer Übersäuerbarkeit durch HyperglykämieIn: Hippokates Verlag Stuttgart, ed.Systemidche Krebs-Mehrschritt-Therapie 199735–45.
Nagata K, Murata T, Shiga T. et al. Enhancement of thermoradiotherapy by glucose administration for superficial malignant tumours. Int J Hyperthermia. 1998;14:157–167. [PubMed: 9589321]
Leeper DB, Engin K, Wang J-H. et al. Effect of I.V. glucose versus combined I.V. plus oral glucose on human tumour extracellular pH for potential sensitisation to Thermotherapy. Int J Hyperthermia. 1998;257-269 [PubMed: 9679706]
Engin K, Leeper DB, Cater JR. et al. Extracellular pH distribution in human tumors. Int J Hyperthermia. 1995;11:211–216. [PubMed: 7790735]
Han JS, StorcK CW, Wachsberger PR. et al. Acute extracellular acidification increases nuclear associated protein levels in human melanoma cells during 42°C hyperthermia and enhances cell killing. Int J Hyperthermia. 2002;18:404–415. [PubMed: 12227927]
Coss R, Storck CW, Daskalaqkis C. et al. Intracellularacidification abrogates theheat shock response andcompromises survival of human melanomacells. Mol Cancer Therapeut. 2003:383–388. [PubMed: 12700282]
Burd R, Wachsberger PR, Biaglow JE. et al. Absence of Crabtree effect in human melanoma cells adapted to growth at low pH: Reversal by respiratory inhibitors. Cancer Res. 2001;61:5630–5635. [PubMed: 11454717]
Zhou R, Bansal N, Leeper DR. et al. Enhancement of hyperglycemia-induced acidification of human melanoma xenografts with inhibitors of respiration and ion transport. Acad Radiol. 2001;8:571–582. [PubMed: 11450957]
Zhou R, Bansal N, Leeper DR. et al. Intracellular acidification of human melanoma xenografts by respiratory inhibitor m-Iodio-benzylguanidine plus hyperglycemia: A31 P Magnetic resonance spectroscopy study. Cancer Res. 2000;61:3532–3536. [PubMed: 10910065]
Hahn GM. Thermal Enhancement of the actions of anticancer agentsIn: Hahn GM, ed.Hyperthermia and CancerNew York, London: Plenum Press,198255–85.
Sensiterra GA, Lepock JR. Thermal destabilization of transmembrane proteins by local anesthetics. Int J Hyperthermia. 2000;16:1–17. [PubMed: 10669313]
Kameda K, Kondo T, Tanabe K. et al. The role of intracellular Ca2+ in apoptosis induced hyperthermia and its enhancement by verapamil in U937 cells. Int J Radiat Oncol Biol Phys. 2001;49:1369–1379. [PubMed: 11286845]
Kokura S, Yoshikawa T, Kaneko T. et al. Efficacy of hyperthermia and polyunsaturated fatty acids on experimental carcinoma. Cancer Res. 1997;57:2200–2202. [PubMed: 9187121]
Asea A, Mallick R, Lechpammer S. et al. Cycloxygenase inhibitors are potent sensitizers of prostate tumours to hyperthermia and radiation. Int J Hyperthermia. 2001;17:401–414. [PubMed: 11587078]
Wachsberger PR, Burd R, Wahl ML. et al. Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia. Int J Hyperthermia. 2002;18:153–164. [PubMed: 11911485]
Kim JH. Modification of thermal effects: Chemical modifiersIn: Urano M, Douple E, eds.Hyperthermia and Oncology. Vol 1The Netherlands: VSP,198883–119.
Prasad K, Kumar B, Yan X-D. et al. α-Tocopheryl succinate the most effective form of Vit E for adjuvant cancer treatment A review. J Am Coll Nutr. 2003;22:108–117. [PubMed: 12672706]
Callari D, Sinatra F, Paravizzini GL. et al. All trans retionic acid sensitizes colon cancer cells to hyperthermia cytotoxic effects. Int J Oncol. 2003;23:181–188. [PubMed: 12792792]
Wachsberger PR, Burd R, Bhala SB. et al. Quercetin sensitizes cells to hyperthermia. Int J Hyperthermia. 2003;19:507–519. [PubMed: 12944166]
Van der Zee J. Heating the patient: A promising approach? Annals of Oncology. 2002;13:1173–1184. [PubMed: 12181239]
Kampinga KH, Dikomey E. Hyperthermia radiosensitization: Mode of action and clinical relevance. Int J Radiat Biol. 2001;77:399–408. [PubMed: 11304434]
Hasegawa T, Gu YH, Takahashi T. et al. Enhancement of hyperthermic effects using rapid heatingIn: Kosaka M, Sugahara T, Schmidt KL, Simon E, eds.Thermotherapy for neoplasia, inflammation, and painTokyo: Springer Verlag,2001439–444.
Vujaskovic Z, Song CW. Physiological mechanisms underlying heat-induced radiosensitization. Int J Hyperthermia. 2004;20:163–174. [PubMed: 15195511]
Song CW, Park H, Griffin RJ. Improvement of tumour oxygenation by mild hyperthermia. Radiat Res. 2001;155:515–528. [PubMed: 11260653]
Jones EL, Prosnitz LR, Dewhirst MW. et al. Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer. Clin Cancer Res. 2004;10:4287–4293. [PubMed: 15240513]
Pontiggia P, Mc LarenJR, Baronzio GF. et al. The biological responses to heat. Adv Exp Med Biol. 1990;267:271–291. [PubMed: 2088044]



Enzymes HIF Induced: [GLUT-1, type I exokinase, Aldolase A, Lactate dehydrogenase, Phosphofructokinase L , Posphoglycerate kinase 1 and pyruvate kinase M].

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