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Overview of Resistance to Systemic Therapy in Patients with Breast Cancer

, , and *.

* Corresponding Author: Department of Breast Medical Oncology, Unit 424, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, U.S.A. Email: ghortoba@mdanderson.org

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described.

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it.1 In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States.2 World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years.1

Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens.

Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases.3 The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment.4

To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors.5 A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment.6 The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage.7 However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression,8,9 expression of other members of the epithelial growth factor receptor family,10,11 S phase fraction, DNA ploidy,12 p53 gene mutations,13 cyclin E,14 p27 dysregulation,15 the presence of tumor cells in the circulation16 or bone marrow,17 and perineural and lymphovascular space invasion.18

Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates.19 Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease.20 Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer.21 Tamoxifen is considered the standard of care in premenopausal patients.22 In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer.23 The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events.24,25

Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents.26 The pathological response to neoadjuvant systemic therapy in the breast and lymph nodes correlates with patient survival.27,28 Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach.29 The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens30,31 to almost 30% with the addition of a non-cross-resistant agent such as a taxane.32,33 In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%.34 Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation.35,36 Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy.37

The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence.2,3,38 Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months.39 In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.

Table 1. Response of metastatic breast cancer to single-agent systemic therapy.

Table 1

Response of metastatic breast cancer to single-agent systemic therapy.

Resistance to Systemic Therapy

In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. This is demonstrated by reduced tumor volume, improved symptoms, and decreased serological tumor markers. However, after a variable period, progression occurs. At this point, resistance to therapy is not only common, it is expected. With the objective of overcoming resistance to single agents, the use of combinations of noncross-resistant regimens has been adopted.40,41 However, tumors continue to develop resistance to these combinations. Attributing treatment failure to a single factor is incorrect because of the multifactorial nature of carcinogenesis. The search for biological explanations for treatment failure at the molecular level is finally helping to explain this phenomenon and providing appropriate solutions to overcome it.

Resistance to therapy is caused in part by a process called genetic amplification. This process allows cancer cells to increase their immortality and invasion properties. Each treatment regimen with a single systemic agent selects a group of cancer cells that is increasingly resistant to therapy, decreasing the rate of response to further therapies.42 The identification of P-glycoprotein (P-gp), as a direct transporter of multiple hydrophobic cations and of multidrug resistance (MDR) protein 1 (MRP1) as a transporter of hydrophilic anionic and glutathione-conjugated drugs advanced the study of resistance to cancer therapy. Since then, multiple mechanisms of both in vitro and in vivo resistance have been identified. These mechanisms range from those with anatomic characteristics and pharmacological properties to those with host-drug-tumor interaction. Table 2 summarizes the different mechanisms of resistance to systemic therapy described at the molecular level and those demonstrated in vivo.

Table 2. General mechanisms of resistance to systemic therapy.

Table 2

General mechanisms of resistance to systemic therapy.

General Mechanisms of Drug Resistance

Experimental selection of drug resistance by repeated exposure to single antineoplastic agents will generally result in cross-resistance to some agents of the same class. This phenomenon is explained by shared drug transport carriers, drug-metabolizing pathways, and intracellular cytotoxic targets of these structurally and biochemically similar compounds. Generally, resistant cells retain sensitivity to drugs of different classes with alternate mechanisms of cytotoxic action. Thus, cells selected for resistance to alkylating agents or antifolates will usually remain sensitive to unrelated drugs, such as anthracyclines. Exceptions include cases with emergence of cross-resistance to multiple, apparently structurally and functionally unrelated drugs that the patient or cancer cells were never exposed to during the initial treatment.43 Despite apparent differences within the families of drugs associated with MDR phenotypes, when the mechanisms underlying these phenotypes are identified, the involved antineoplastic agents frequently share common metabolic pathways, efflux transport systems, or sites of cytotoxic action (Table 3).

Table 3. Mechanisms of resistance for specific chemotherapeutic agents.

Table 3

Mechanisms of resistance for specific chemotherapeutic agents.

MDR

Classic (P-Glycoprotein-Dependent) MDR

An in vitro model of MDR was described by Biedler and Riehm 3 decades ago.44 In their studies, cultured cells selected for resistance by exposure to actinomycin D developed cross-resistance to a surprising array of structurally diverse compounds, including vinca alkaloids, puromycin, daunomycin, and mitomycin C. Induction of this pattern of cross-resistance has since been observed by numerous investigators. This resulted in initiation of the study of drug resistance. Generally, exposure of cells to drugs such as anthracyclines, vinca alkaloids, and epipodophyllotoxins is related to the classic MDR phenotype and can result in cross-resistance to all other members of the phenotype. The emergence of MDR has been associated with increased levels of expression of a membrane-bound P-glycoprotein (P-170 or MDR1 protein).

De novo and acquired cross-resistance to multiple antineoplastic agents may result from several alternative factors and processes. First, MDR patterns of cross-resistance were found to be frequently associated with decreased drug accumulation, usually because of increased drug efflux.45 Classic MDR-associated drug resistance is mediated by P-glycoproteins. More recently, a similar but distinct MDR phenotype was attributed to the energy-dependent drug-efflux activities of MDR protein (MRP) family members.43 An overlapping but discrete resistant MDR phenotype is associated with increased expression of the recently isolated putative efflux breast cancer resistance protein (BCRP).46 MDR has also been described in association with overexpression of the lung resistance protein (LRP). The mechanism of LRP-associated resistance is unclear, and whether LRP alone is sufficient to confer resistance is unknown. Some have speculated that as a major vault protein, LRP is involved in nucleocytoplasmic transport and cytoplasmic sequestration of drugs.47 Drug resistance defined by alterations in topoisomerases represents a third major category of MDR.48,49

MRP Family

Similar phenotypes of multiple resistance to antineoplastic agents that are associated with the expression of other membrane proteins have been described. In many of these phenotypes, resistance occurs independently of P-glycoprotein expression.50

A distinct gene, mrp1 (MRP1 or MDR-associated protein 1), was isolated from a doxorubicin-selected MDR lung cancer cell line. This gene encodes a 190-kDa transmembrane protein whose structure is strikingly homologous with that of P-glycoprotein/MDR1 and other members of the ATP-binding cassette transmembrane transporter proteins.51,52 The importance of MRP1 overexpression in clinical drug resistance is unknown. However, because MRP1 expression varies widely in tumor cells, MRP1 may be a significant mediator of drug resistance in human cancer. At least five other human MRP isoforms have been identified.53 Among them, MRP2 (cMOAT) and MRP3 are capable of supporting efflux detoxification of cancer drugs, including epipodophyllotoxins (MRP2 and MRP3), doxorubicin (MRP2), and cisplatin (MRP2). Recent results indicated that MRP1 and MRP2 are also able to confer resistance to the polyglutamatable antifolate methotrexate (MTX).54

MDR Associated with Topoisomerase Poisons

Topoisomerases are nuclear enzymes that catalyze the formation of transient single- or double-stranded DNA breaks, facilitate the passage of DNA strands through these breaks, and promote rejoining of the DNA strands.55 As a consequence of these activities, topoisomerases are thought to be critical for DNA replication, transcription, and recombination. The drugs responsible for these activities are called topoisomerase poisons and include anthracyclines, epipodophyllotoxins, and actinomycin D. Their effect is thought to depend on the DNA cleavage activities of topoisomerases. There are two classes of mammalian enzymes: topoisomerase I and topoisomerase II. Topoisomerase I catalyzes the formation of single-stranded DNA breaks, whereas topoisomerase II as well as β isoforms catalyzes both single- and double-stranded breaks.

The formation of these stabilized DNA-topoisomerase-drug complexes is thought to initiate the production of lethal DNA strand breaks. Of the chemotherapeutic drugs that affect topoisomerase activities, the topoisomerase II poisons have been found to be the most clinically important. Hence, decreased drug accumulation caused by increased expression of P-glycoprotein or MRP1 is a potential mechanism of resistance to these topoisomerase II poisons. However, a distinct pattern of topoisomerase II-related MDR that differs from the pattern of P-glycoprotein-associated MDR in several important ways has been described. For example, cells that develop topoisomerase II alterations following exposure to amsacrine may show cross-resistance to other intercalating topoisomerase II poisons but not to epipodophyllotoxins. Finally, two mammalian isozymes of topoisomerase II have been found: a 170-kDa form (topoisomerase Iα) and a 180-kDa form (topoisomerase IIβ).56 These isozymes differ in their regulation during the cell cycle and their relative sensitivity to topoisomerase II poisons.57 Hence, both the relative levels of the specific topoisomerase II isozymes and the total topoisomerase II activity may be significant determinants of the sensitivity of tumor cells to topoisomerase II drugs.

The molecular bases of drug resistance associated with qualitatively altered topoisomerase II expression have been described in several reports. However, the relevance of topoisomerase I for clinical drug resistance is unknown. Alternatively, altered subcellular localization of topoisomerase II isoforms58 and altered posttranslational phosphorylation have been reported in association with some etoposide-resistant cell lines.59,60 The cytotoxicity of topoisomerase II poisons is believed to depend on the formation of DNA strand breaks secondary to stabilization of the reversible enzyme-DNA cleavable complex.61 A new family of drugs targeting topoisomerase II function that includes fostriecin, merbarone, aclarubicin, and bis(2,6-dioxopiperazine) derivatives (e.g., ICRF193, ICRF 187) has emerged. Also, the cytotoxic agent camptothecin has been shown to enhance topoisomerase I-mediated strand breaks. Previously, host toxicity was found to prohibit the clinical use of such topoisomerase I poisons. However, the prospect of less toxic analogues of this drug that maintain a high level of activity against topoisomerase I-rich human cancer cells has renewed interest in the clinical application of this class of compounds.62 Consequently, the emergence of resistance to these agents may become an increasingly important consideration.

MDR Associated with Altered Expression of Drug-Metabolizing Enzymes and Drug-Conjugate Export Pumps

The manner in which cells metabolize cancer drugs and other xenobiotics is often described as three phases of detoxification. Alterations in any of these phases can influence the sensitivity and resistance to a particular drug or xenobiotic toxin. For example, phase I metabolism is mediated by cytochrome P450 mixed-function oxidases. These metabolites or the unmodified drug may then be converted to a less reactive, presumably less toxic form in phase II reactions. Phase II detoxifications include the formation of drug/xenobiotic conjugations with glutathione, glucuronic acid, or sulfate, reactions that are catalyzed by multiple isozymes of glutathione S-transferase (GST), UDP-glucuronosyl transferase, and sulfatase, respectively.63-65 Phase III detoxification consists of exportation of the parent drug/xenobiotic or its metabolites with the use of energy-dependent transmembrane efflux pumps, including P-glycoprotein, MRP family members, and breast cancer resistance protein. Frequently, coordinated downregulation of phase I drug-activating enzymes and upregulation of specific phase II drug-conjugating enzymes are observed in cellular and animal models of drug or xenobiotic resistance.66,67 Such a programmed cellular stress response offers a versatile, generalized protective mechanism against exposure to a variety of exogenous toxins.

Whether GST levels in tumor cells are sufficient to detoxify antineoplastic drugs to a clinically significant degree is a matter of considerable debate, and the role of GSTs in drug resistance remains uncertain because of inconsistent results from different laboratories.68-70 Thus, the relative resistance of cells expressing drug-metabolizing enzymes may depend on cellular levels of drug conjugate transporters, including the glutathione conjugate transporters,71 such as the MRP family proteins.72 Indeed, recent results using model cell lines have demonstrated that combined expression of specific isozymes of GST with MRP1 is necessary to achieve full protection from the toxic effects of the cancer drug chlorambucil41 and the carcinogen 4-nitroquinoline 1-oxide. In these studies, the expression of either GST or MRP1 alone provided little if any protection from toxic effects, a finding that illustrates the synergistic interaction of phase II and III detoxification processes in the emergence of resistance to some drugs.

Emergence of Refractory Tumors Associated with Multiple Resistance Mechanisms

The backbone of many treatment regimens designed to circumvent the proliferation of resistant tumor cells is the administration of multiple drugs with different structural properties and mechanisms of action. This approach supposes that if enough carefully selected drugs are delivered at optimal doses and intervals, individual clones of cells resistant to one class of drug will be effectively killed by another drug in the regimen. The rapid appearance of a refractory tumor despite an initially favorable cytoreductive response suggests that the emergence of tumor cell clones with resistance to multiple drugs is a common clinical occurrence. We have seen how a single genetic change such as increased P-glycoprotein or altered topoisomerase II can mediate cross-resistance to several, but not all, useful antineoplastic drugs. Although these mechanisms provide a molecular explanation for broad-spectrum resistance, it is clear that many refractory tumor clones must simultaneously develop multiple resistance mechanisms. These mechanisms may arise from multiple independent genetic changes in single-cell clones or, as suggested by Muller et al,73 cell-to-cell transfer of genetic information.

Resistance to Free-Radical-Mediated Drug Cytotoxicity

Several antineoplastic agents form free radical intermediates that are thought to contribute to drug cytotoxicity. Anthracyclines, such as doxorubicin, are among the most important members of this class of compounds. Whereas DNA-intercalating anthracyclines can damage cells through multiple mechanisms, including inhibition of nucleic acid synthesis, induction of topoisomerase II-mediated DNA strand breaks, and perturbation of cell membranes, these quinone-hydroquinone compounds can also generate toxic free radical species that may cause cell death.74 The semiquinone radical thus generated may either form a covalently binding free radical derivative or, in the presence of oxygen, be reoxidized to the quinone species in a reaction producing superoxide anion. Decomposition of hydrogen peroxide formed by dismutation of superoxide anion produces the highly reactive hydroxyl radical, which may directly damage DNA, lipids, and proteins. Thus, cellular factors that limit hydrogen peroxide production or repair peroxidative damage to macromolecules could theoretically confer some resistance to anthracyclines. Several pathways may contribute to protection of tumor cells from anthracycline-mediated free radical damage. First, superoxide anion formation is limited in poorly vascularized, relatively hypoxemic tissues, such as in the center of large solid tumors. Second, increased intracellular levels of catalase and glutathione peroxidase can deplete hydrogen peroxide, thus reducing the formation of toxic hydroxyl radicals.75

Resistance to Genotoxic Cancer Treatments Related to Suppression of Apoptotic Pathways

Chemotherapeutic drugs are cytotoxic because of their interactions with a variety of molecular targets. Despite these varied primary targets, most, if not all, cancer drugs instigate cell death, at least partially, via downstream events, especially those that converge upon pathways mediating programmed cell death or apoptosis. This process is conveniently conceptualized in three phases. First, initiation of apoptosis (e.g., secondary to chemotherapy-mediated DNA damage) is characterized by its reversibility. Second, the decision to complete the death program is irreversible. The commitment phase may involve mitochondrial changes and the release of cytochrome-c and apoptosis-inducing factor, which are hallmarks of apoptosis. Third, the degradation or execution phase includes downstream events, such as DNA fragmentation and morphological changes. Prior to commitment, apoptosis can be modulated by regulatory elements, such as p53 and the Bcl-2 family of proteins. Although apoptosis may be either p53 dependent or p53 independent, frequently, the cellular response to DNA damage is regulated by p53.76 Depending on the particular cell type and damage, p53 may then initiate one of two possible pathways: apoptosis or cell cycle arrest and repair.

The mitogen-activated protein kinase-signaling cascades are involved in the regulation of cellular response to exogenous factors, including genotoxic and cytotoxic anticancer agents.77 Additionally, the extracellular signal-regulated kinase pathway is implicated in the proliferative response to growth factors. In cells treated with potentially cytotoxic stressors, such as radiation and anticancer drugs, the p38 and stress-activated/c-Jun N-terminal protein kinase (SAPK/JNK) pathways are implicated in mediating cell cycle arrest and apoptosis. Furthermore, the Bcl-2 family of proteins comprises several important regulators of apoptosis. Although their mechanism or mechanisms of action are not completely known, the balance of expressed antiapoptotic family members (Bcl-2, Bcl-XL, Bcl-w, A1, and Mcl-1) and proapoptotic family members (Bax, Bak, Bad, Bik, and Bid) can influence the relative sensitivity of cells to toxic stressors.78 This genomic instability may further lead to mutations that activate additional resistance mechanisms and confer more aggressive tumor behavior.79 Thus, the expression of mutant and wild-type p53, Bcl-2 family members, mitogen-activated protein kinase (MAPK) family members, and other proteins associated with the control of apoptosis may contribute significantly to the clinical sensitivity of tumor cells. These proteins are the targets of investigational agents that may become important in future strategies for overcoming clinical drug resistance.

Resistance Factors Unique to Tumor Cells in Vivo: Host-Tumor-Drug Interactions

The failure of chemotherapy to eradicate a tumor in vivo despite exquisite sensitivity to the chemotherapeutic drug or drugs in vitro may be caused by anatomic or pharmacological sanctuaries. For example, brain and testicular barriers probably account for the relatively high frequency of acute lymphoblastic leukemia relapse at these sites.80 In cases with a large solid tumor, failure of chemotherapy is frequently attributed to decreased drug delivery to a tumor that has overgrown its vascular supply. Additionally, development of acidosis and hypoxia in poorly perfused areas of large tumors may interfere with the cytoxicity of some drugs. Finally, altered prodrug activation by the liver or other normal tissues may profoundly influence the efficacy of drugs such as cyclophosphamide.

Mechanisms of Resistance for Agents Used to Treat Breast Cancer

Anthracyclines

Mechanism of Action

The mechanisms of action of anthracyclines are pleiotropic effects, including activation of signal transduction pathways, generation of reactive oxygen intermediates, stimulation of apoptosis, and inhibition of DNA topoisomerase II catalytic activity.

Metabolism

Anthracyclines are metabolized by reduction of a side-chain carbonyl to alcohol, resulting in some loss of cytotoxicity, and a one-electron reduction to a semiquinone free radical intermediate by flavoproteins, leading to aerobic production of superoxide anion, hydrogen peroxide, and hydroxyl radical.

Pharmacokinetics

The protein-binding rate of doxorubicin ranges from 60% to 70%, whereas its cerebro-spinal fluid (CSF)/plasma ratio is very low. Doxorubicin circulates predominantly as a parent drug, and doxorubicinol is its most common metabolite, although doxorubicin 7-deoxyaglycone and doxorubicinol 7-deoxyaglycone form in a substantial fraction of patients. In addition, substantial interpatient variation in biotransformation has been observed, and dose-related changes in clearance do not appear to be greater in men than in women. Daunorubicin metabolizes faster than an equivalent dose of doxorubicin does.

Elimination

Only 50% to 60% of the parent drug is eliminated by known routes. A substantial fraction of the parent compound is bound to DNA and cardiolipin in tissues. Although changes in anthracycline pharmacokinetics may be difficult to demonstrate in patients with mild alterations in liver function, anthracycline clearance is definitely decreased in patients with significant hyperbilirubinemia or a marked burden of metastatic tumor in the liver.

Mechanism of Resistance

The mechanism of resistance in anthracyclines is increased expression of the P-170 glycoprotein related to the enhancement of drug efflux. The evidence supporting this role includes correlation between this protein and resistance, transfer of the cloned MDR1 gene, and reversal of resistance by agents that block P-170. The in vivo cells are different from the in vitro cells. The nature of resistance that develops after a single prolonged exposure to doxorubicin was evaluated by using classic fluctuation analysis.81 The researchers found that MDR1 expression did not occur and that the resistance arose from a spontaneous mutation with an apparent generation rate of approximately 2 x 10-6 per cell. Also, under certain circumstances, expression of the MDR1 gene clearly may be transcriptionally modulated by doxorubicin itself as well as by inhibitors of protein kinase C and calmodulin. In vivo, the resistance is more complex, with most tumors and many normal tissues exhibiting increased expression of a gene copy.82 Other mechanisms of resistance include a 190-kDa protein that is a member of the ATP-binding cassette transmembrane transporter superfamily. MRP expression alone, in the absence of alterations in MDR1 or topoisomerase II expression, can also produce anthracycline resistance.83 Furthermore, altered topoisomerase II activity has been implicated in resistance to anthracyclines. Overexpression of bcl-2 can significantly diminish the toxicity of doxorubicin, as can mutations of the p53 gene.84 Potent nuclear DNA repair systems also contribute substantially to the ability of tumor cells to withstand the cytotoxic effects of doxorubicin. For example, ADP ribosylation is a well-known posttranslational modification of topoisomerase II and plays an important role in the use of nicotinamide adenine dinucleotide (oxidized form). These results suggest that intermediary metabolism affects DNA cleavage and doxorubicin resistance.85

Overcoming Resistance

As discussed above, resistance to anthracyclines may occur as a consequence of P-glycoprotein overexpression or altered topoisomerase II activities. However, neither of these mechanisms will necessarily result in cross-resistance to topoisomerase II in all cases. Additionally, tumor cells resistant to classic topoisomerase II poisons frequently retain sensitivity to the cytotoxic effects of the novel class of topoisomerase II catalytic inhibitors (fostriecin, merbarone, aclarubicin, and bis(2,6-dioxopiperazine)).86,87 This class of topoisomerase-directed drugs offers an alternative for the treatment of topoisomerase-poison-resistant tumors. Finally, structural analogues of parent topoisomerase II poisons may overcome resistance based on altered topoisomerase II.88-89 The use of noncross-resistant agents with cytotoxic activity but different mechanisms of action after administration of anthracycline-based regimens has proven to be beneficial in patients with breast cancer.90,91 Finally, the time and method of delivering anthracyclines affects toxicity and results. For example, continuous infusion of doxorubicin (Adriamycin) increases its therapeutic index (Table 4).92

Table 4. Approaches to overcoming or circumventing drug resistance.

Table 4

Approaches to overcoming or circumventing drug resistance.

Taxanes

Mechanism of Action

The mechanisms of action of taxanes are high-affinity binding to microtubules with enhanced microtubule formation at high drug concentrations and inhibition of mitosis.

Metabolism

The effects of taxanes on microtubules differ from those of the vinca alkaloids. Unlike colchicine and the vinca alkaloids, which prevent microtubule assembly, submicromolar concentrations of the taxanes decrease the lag time and shift the dynamic equilibrium between tubulin dimers and microtubule assembly and stabilize microtubules against depolymerization.93 The metabolism and elimination of paclitaxel and docetaxel are similar. In humans, urinary excretion accounts for a small percentage of drug disposition, averaging 2%. Both hepatic metabolism and biliar excretion are also important. Approximately 80% of the administered dose is excreted in the feces within 7 days after treatment. Also, the hepatic cytochrome P450 is responsible for the bulk of drug metabolism, and the cytochrome P450 isoforms CYP3A, CYP2B, and CYP1A may play a role in biotransformation. The main metabolic pathway for taxanes consists of oxidation of a tertiary butyl group on the side chain at the C-13 position of the taxane ring as well cyclization of the side chain.94

Pharmacokinetics

The pharmacokinetics of taxanes consist of saturable elimination and distribution, which are particularly evident with a short (3-hour) schedule.

Elimination

Taxanes are eliminated predominantly by hepatic hydroxylation of cytochrome P450 enzymes and biliary excretion of metabolites. Less than 10% of each dose is eliminated intact in the urine.

Mechanism of Resistance

Two main mechanisms of taxane resistance have been described in cells exposed to taxanes at low concentrations for prolonged periods pf time. The first is changes in the expression of β-tubulin isotopes, mainly β-III, whereas the second is part of the MDR system. Upregulation of caveolin-1, a membrane component involved in small molecule transport and intracellular signaling, has also been found to be related to taxane resistance.95

Overcoming Resistance

The use of a polyoxyl compound (Cremophor) as an MDR expression modulator has been evaluated. Other modulators of MDR that have been studied include verapamil, cyclosporine A, and PC 833.96,97 When paclitaxel is given over 3 hours at 135 to 175 mg/m2, plasma concentrations of Cremophor are able to revert MDR in vitro.98

Antimetabolites

Mechanism of Action

The cytotoxic effects of antimetabolites stem from their ability to interfere with key enzymatic steps in nucleic acid metabolism. This group of agents includes three well-studied compounds: the antifolate MTX and the pyrimidine analogues 5-fluorouracil (5-FU) and arabinosylcytosine. Inhibition of dihydrofolate reductase (DHFR) leads to partial depletion of reduced folates. Polyglutamates of MTX and dihydrofolate inhibit purine and thymidylate biosynthesis.

Metabolism

The metabolism of 5-FU is complex. The best characterized mechanism of fluoropyrimidine cytotoxicity involves the inhibition of thymidylate synthase by 5-fluoro-2'-deoxyuridine monophosphate (FdUMP). Additionally, the incorporation of the metabolite 5-fluorouridine triphosphate into RNA has been correlated with cytotoxicity in some systems. Although 5-fluoro-2'-deoxyuridine triphosphate can be incorporated into DNA, the relationship between this process and the cytocidal activity of fluoropyrimidines remains undetermined.

Pharmacokinetics

Following uptake by a folate transport system, MTX can bind avidly to and inhibit DHFR, its primary enzyme target. In the presence of adequate thymidylate synthase activity, inhibition of DHFR results in depletion of the reduced folate pools essential for thymidylate and de novo purine synthesis. The cytotoxicity of MTX is significantly influenced by intracellular polyglutamation. MTX polyglutamates are retained preferentially by cells and bind more effectively to DHFR. Additionally, these polyglutamyl derivatives can inhibit other folate-dependent enzymes, including thymidylate synthase and 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) trans-formylase,99 enzymes involved in thymidylate and de novo purine synthesis, respectively.

Elimination

Antimetabolites are eliminated primarily in the urine.

Mechanism of Resistance

Resistance to 5-FU may be conferred by alterations in enzymes involved in fluoropyrimidine metabolism, particularly those enzymes associated with the conversion of 5-FU to the thymidylate synthase inhibitor FdUMP.100 Furthermore, changes in the thymidylate synthase level or its affinity for FdUMP have been associated with 5-FU resistance.101

A multifactorial process involving DHFR gene amplification, a transport defect, and a decrease in the formation of polyglutamic acid has been seen in patients with tumors resistant to MTX.102,103 Resistance to MTX may result from a number of alternative mechanisms, including (1) reduced MTX uptake via defective folate transport systems,104,105 such as decreased expression of the reduced folate carrier106 or folate receptors;107 (2) increased exportation via MRPs108,109 or other exporters of polyglutamatable antifolates; (3) reduced polyglutamation leading to decreased drug retention as well as reduced inhibition of thymidylate synthase and AICAR transformylase;110 (4) elevated levels of DHFR or reduced affinity of DHFR for MTX;111,112 and (5) expression of Bcl-2 during apoptosis.

Overcoming Resistance

Strategies designed to overcome resistance to antimetabolites include dose escalation, pharmacological manipulation of drug metabolism, and rational design of new antimetabolites.113 The rationale for the use of high-dose MTX with subsequent rescue of normal tissues by administration of the reduced folate leucovorin (N5-formyl tetrahydrofolate) in the treatment of cancers other than breast cancer was recently questioned.114,115 Other antifolate compounds capable of inhibiting folate-dependent enzymes besides DHFR have been investigated. In particular, trimetrexate, 10-propargyl-5,8-dideazafolate, and 5,10-dideazatetra-5,6,7,8-tetrahydrofolate have shown promise in cells resistant to MTX.116,117 Finally, the synergistic interaction between interferon and halogenated pyrimidines has been described.118,119

Alkylating Agents and Platinum Compounds

Mechanism of Action

All alkylating agents and platinum compounds produce alkylation of DNA through the formation of reactive intermediates that attack nucleophilic sites.

Metabolism

Cyclophosphamide is metabolized by microsomal hydroxylation and hydrolysis to phosphoramide mustard (active) and acrolein. It is excreted as inactive oxilation products. Chlorambucil undergoes chemical decomposition to active phenyl acetic acid mustard and to inert dechlorination products. Melphalan undergoes chemical decomposition to inert dechlorination products, and 20% to 35% of it is excreted unchanged in the urine. Carmustine undergoes chemical decomposition to active and inert products and enzymatic conjugation with glutathione. Finally, cisplatin covalently binds to DNA bases and disrupts DNA function. The toxicity of these agents may be related to DNA damage.

Elimination

Approximately 25% of each dose of alkylating agents and platinum compounds is excreted from the body during the first 24 hours after administration. About 90% of excretion is renal, whereas about 10% is biliary. Extensive long-term protein binding has been observed in many tissues.

Mechanism of Resistance

Resistance to alkylating agents and platinum compounds can be described by at least four broad mechanistic categories: (1) decreased alterations in transmembrane cellular drug accumulation;120 (2) increased cytosolic drug inactivation; (3) enhanced repair of DNA damage;121 and (4) resistance to apoptosis.122 The correlation between the glutathione or GST level and drug resistance is variable. Indeed, some investigators have been unable to demonstrate a relationship between overexpression of multiple isozymes of GST and antineoplastic resistance.123-124

Aldehyde dehydrogenase is another drug-metabolizing enzyme that has been linked with resistance to cyclophosphamide derivatives in murine and human models of drug resistance.125 These results suggest that coadministration of DNA polymerase alpha inhibitors with cisplatin is useful in overcoming cisplatin resistance. Also implicated in platinum sensitivity and resistance are alterations in mismatch repair or regulators of apoptosis, such as Bcl-2, Bax, p21, and p53.126 Modulation of these pathways by therapeutic agents now in development represents an emerging strategy for overcoming resistance to platinum and other alkylating compounds.

Overcoming Resistance

Other results also suggest that coadministration of DNA polymerase alpha inhibitors with cisplatin is useful in overcoming cisplatin resistance. Also implicated in platinum sensitivity and resistance are alterations in mismatch repair or regulators of apoptosis, such as Bcl-2, Bax, p21, and p53.127 Modulation of these pathways by therapeutic agents now in development represents an emerging strategy for overcoming resistance to platinum and other alkylating compounds.

Vinca Alkaloids

This group of drugs includes vincristine sulfate, vinblastine sulfate, vindesine sulfate, and vinorelbine tartrate.

Mechanism of Action

The mechanism of action of the vinca alkaloids is inhibition of polymerization of tubulin.

Metabolism

Vinca alkaloids are metabolized hepatically. Metabolites accumulate rapidly in the bile so that only 46.5% of the total biliary product is the parent compound. The specific contribution of cytochrome P450-mediated metabolism of vincristine is uncertain, although its importance is suggested by observations of enhanced clearance with phenytoin and increased toxicity with the 3A inducer itraconazole.

Pharmacokinetics

The pharmacokinetics of vinca alkaloids is characterized by large distribution volumes, high clearance rates, and long terminal half-lives. At conventional dosages, the peak plasma concentrations, which persist for only a few minutes, range from 100 to 500 nmol/L, and plasma levels remain above 1 to 2 nmol/L for relatively long durations.

Elimination

The vinca alkaloids are eliminated by biliary excretion.

Mechanism of Resistance

Resistance to vinca alkaloids arises by at least two different mechanisms and is associated with decreased drug accumulation and retention. The first mechanism is implicated by the phenomenon of pleiotropic resistance or MDR, whereas the second mechanism is one of resistance to antimicrotubule agents in vitro resulting from alterations in α- and β-tubulin proteins. An important feature of this type of resistance to the vinca alkaloids is that collateral sensitivity is conferred to the taxanes, which inhibit microtubule disassembly.

Overcoming Resistance

Studies have suggested that coadministration of DNA polymerase alpha inhibitors with vinca alkaloids is useful in overcoming resistance. Also, modulation of pathways such as Bcl, Bax, p21, and p53 by therapeutic agents now in development represents an emerging strategy for overcoming resistance to alkylating compounds.

Gemcitabine

Mechanism of Action

Gemcitabine inhibits DNA polymerase α, is incorporated into DNA, and terminates DNA-chain elongation.

Metabolism

Gemcitabine is activated to triphosphate in tumor cells, degraded to inactive uracil arabinoside by deamination, and converted to an arabinosylcytosine diphosphate choline derivative.

Elimination

Gemcitabine is eliminated by deamination in the liver, plasma, and peripheral tissues.

Mechanism of Resistance

Resistance to gemcitabine is not fully understood, although several mechanisms of resistance to gemcitabine have been described. In general, cells with deficient nucleoside transport are highly resistant to gemcitabine,128 and the degree of resistance may vary according to the nucleoside transporter expressed on the cellular surface.129 Also, enzymes involved in gemcitabine cell metabolism have been associated with the development of resistance to it. The initial in vitro studies suggested that deficiency in deoxycytidine kinase enzymatic activity was the most important cause of gemcitabine resistance, as gemcitabine-sensitive cell lines expressed 10 times more deoxycytidine kinase than gemcitabine-resistant ones.130 However, experiments using KB cells from human epidermoid carcinoma suggested that the enzyme ribonucleotide reductase (RR) could play an important role. RR is specific for S phase and limits DNA synthesis. Resistant cells have 9.0 times greater expression of RR mRNA and 2.3 times greater RR activity than sensitive cells do.131 The role of RR as a determinant of resistance to gemcitabine has been confirmed with the use of K563 erythroleukemia cell lines, in which the enzymatic activity of RR correlated with resistance to gemcitabine.132 A cross-resistance pattern between nucleoside analogues also may have potential implications. Researchers have shown that gemcitabine has more antitumor activity than cytarabine does in sensitive (L1210 and BCLO) and resistant (LA46 and Bara C) cell lines.133 An in vitro experiment using HL-60 promyelocytic leukemic cells made resistant to cladribine created two resistant sublines with no cross-resistance to gemcitabine.134

Overcoming Resistance

No strategies for overcoming gemcitabine resistance have proven to be effective. Use of combination schedules is the main approach.

Tamoxifen

Mechanism of Action

Tamoxifen binds to the estrogen receptor (ER) and induces dimerization and DNA binding to finally inactivate it.

Metabolism

Tamoxifen metabolism is mediated in the liver by cytochrome P450-dependent oxidases into 10 major metabolites.

Pharmacokinetics

After initiation of therapy, steady-state concentrations of the active metabolites of tamoxifen are achieved in 4 weeks, suggesting a half-life of 14 days.

Elimination

Metabolites and a small portion of tamoxifen are excreted in the bile as conjugates.

Mechanisms of Resistance

Several mechanisms of resistance to tamoxifen have been described. Absence of ER expression explains primary resistance in certain tumors. ER mutations may explain the variability in response to tamoxifen in patients with ER-positive tumors; however, these mutations occur in less than 1% of patients with breast cancer.135 Alternative mRNA splicing has been identified in normal and malignant breast tissue with variants lacking one or more exons. The transcript with deleted exon 5 binds to DNA but not to estrogen and activates transcription in an estrogen-independent manner.136 Because ER function is strongly influenced by growth factor signaling, studies have shown decreased tamoxifen response in patients whose tumors coexpress ER and HER-2.137 Finally, the information on coactivators and coexpressors of tamoxifen resistance is limited; however, evidence of the importance of these molecules has been shown. MCF-7 tumor cells regress with the use of tamoxifen, but if tamoxifen administration is continued, they grow back in a tamoxifen-dependent manner; subsequently, withdrawal of tamoxifen causes regression.138 N-CoR corepressor levels are suppressed in tumors stimulated by tamoxifen when compared with tumors that are sensitive to tamoxifen.139

Overcoming Resistance

The use of aromatase inhibitors that block ligand production is an alternative for treating tumors that are resistant to tamoxifen. Also, the use of pure antiestrogens like fulvestrant that block ER function before coactivator binding theoretically may overcome tamoxifen resistance.140,141 Finally, the use of growth factor receptor inhibitors in the form of monoclonal antibodies and small tyrosine kinase inhibitors to reestablish tamoxifen sensitivity is being studied.

Aromatase Inhibitors, Antiestrogens, and Progestins

The mechanisms and percentages of resistance in these groups of drugs are currently being investigated.

Trastuzumab

Mechanism of Action

Trastuzumab is a humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of HER-2. It inhibits tumor-cell proliferation through antibody-dependent cellular toxicity,142 inducing apoptosis,143 inhibiting HER-2/neu intracellular signaling pathways,144 and downregulating expression of HER-2 receptors.145 It also has synergistic action in combination with chemotherapy drugs.146,147

Metabolism

The metabolism of trastuzumab is not clear. Clearance of it by the liver and kidneys is minimal.

Pharmacokinetics

The mean half life of trastuzumab is 21 days. Its disposition is not altered by age or renal function.

Mechanism of Resistance

Resistance to trastuzumab is an active research field. Several known mechanisms of resistance have been identified: increased production of insulin-like growth factor (insulin-like growth factor-1 or insulin-like growth factor-I receptor),148 dysregulation of p27,149 overexpression of epidermal growth factor receptor with activation of the AKT pathway,150 and decreased PTEN function.151

Overcoming Resistance

Targeting the epidermal growth factor receptor family with monoclonal antibodies or single or multiple tyrosine kinase inhibitors to prevent or overcome trastuzumab resistance is a subject of active research. Combinations of trastuzumab with both gefitinib and erlotinib are being evaluated in phase I and II studies.152 Several strategies for blocking insulin-like growth factor-1 signaling, including the use of monoclonal antibodies with antitumor effects in breast cancer such as αIR3153 and antisense molecules, are being developed.154

Chemotherapy Sensitivity and Resistance Assays

Chemotherapy sensitivity and resistance assays are laboratory tests that pretend to select the most appropriate treatment by studying an individual's tumor behavior when exposed to certain drugs. The goal is to individualize therapy, optimize resources, and reduce toxicity. These assays are also known as chemosensitivity tests. Several of these assays have been discarded, whereas others are being studied in clinical trials. The American Society of Clinical Oncology does not recommend the use of these assays to select a therapeutic agent outside of a clinical trial, because even the assays with better potential still require more evaluation.155

The 3-(4,5-dimethylthyazol-2-yl)-2,5-dyphenil tetrazolium bromide assay has been studied in patients with breast cancer. Using tumor-cell suspension cultures incubated with various chemotherapeutic agents, 3-(4,5-dimethylthyazol-2-yl)-2,5-dyphenil tetrazolium bromide is added after 4 days to reduce intercellularity and generate a blue staining. The number of viable cells treated is determined according to the field intensity.156

In general, applying these techniques in the clinical field is significantly limited. The applicability of the results for all tumor cells, impact of the results on selecting and discarding treatments, and difficulty in accessing laboratories with the appropriate technology to apply and interpret the assays are issues that must be addressed before chemotherapy sensitivity and resistance assays are ready for prime time.

Conclusions and Future Directions

Different studies, the majority of which were performed in vitro, have identified several mechanisms of drug resistance in breast cancer. How these processes operate in vivo and their clinical impact must be further studied in controlled prospective examinations of patient tumor specimens correlated with therapeutic responses to different agents. The search for these mechanisms continues to aid the development of useful approaches to overcoming drug resistance. The use of newer technologies such as genomics and proteomics will continue to expand this field of study. For instance, recent studies using gene arrays of breast tumor tissue were able to predict response to neoadjuvant chemotherapy.157,158

These discoveries should impact the rationale for designing clinical trials to continue studying drug resistance and achieve the goal of being able to administer tailored therapy for breast cancer.

Acknowledgements

Funding/Support: Supported in part by the Nellie B. Connally Breast Cancer Fund.

References

1.
Anonymous Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. GLOBOCAN: IARC Press 2002 . (http​//www-depiarcfr/daba/infodatahtm)
2.
Jemal A, Murray T, Samuels A. et al. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5–26. [PubMed: 12568441]
3.
Pisani P, Bray F, Parkim DN. Estimates of the worldwide prevalence of cancer for 25 sites in the adult population. Int J Cancer. 2002;97:72–81. [PubMed: 11774246]
4.
Collyar DE. Breast cancer; a global prespective. J Clin Oncol. 2002;19(18 Suppl):101S–105S. [PubMed: 11560983]
5.
McGuire WL. Breast cancer prognostic factors: Evaluation guidelines. J Natl Cancer Inst. 1991;83:154–155. [PubMed: 1988696]
6.
Winer EP, Morrow M, Osborne CK. et al. Malignat tumors of the breast. In: DeVita VT, Hellman S, Rosenberg S, eds. Cancer Principles and Practices of Oncology, chap 37.2. Philadephia, PA. 2001:1651–1717.
7.
Singletary SE, Allred C, Ashley P. et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol. 2002;20:3628–3636. [PubMed: 12202663]
8.
Slamon DJ, Clark GM, Wong SG. et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. [PubMed: 3798106]
9.
Tommasi S, Paradiso A, Mangia A. et al. Biological correlation between HER-2/neu and proliferative activity in human breast cancer. Anticancer Res. 1991;11:1395–1400. [PubMed: 1684096]
10.
Fox SB, Leek RD, Smith K. et al. Tumor angiogenesis in node-negative breast carcinomas - Relationship with epidermal growth factor receptor, estrogen receptor, and survival. Breast Cancer Res Treat. 1994;29:109–116. [PubMed: 7517221]
11.
Gasparini G, Boracchi P, Bevilacqua P. et al. A multiparametric study on the prognostic value of epidermal growth factor receptor in operable breast carcinoma. Breast Cancer Res Treat. 1994;29:59–71. [PubMed: 7912568]
12.
Hedley DW, Clark GM, Cornelisse CJ. et al. Consensus review of the clinical utility of DNA cytometry in carcinoma of the breast. Report of the DNA Cytometry Consensus Conference. Cytometry. 1993;14:482–485. [PubMed: 8354119]
13.
Makris A, Powles TJ, Dowsett M. et al. p53 protein overexpression and chemosensitivity in breast cancer. The Lancet. 1995;345:1181–1182. [PubMed: 7723571]
14.
Keyomarsi K, Tucker SL, Buchholz TA. et al. Cyclin E and survival in patients with breast cancer. New England Journal of Medicine Online. 2002;347:1566–1575. [PubMed: 12432043]
15.
Alkarain A, Slingerland J. Deregulation of p27 by oncogenic signaling and its prognostic significance in breast cancer. Breast Cancer Res. 2004;6:13–21. [PMC free article: PMC314445] [PubMed: 14680481]
16.
Cristofanilli M, Budd GT, Ellis MJ. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–791. [PubMed: 15317891]
17.
Funke IM, Zia A, Wild C. et al. Phenotype of disseminated tumor cells in bone marrow of breast cancer patients. J Clin Oncol. 2001;7:3670S. [PubMed: 11477561]
18.
Gasparini G, Weidner N, Bevilacqua P. et al. Tumor microvessel density, p53 expression, tumor size, and peritumoral lymphatic vessel invasion are relevant prognostic markers in node-negative breast carcinoma. J Clin Oncol. 1994;12:454–466. [PubMed: 7509851]
19.
Anonymous. The national institutes of health consensus development conference: Adjuvant therapy for breast cancer. Bethesda, Maryland, USA. November 1-3, 2000. Proceedings. J Natl Cancer Inst Monogr. 2001;1-152 [PubMed: 12083020]
20.
Henderson IC, Berry DA, Demetri GD. et al. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003;21:976–983. [PubMed: 12637460]
21.
Early Breast Cancer Trialists' CollaborativeGroup. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet. 1998;351:1451–1467. [PubMed: 9605801]
22.
Early Breast Cancer Trialists' CollaborativeGroup. Tamoxifen for early breast cancer. Cochrane Database Syst Rev. 2001;1:CD000486. [PubMed: 11279694]
23.
Buzdar AU. Data from the Arimidex, tamoxifen, alone or in combination (ATAC) trial: Implications for use of aromatase inhibitors in 2003. Clin Cancer Res. 2004;10:355S–361S. [PubMed: 14734491]
24.
Haq R, Zanke B. Inhibition of apoptotic signaling pathways in cancer cells as a mechanism of chemotherapy resistance. Cancer Metastasis Rev. 1998;17:233–239. [PubMed: 9770120]
25.
DeVita JrVT. The James Ewing lecture. The relationship between tumor mass and resistance to chemotherapy. Implications for surgical adjuvant treatment of cancer. Cancer. 1983;51:1209–1220. [PubMed: 6825044]
26.
Green M, Hortobagyi GN. Neoadjuvant chemotherapy for operable breast cancer. Oncology (Huntingt) 2002;16:871–84 (889). [PubMed: 12164555]
27.
Fisher B, Bryant J, Wolmark N. et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–2685. [PubMed: 9704717]
28.
Kuerer HM, Newman LA, Buzdar AU. et al. Pathologic tumor response in the breast following neoadjuvant chemotherapy predicts axillary lymph node status. Cancer Journal From Scientific American. 1998;4:230–236. [PubMed: 9689981]
29.
Fisher B, Bryant J, Wolmark N. et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–2685. [PubMed: 9704717]
30.
Fisher B, Bryant J, Wolmark N. et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–2685. [PubMed: 9704717]
31.
Bear HD, Anderson S, Brown A. et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003;21:4165–4174. [PubMed: 14559892]
32.
Bear HD, Anderson S, Brown A. et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003;21:4165–4174. [PubMed: 14559892]
33.
Heys SD, Hutcheon AW, Sarkar TK. et al. Neoadjuvant docetaxel in breast cancer: 3-year survival results from the Aberdeen trial. Clin Breast Cancer. 2002;3(Suppl 2):S69–S74. [PubMed: 12435290]
34.
Buzdar AU, Hunt KK, Smith T. et al. Significantly higher pathological complete remission (PCR) rate following neoadjuvant therapy with trastuzumab (H), paclitaxel (P), and anthracycline-containing chemotherapy (CT): Initial results of a randomized trial in operable breast cancer (BC) with HER/ 2 positive disease. Proc Am Soc Clin Oncol. 2004;22(14S)
35.
Ellis MJ, Rosen E, Dressman H. et al. Neoadjuvant comparisons of aromatase inhibitors and tamoxifen: Pretreatment determinants of response and on-treatment effect. J Steroid Biochem Mol Biol. 2003;86:301–307. [PubMed: 14623525]
36.
Huober J, Krainick-Strobel U, Kurek R. et al. Neoadjuvant endocrine therapy in primary breast cancer. Clin Breast Cancer. 2004;5:341–347. [PubMed: 15585070]
37.
Muggia FM. Primary chemotherapy: Concepts and issues. Prog Clin Biol Res. 1985;201:377–383. [PubMed: 4095118]
38.
Parkin DM, Bray F, Ferlay J. et al. Estimating the world cancer burden. Globocan 2000. Int J Cancer. 2001;94:153–156. [PubMed: 11668491]
39.
Cardoso F, Di LeoA, Lohrisch C. et al. Second and subsequent lines of chemotherapy for metastatic breast cancer: What did we learn in the last two decades? Annals Oncol. 2002;3:197–207. [PubMed: 11885995]
40.
Thomas E, Holmes FA, Smith TL. et al. The use of alternate, noncross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: Long-term results from a prospective randomized trial. J Clin Oncol. 2004;22:2294–2302. [PubMed: 15197190]
41.
Strumberg D, Nitiss JL, Rose A. et al. Mutation of a conserved serine residue in a quinolone-resistant type II topoisomerase alters the enzyme-DNA and drug interactions. J Biol Chem. 1999;274:7292–7301. [PubMed: 10066792]
42.
Biedler JL, Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: Cross-resistance, radioautographic, and cytogenetic studies. Cancer Res. 1970;30:1174–1184. [PubMed: 5533992]
43.
Riordan JR, Ling V. Genetic and biochemical characterization of multidrug resistance. Pharmacol Ther. 1985;28:51–75. [PubMed: 2865753]
44.
Biedler JL, Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: Cross-resistance, radioautographic, and cytogenetic studies. Cancer Res. 1970;30:1174–1184. [PubMed: 5533992]
45.
Gros P, Croop J, Housman D. Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell. 1986;47:371–380. [PubMed: 3768958]
46.
Volk EL, Rohde K, Rhee M. et al. Methotrexate cross-resistance in a mitoxantrone-selected multidrug-resistant MCF7 breast cancer cell line is attributable to enhanced energy-dependent drug efflux. Cancer Res. 2000;60:3514–3521. [PubMed: 10910063]
47.
Izquierdo MA, Scheffer GL, Flens MJ. et al. Relationship of LRP-human major vault protein to in vitro and clinical resistance to anticancer drugs. Cytotechnology. 1996;19:191–197. [PubMed: 8862006]
48.
Vassetzky YS, Alghisi GC, Gasser SM. DNA topoisomerase II mutations and resistance to anti-tumor drugs. Bioessays. 1995;17:767–774. [PubMed: 8763829]
49.
Fernandes DJ, Qiu J, Catapano CV. DNA topoisomerase II isozymes involved in anticancer drug action and resistance. Adv Enzyme Regul. 1995;35:265–281. [PubMed: 7572348]
50.
Chen YN, Mickley LA, Schwartz AM. et al. Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein. J Biol Chem. 1990;265:10073–10080. [PubMed: 1972154]
51.
Safa AR, Glover CJ, Meyers MB. et al. Vinblastine photoaffinity labeling of a high molecular weight surface membrane glycoprotein specific for multidrug-resistant cells. J Biol Chem. 1986;261:6137–6140. [PubMed: 3700389]
52.
Choi KH, Chen CJ, Kriegler M. et al. An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell. 1988;53:519–529. [PubMed: 2897240]
53.
Lee K, Belinsky MG, Bell DW. et al. Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Res. 1998;58:2741–2747. [PubMed: 9661885]
54.
Zhan Z, Sandor VA, Gamelin E. et al. Expression of the multidrug resistance-associated protein gene in refractory lymphoma: Quantitation by a validated polymerase chain reaction assay. Blood. 1997;89:3795–3800. [PubMed: 9160686]
55.
Zhang H, D'Arpa P, Liu LF. A model for tumor cell killing by topoisomerase poisons. Cancer Cell. 1990;2:23–27. [PubMed: 2167111]
56.
Hochhauser D, Harris AL. The role of topoisomerase II alpha and beta in drug resistance. Cancer Treat Rev. 1993;19:181–194. [PubMed: 8386983]
57.
Drake FH, Hofmann GA, Bartus HF. et al. Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II. Biochemistry. 1989;28:8154–8160. [PubMed: 2557897]
58.
Larsen AK, Skladanowski A. Cellular resistance to topoisomerase-targeted drugs: From drug uptake to cell death. Biochim Biophys Acta. 1998;1400:257–274. [PubMed: 9748618]
59.
Larsen AK, Skladanowski A. Cellular resistance to topoisomerase-targeted drugs: From drug uptake to cell death. Biochim Biophys Acta. 1998;1400:257–274. [PubMed: 9748618]
60.
Matsumoto Y, Takano H, Fojo T. Cellular adaptation to drug exposure: Evolution of the drug-resistant phenotype. Cancer Res. 1997;57:5086–5092. [PubMed: 9371507]
61.
Liu LF. DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem. 1989;58:351–375. [PubMed: 2549853]
62.
Giovanella BC, Stehlin JS, Wall ME. et al. DNA topoisomerase I—targeted chemotherapy of human colon cancer in xenografts. Science. 1989;246:1046–1048. [PubMed: 2555920]
63.
Mannervik B, Danielson UH. Glutathione transferases—structure and catalytic activity. CRC Crit Rev Biochem. 1988;23:283–337. [PubMed: 3069329]
64.
Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30:445–600. [PubMed: 8770536]
65.
Brix LA, Nicoll R, Zhu X. et al. Structural and functional characterisation of human sulfotransferases. Chem Biol Interact. 1998;109:123–127. [PubMed: 9566739]
66.
Ivy SP, Tulpule A, Fairchild CR. et al. Altered regulation of P-450IA1 expression in a multidrug-resistant MCF-7 human breast cancer cell line. J Biol Chem. 1988;263:19119–19125. [PubMed: 3143724]
67.
Thorgeirsson SS, Huber BE, Sorrell S. et al. Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver. Science. 1987;236:1120–1122. [PubMed: 3576227]
68.
Schecter RL, Alaoui-Jamali MA, Woo A. et al. Expression of a rat glutathione-S-transferase complementary DNA in rat mammary carcinoma cells: Impact upon alkylator-induced toxicity. Cancer Res. 1993;53:4900–4906. [PubMed: 8402679]
69.
Leyland-Jones BR, Townsend AJ, Tu CP. et al. Antineoplastic drug sensitivity of human MCF-7 breast cancer cells stably transfected with a human alpha class glutathione S-transferase gene. Cancer Res. 1991;51:587–594. [PubMed: 1985777]
70.
Berhane K, Hao XY, Egyhazi S. et al. Contribution of glutathione transferase M3-3 to 1,3-bis(2-chloroethyl)-1-nitrosourea resistance in a human nonsmall cell lung cancer cell line. Cancer Res. 1993;53:4257–4261. [PubMed: 8395980]
71.
Awasthi S, Singhal SS, Srivastava SK. et al. Adenosine triphosphate-dependent transport of doxorubicin, daunomycin, and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein. J Clin Invest. 1994;93:958–965. [PMC free article: PMC294005] [PubMed: 7907606]
72.
Jedlitschky G, Leier I, Buchholz U. et al. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res. 1994;54:4833–4836. [PubMed: 7915193]
73.
Muller M, Meijer C, Zaman GJ. et al. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci USA. 1994;91:13033–13037. [PMC free article: PMC45575] [PubMed: 7809167]
74.
Sinha BK, Mimnaugh EG, Rajagopalan S. et al. Adriamycin activation and oxygen free radical formation in human breast tumor cells: Protective role of glutathione peroxidase in adriamycin resistance. Cancer Res. 1989;49:3844–3848. [PubMed: 2544260]
75.
Sinha BK. Free radicals in anticancer drug pharmacology. Chem Biol Interact. 1989;69:293–317. [PubMed: 2659197]
76.
Hall AG. Review: The role of glutathione in the regulation of apoptosis. Eur J Clin Invest. 1999;29:238–245. [PubMed: 10202381]
77.
Bellamy CO. p53 and apoptosis. Br Med Bull. 1997;53:522–538. [PubMed: 9374035]
78.
Reed JC, Miyashita T, Takayama S. et al. BCL-2 family proteins: Regulators of cell death involved in the pathogenesis of cancer and resistance to therapy. Journal of Cellular Biochemistry. 1996;60:23–32. [PubMed: 8825412]
79.
Reed JC. Bcl-2 family proteins: Regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol. 1997;34:9–19. [PubMed: 9408956]
80.
Poplack DG, Reaman G. Acute lymphoblastic leukemia in childhood. Pediatr Clin North Am. 1988;35:903–932. [PubMed: 3138626]
81.
Chen G, Jaffrezou JP, Fleming WH. et al. Prevalence of multidrug resistance related to activation of the mdr1 gene in human sarcoma mutants derived by single-step doxorubicin selection. Cancer Res. 1994;54:4980–4987. [PubMed: 7915196]
82.
Laredo J, Huynh A, Muller C. et al. Effect of the protein kinase C inhibitor staurosporine on chemosensitivity to daunorubicin of normal and leukemic fresh myeloid cells. Blood. 1994;84:229–237. [PubMed: 7912555]
83.
van der Kolk DM, de VriesEG, Koning JA. et al. Activity and expression of the multidrug resistance proteins MRP1 and MRP2 in acute myeloid leukemia cells, tumor cell lines, and normal hematopoietic CD34+ peripheral blood cells. Clin Cancer Res. 1998;4:1727–1736. [PubMed: 9676848]
84.
Chernov MV, Stark GR. The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate. Oncogene. 1997;14:2503–2510. [PubMed: 9191050]
85.
Tanizawa A, Kubota M, Takimoto T. et al. Prevention of adriamycin-induced interphase death by 3-aminobenzamide and nicotinamide in a human promyelocytic leukemia cell line. Biochem Biophys Res Commun. 1987;144:1031–1036. [PubMed: 2953339]
86.
Larsen AK, Skladanowski A. Cellular resistance to topoisomerase-targeted drugs: From drug uptake to cell death. Biochim Biophys Acta. 1998;1400:257–274. [PubMed: 9748618]
87.
Withoff S, de JongS, de Vries EG. et al. Human DNA topoisomerase II: Biochemistry and role in chemotherapy resistance (review) Anticancer Res. 1996;16:1867–1880. [PubMed: 8712715]
88.
Withoff S, de JongS, de Vries EG. et al. Human DNA topoisomerase II: Biochemistry and role in chemotherapy resistance (review) Anticancer Res. 1996;16:1867–1880. [PubMed: 8712715]
89.
Finlay GJ, Baguley BC, Snow K. et al. Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues. J Natl Cancer Inst. 1990;82:662–667. [PubMed: 2157028]
90.
Seidman AD, Reichman BS, Crown JP. et al. Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol. 1995;13:1152–1159. [PubMed: 7537798]
91.
Wilson WH, Berg SL, Bryant G. et al. Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: A phase I/II trial of 96-hour infusion. J Clin Oncol. 1994;12:1621–1629. [PubMed: 7913721]
92.
Anderson H, Hopwood P, Prendiville J. et al. A randomised study of bolus vs continuous pump infusion of ifosfamide and doxorubicin with oral etoposide for small cell lung cancer. Br J Cancer. 1993;67:1385–1390. [PMC free article: PMC1968524] [PubMed: 8390287]
93.
Wilson L, Miller HP, Farrell KW. et al. Taxol stabilization of microtubules in vitro: Dynamics of tubulin addition and loss at opposite microtubule ends. Biochemistry. 1985;24:5254–5262. [PubMed: 2866793]
94.
Sparreboom A, van TellingenO, Nooijen WJ. et al. Preclinical pharmacokinetics of paclitaxel and docetaxel. Anticancer Drugs. 1998;9:1–17. [PubMed: 9491787]
95.
Greenberger LM, Williams SS, Horwitz SB. Biosynthesis of heterogeneous forms of multidrug resistance-associated glycoproteins. J Biol Chem. 1987;262:13685–13689. [PubMed: 2888763]
96.
Tolcher AW, Cowan KH, Solomon D. et al. Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer. J Clin Oncol. 1996;14:1173–1184. [PubMed: 8648372]
97.
Horwitz SB, Lothstein L, Manfredi JJ. et al. Taxol: Mechanisms of action and resistance. Annals of the New York Academy of Sciences. 1986;466:733–744. [PubMed: 2873780]
98.
Torres K, Horwitz SB. Mechanisms of Taxol-induced cell death are concentration dependent. Cancer Research. 1998;58:3620–3626. [PubMed: 9721870]
99.
Allegra CJ, Chabner BA, Drake JC. et al. Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates. J Biol Chem. 1985;260:9720–9726. [PubMed: 2410416]
100.
Priest DG, Ledford BE, Doig MT. Increased thymidylate synthetase in 5-fluorodeoxyuridine resistant cultured hepatoma cells. Biochem Pharmacol. 1980;29:1549–1553. [PubMed: 6446915]
101.
Bapat AR, Zarow C, Danenberg PV. Human leukemic cells resistant to 5-fluoro-2'-deoxyuridine contain a thymidylate synthetase with lower affinity for nucleotides. J Biol Chem. 1983;258:4130–4136. [PubMed: 6220000]
102.
Hsueh CT, Dolnick BJ. Regulation of folate-binding protein gene expression by DNA methylation in methotrexate-resistant KB cells. Biochem Pharmacol. 1994;47:1019–1027. [PubMed: 7511899]
103.
Cowan KH, Jolivet J. A methotrexate-resistant human breast cancer cell line with multiple defects, including diminished formation of methotrexate polyglutamates. J Biol Chem. 1984;259:10793–10800. [PubMed: 6206061]
104.
Grant SC, Kris MG, Young CW. et al. Edatrexate, an antifolate with antitumor activity: A review. [Review] Cancer Invest. 1993;11:36–45. [PubMed: 8422595]
105.
Sirotnak FM, Moccio DM, Kelleher LE. et al. Relative frequency and kinetic properties of transport-defective phenotypes among methotrexate-resistant L1210 clonal cell lines derived in vivo. Cancer Res. 1981;41:4447–4452. [PubMed: 7306968]
106.
Dixon KH, Lanpher BC, Chiu J. et al. A novel cDNA restores reduced folate carrier activity and methotrexate sensitivity to transport deficient cells. J Biol Chem. 1994;269:17–20. [PubMed: 8276792]
107.
Chung KN, Saikawa Y, Paik TH. et al. Stable transfectants of human MCF-7 breast cancer cells with increased levels of the human folate receptor exhibit an increased sensitivity to antifolates. J Clin Invest. 1993;91:1289–1294. [PMC free article: PMC288097] [PubMed: 7682567]
108.
Kool M, van derLM, de Haas M. et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA. 1999;96:6914–6919. [PMC free article: PMC22016] [PubMed: 10359813]
109.
Hooijberg JH, Broxterman HJ, Scheffer GL. et al. Potent interaction of flavopiridol with MRP1. British Journal of Cancer. 1999;81:269–276. [PMC free article: PMC2362861] [PubMed: 10496352]
110.
Cowan KH, Jolivet J. A methotrexate-resistant human breast cancer cell line with multiple defects, including diminished formation of methotrexate polyglutamates. J Biol Chem. 1984;259:10793–10800. [PubMed: 6206061]
111.
Volk EL, Rohde K, Rhee M. et al. Methotrexate cross-resistance in a mitoxantrone-selected multidrug-resistant MCF7 breast cancer cell line is attributable to enhanced energy-dependent drug efflux. Cancer Res. 2000;60:3514–3521. [PubMed: 10910063]
112.
Rhee MS, Wang Y, Nair MG. et al. Acquisition of resistance to antifolates caused by enhanced gamma-glutamyl hydrolase activity. Cancer Res. 1993;53:2227–2230. [PubMed: 7683570]
113.
Spears CP. Clinical resistance to antimetabolites. Hematol Oncol Clin North Am. 1995;9:397–413. [PubMed: 7642470]
114.
Ackland SP, Schilsky RL. High-dose methotrexate: A critical reappraisal. J Clin Oncol. 1987;5:2017–2031. [PubMed: 3316519]
115.
Kamen BA, Winick NJ. High dose methotrexate therapy: Insecure rationale? Biochem Pharmacol. 1988;37:2713–2715. [PubMed: 3395351]
116.
Jackson RC, Jackman AL, Calvert AH. Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L-glutamic acid (CB3717), on human lymphoblastoid cells. Biochem Pharmacol. 1983;32:3783–3790. [PubMed: 6661252]
117.
Beardsley GP, Moroson BA, Taylor EC. et al. A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis. J Biol Chem. 1989;264:328–333. [PubMed: 2909524]
118.
Elias L, Crissman HA. Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: Antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites. Cancer Res. 1988;48:4868–4873. [PubMed: 2457431]
119.
Auerbach M, Elias EG, Orford J. Experience with methotrexate, 5-fluorouracil, and leucovorin (MFL): A first line effective, minimally toxic regimen for metastatic breast cancer. Cancer Invest. 2002;20:24–28. [PubMed: 11852998]
120.
Klatt O, Stehlin JrJS, McBride C. et al. The effect of nitrogen mustard treatment on the deoxyribonucleic acid of sensitive and resistant Ehrlich tumor cells. Cancer Res. 1969;29:286–290. [PubMed: 5765411]
121.
Nogae I, Kohno K, Kikuchi J. et al. Analysis of structural features of dihydropyridine analogs needed to reverse multidrug resistance and to inhibit photoaffinity labeling of P-glycoprotein. Biochem Pharmacol. 1989;38:519–527. [PubMed: 2563655]
122.
Zamble DB, Lippard SJ. Cisplatin and DNA repair in cancer chemotherapy. Trends Biochem Sci. 1995;20:435–439. [PubMed: 8533159]
123.
Fairchild CR, Moscow JA, O'Brien EE. et al. Multidrug resistance in cells transfected with human genes encoding a variant P-glycoprotein and glutathione S-transferase-pi. Mol Pharmacol. 1990;37:801–809. [PubMed: 1972772]
124.
Townsend AJ, Tu CP, Cowan KH. Expression of human mu or alpha class glutathione S-transferases in stably transfected human MCF-7 breast cancer cells: Effect on cellular sensitivity to cytotoxic agents. Mol Pharmacol. 1992;41:230–236. [PubMed: 1538704]
125.
Hilton J. Deoxyribonucleic acid crosslinking by 4-hydroperoxycyclophosphamide in cyclophosphamide-sensitive and -Resistant L1210 cells. Biochem Pharmacol. 1984;33:1867–1872. [PubMed: 6732847]
126.
Perez RP. Cellular and molecular determinants of cisplatin resistance. Eur J Cancer. 1998;34:1535–1542. [PubMed: 9893624]
127.
Perez RP. Cellular and molecular determinants of cisplatin resistance. Eur J Cancer. 1998;34:1535–1542. [PubMed: 9893624]
128.
Mackey JR, Mani RS, Selner M. et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998;58:4349–4357. [PubMed: 9766663]
129.
Mackey JR, Mani RS, Selner M. et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998;58:4349–4357. [PubMed: 9766663]
130.
Ruiz VHV, Veerman G, Eriksson S. et al. Development and molecular characterization of a 2',2'-difluorodeoxycytidine-resistant variant of the human ovarian carcinoma cell line A2780. Cancer Res. 1994;54:4138–4143. [PubMed: 8033147]
131.
Goan YG, Zhou B, Hu E. et al. Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res. 1999;59:4204–4207. [PubMed: 10485455]
132.
Bergman AM, Pinedo HM, Jongsma AP. et al. Decreased resistance to gemcitabine (2',2'-difluorodeoxycitidine) of cytosine arabinoside-resistant myeloblastic murine and rat leukemia cell lines: Role of altered activity and substrate specificity of deoxycytidine kinase. Biochem Pharmacol. 1999;57:397–406. [PubMed: 9933028]
133.
Schirmer M, Stegmann AP, Geisen F. et al. Lack of cross-resistance with gemcitabine and cytarabine in cladribine-resistant HL60 cells with elevated 5'-nucleotidase activity. Exp Hematol. 1998;26:1223–1228. [PubMed: 9845378]
134.
Abbruzzese JL, Grunewald R, Weeks EA. et al. A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol. 1991;9:491–498. [PubMed: 1999720]
135.
Roodi N, Bailey LR, Kao WY. et al. Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. J Natl Cancer Inst. 1995;87:446–451. [PubMed: 7861463]
136.
Gottardis MM, Jordan VC. Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. Cancer Res. 1988;48:5183–5187. [PubMed: 3409244]
137.
Pietras RJ, Arboleda J, Reese DM. et al. Her-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene. 1995;10:2435–2446. [PubMed: 7784095]
138.
Gottardis MM, Martin MK, Jordan VC. Long-term tamoxifen therapy to control transplanted human breast tumor growth in athymic mice. In: Salmon SE, ed. Adjuvant Therapy of Cancer V. Orlando. 1987:447–453.
139.
Lavinsky RM, Jepsen K, Heinzel T. et al. Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proc Natl Acad Sci USA. 1998;95:2920–2925. [PMC free article: PMC19670] [PubMed: 9501191]
140.
Dauvois S, White R, Parker MG. The antiestrogen ICI 182780 disrupts estrogen receptor nucleocytoplasmic shuttling. J Cell Sci. 1993;106(Pt 4):1377–1388. [PubMed: 8126115]
141.
Parker MG, Arbuckle N, Dauvois S. et al. Structure and function of the estrogen receptor. Ann NY Acad Sci. 1993;684:119–126. [PubMed: 8317825]
142.
Baselga J, Norton L, Albanell J. et al. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Research. 1998;58:2825–2831. [PubMed: 9661897]
143.
Sliwkowski MX, Lofgren JA, Lewis GD. et al. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin) Semin Oncol. 1999;26:60–70. [PubMed: 10482195]
144.
Lewis GD, Figari I, Fendly B. et al. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;37:255–263. [PubMed: 8102322]
145.
Pegram MD, Baly D, Wirth C. et al. Antibody dependent cell-mediated cytotoxicity in breast cancer patients in Phase III clinical trials of a humanized anti-HER2 antibody. Proceedings of the American Association for Cancer Research. 1997;38:602.
146.
Pegram M, Hsu S, Lewis G. et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999;18:2241–2251. [PubMed: 10327070]
147.
Argiris A, Wang CX, Whalen SG. et al. Synergistic interactions between tamoxifen and trastuzumab (Herceptin) Clin Cancer Res. 2004;10:1409–1420. [PubMed: 14977844]
148.
Sachdev D, Yee D. The IGF system and breast cancer. 2001;8:197–209. [PubMed: 11566611]
149.
Miller KD. The role of ErbB inhibitors in trastuzumab resistance. Oncologist. 2004;9(Suppl 3):16–19. [PubMed: 15163843]
150.
Moulder SL, Yakes FM, Muthuswamy SK. et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res. 2001;61:8887–8895. [PubMed: 11751413]
151.
Esteva FJ. Monoclonal antibodies, small molecules, and vaccines in the treatment of breast cancer. Oncologist. 2004;9(Suppl 3):4–9. [PubMed: 15163841]
152.
Chernicky CL, Tan H, Yi L. et al. Treatment of murine breast cancer cells with antisense RNA to the type I insulin-like growth factor receptor decreases the level of plasminogen activator transcripts, inhibits cell growth in vitro, and reduces tumorigenesis in vivo. Mol Pathol. 2002;55:102–109. [PMC free article: PMC1187158] [PubMed: 11950959]
153.
Lu YH, Zi XL, Zhao YH. et al. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin) J Natl Cancer Inst. 2001;93:1852–1857. [PubMed: 11752009]
154.
Nagata Y, Lan KH, Zhou X. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–127. [PubMed: 15324695]
155.
Schrag D, Garewal HS, Burstein HJ. et al. American society of clinical oncology technology assessment: Chemotherapy sensitivity and resistance assays. J Clin Oncol. 2004;22:3631–3638. [PubMed: 15289488]
156.
Xu JM, Song ST, Tang ZM. et al. Predictive chemotherapy of advanced breast cancer directed by MTT assay in vitro. Breast Cancer Res Treat. 1999;53:77–85. [PubMed: 10206075]
157.
Symmans WF, Ayers M, Clark EA. et al. Total RNA yield and microarray gene expression profiles from fine-needle aspiration biopsy and coreneedle biopsy samples of breast carcinoma. Cancer. 2003;97:2960–71. [PubMed: 12784330]
158.
Chang JC, Wooten EC, Tsimelzon A. et al. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet. 2003;2(362):362–9. [PubMed: 12907009]
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