Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efflux of cytotoxic agents mediated by P-glycoprotein is believed to be an important mechanism of multidrug resistance, which remains a serious limitation to successful chemotherapy in cancers such as metastatic breast cancer. A series of 4-aryl-1,4-dihydropyridines and corresponding aromatized 4-arylpyridines have been synthesized based on structure modifications of niguldipine to enhance multidrug resistance reversal activity, while minimizing calcium channel binding. Thirty new compounds were characterized. [(3)H]Vinblastine accumulation studies indicated that at a concentration level of 3 muM, 15 of 18 4-aryl-1,4-dihydropyridines and all 4-arylpyridines can successfully restore intracellular accumulation of vinblastine in a resistant human breast adenocarcinoma cell line, MCF-7/adr, which overexpresses P-glycoprotein. The most potent compounds led to an approximately 15-fold increase of vinblastine accumulation. All of the test compounds that significantly increased vinblastine accumulation in MCF/adr cells were able to substantially reduce IC(50) values of daunomycin and increase its cytotoxicity in MCF-7/adr-resistant cells, confirming the results of the vinblastine accumulation studies. Calcium channel binding assays for these newly synthesized compounds were conducted using rat cerebral cortex membrane. All but eight compounds demonstrated negligible calcium channel binding over the concentration range from 15 to 2500 nM. The results demonstrate that the newly synthesized series of 1,4-dihydropyridines and pyridines represent P-glycoprotein modulators with negligible calcium channel blocking activity.
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PMID:New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. 1558 8

Doxorubicin (DOX) has excellent antitumor activity when combined with paclitaxel (PTX) and this combination is used as first-line treatment for metastatic breast cancer. Results from clinical studies on pharmacokinetic interaction of these agents are not conclusive and pre-clinical studies are still needed. Pharmacokinetic studies were carried out in female Balb/c mice with combined DOX (6 mg/kg) and PTX (10 mg/kg) treatment. Combined treatment with PTX and DOX leads to alterations in the pharmacokinetics of both agents, with the predominant effect being elevated drug levels in liver and gut tissues. DOX levels in kidney and heart tissues were unaffected by concurrent PTX treatment. Further, plasma levels of DOX are not changed by concurrent PTX treatment suggesting that monitoring of plasma levels of DOX, when used in combination with another drug that is a P-glycoprotein (PGP) substrate, will not reflect actual pharmacokinetic changes occurring in other tissues.
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PMID:Pharmacokinetics of combined doxorubicin and paclitaxel in mice. 1576 91

Patients with metastatic breast cancer receive multiple lines of cytotoxic chemotherapy, with taxane and anthracycline-based regimens being the most active. Anthracyclines carry the risk of significant cardiotoxicity at high cumulative doses and when combined with trastuzumab, an anti-HER2 antibody. Carboplatin has shown promising single-agent activity in advanced breast cancer, is not a P-glycoprotein substrate, and is conveniently administered on an outpatient basis. Preclinical experiments demonstrated schedule-dependent synergistic cytotoxic effects of the paclitaxel first/carboplatin last (PC) combination. Pharmacokinetic parameters of paclitaxel and carboplatin were studied by Hellenic Cooperative Oncology Group (HECOG) and no significant interaction or correlation with clinical parameters were found. We assessed PC both as salvage as well as first-line treatment of advanced breast cancer patients in phase II studies which disclosed 40-60% response rates and median survival times of 12-20 mo with manageable toxicity. These results were confirmed by other groups and prompted us to the first randomized phase III trial comparing PC to the standard of epirubicin/paclitaxel (EP), a trial that showed equivalent efficacy and tolerable toxicity for PC. Registry retrospective analysis identified factors prognostic for improved outcome: good performance status, low tumor burden, lack of anthracycline exposure and of hormonal maintenance therapy. PC combinations with HER1 or HER2 modulators are being evaluated both by HECOG and by international groups. Paclitaxel coupled with carboplatin provides an alternative therapeutic option for anthracycline-exposed patients and warrants further clinical research in the direction of anthracycline-free management of metastatic breast cancer.
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PMID:Paclitaxel-carboplatin combination chemotherapy in advanced breast cancer: accumulating evidence for synergy, efficacy, and safety. 1672 Sep 15

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m(2) over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer.
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PMID:Interleukin-6, multidrug resistance protein-1 expression and response to paclitaxel in women with metastatic breast cancer: results of cancer and leukemia group B trial 159806. 1677 37

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor cyclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m-2 combined with CsA 10 mg kg-1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m-2 week-1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.
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PMID:Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer. 1696 54

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. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. 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. 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. 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. 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. 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. 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. 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, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. 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. 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. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. 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. 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. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. 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 regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. 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. 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. 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. 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. 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.
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PMID:Overview of resistance to systemic therapy in patients with breast cancer. 1799 29

When taxanes were introduced as anticancer agents some 20 years ago, their broad spectrum of activity was striking and engendered renewed hope for cancer patients. However, they were not without their problems, including a susceptibility to drug resistance caused by the drug efflux pump protein, P-glycoprotein. The epothilones are a new class of chemotherapeutic agents that have a mechanism of action similar enough to the taxanes to retain their broad spectrum of activity, but different enough to escape the multidrug resistance caused by P-glycoprotein. These properties are especially promising for patients with metastatic breast cancer who have run out of therapeutic options as a result of multidrug resistance. Ixabepilone, a semi-synthetic analogue of epothilone B, has recently been granted US FDA approval for the treatment of chemotherapy-resistant advanced breast cancer. Approval was based on results from a phase III study of ixabepilone in combination with capecitabine, as well as phase II studies of ixabepilone monotherapy. Significantly prolonged progression-free survival and increased objective response rates were demonstrated in the phase III study when ixabepilone was administered in combination with capecitabine compared with capecitabine alone. The phase II trials demonstrated robust antitumour activity with single-agent ixabepilone in women with metastatic breast cancer that was resistant to taxanes, anthracyclines and capecitabine. Early data from phase I trials of KOS-1584 and sagopilone are positive and suggest that these drugs may also develop into useful chemotherapeutic agents. Significant, but manageable, toxicities have been observed with the epothilones. In particular, neuropathy has led to the uneven and slower than expected clinical development of ixabepilone as optimal administration regimens were established. Some differences in tolerability profiles exist between the different analogues. Overall, it is expected that the epothilones will play an important role in the treatment of breast cancer and other tumour types.
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PMID:New therapeutic options for chemotherapy-resistant metastatic breast cancer: the epothilones. 1819 22

Resistance to chemotherapeutic agents is a significant issue in the management of patients with breast cancer. Anthracyclines, although first used over 30 years ago, are still part of the standard chemotherapy for this disease. Subsequently, the taxanes heralded a new era in chemotherapy and have been used extensively in the treatment of metastatic breast cancer. Unfortunately, along with other constituents of combination chemotherapy for metastatic breast cancer such as cyclophosphamide, these agents become increasingly ineffective in progressive disease and tumours are then deemed to be drug resistant - frequently multidrug resistant. A number of processes have been identified that can underlie clinical drug resistance, and these largely stem from in vitro laboratory-based studies in human cancer cell lines. A large proportion of these studies have focused on multidrug resistance associated with resistance to natural product anticancer agents due to the presence of putative drug transporter proteins such as P-glycoprotein, MRP1, and BCRP. Other studies have highlighted mechanisms whereby breast cancer cells show resistance to chemotherapeutic agents by altered regulation of DNA repair processes, with many other factors influencing drug detoxification processes and altering drug targets. New developmental agents with improved specificity for tumour cells, such as trastuzumab, and those with low susceptibility to common tumour-resistance mechanisms, such as ixabepilone, have provided new hope for effective treatment of breast cancer. Ixabepilone is the first in a new class of neoplastics, the epothilones. With these developments in therapy, and the technology of gene expression profiling, the future holds more promise for the development of more effective treatment for metastatic breast cancer.
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PMID:Mechanisms and strategies to overcome chemotherapy resistance in metastatic breast cancer. 1836 36

N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE, tesmilifene), a potent chemopotentiating drug currently in Phase III clinical trials of metastatic breast cancer, increases cytotoxicity of anthracyclines and taxanes in a variety of multi-drug resistance expressing (MDR+) tumor cell lines in vitro; inhibits binding of histamine to CYP3A4, a lipid/prostanoid-regulatory P450; and modulates serum levels of HDL/LDL cholesterol and phospholipids in vivo. Since increased exposure of phosphatidylserine (PS) on the outer cell membrane leaflet is associated with apoptosis, increased clearance of dead cells by phagocytes and inhibition of the P-glycoprotein pump, the effect of DPPE on PS synthesis was assessed in vitro in a human breast cancer cell line. MCF-7 cells were incubated with 5 microM DPPE for 24 hr or 5 days, followed by addition of [1-(14)C]arachidonic acid for 4 hr; or [3H]serine for 8 hr. Compared to untreated cells, a 27-42% (p < 0.05) increase in [1-(14)C]arachidonic acid incorporated into all phospholipids, including a 1.9-fold increase (p < 0.05) in PS was observed in DPPE-treated cells. [3H]Serine incorporation into PS was elevated 37%, while the pool size of PS was elevated 23% (p < 0.05) in DPPE-treated cells, indicating elevated de novo PS biosynthesis. Annexin-5 binding studies indicated an elevation in exposure of PS on the surface of the plasma membrane in DPPE-treated cells. DPPE-treatment also resulted in N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine accumulation indicative of phospholipidosis-inducing potential. Thus, the chemopotentiating effect of DPPE may be due to its phospholipidosis-inducing potential and stimulation of PS synthesis leading to an increased exposure of PS on the cell surface which could potentially enhance cancer cell clearance by phagocytes.
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PMID:The phospholipidosis-lnducing potential of the chemopotentiating drug, N,N-Diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine (DPPE, tesmilifene) correlates with its stimulation of phosphatidylserine synthesis and exposure on the plasma membrane in MCF-7 breast cancer cells. 1860 31

The application of taxane chemotherapy to the treatment of early-stage and advanced breast cancer has resulted in significant improvements in disease-free and overall survival. As a consequence of these improvements in disease outcome, oncologists must face the new challenge of developing additional therapies that are effective against taxane-resistant disease and are associated with a favorable toxicity profile. This article discusses some of the chemotherapeutic options available for the treatment of patients with taxane-resistant metastatic breast cancer. Newer formulations of traditional microtubule-stabilizing agents, such as albumin-bound paclitaxel, which uses a more favorable vehicle for administration compared with conventional paclitaxel, have demonstrated efficacy in this setting. Several novel microtubule-targeting agents have been shown to be less susceptible to traditional mechanisms of taxane resistance, such as the multidrug resistance phenotype associated with increased activity of the P-glycoprotein drug efflux system and the development of structural changes in tubulin. Examples of these therapies include the vinca alkaloids, such as vinorelbine and vinflunine; epothilones; and eribulin. Traditional antimetabolites, such as gemcitabine and capecitabine, used as monotherapy or combination chemotherapy have also shown efficacy in the treatment of patients with taxane-resistant breast cancer. A greater understanding of the mechanism of drug resistance, as it pertains to taxanes, will enable further development and the effective application of chemotherapeutic agents that will circumvent drug resistance and result in improvement in breast cancer control.
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PMID:Options for the treatment of patients with taxane-refractory metastatic breast cancer. 1863 1


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