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)

Prior studies have shown that the P-glycoprotein is a cell membrane efflux pump that is quantitatively increased in expression in multidrug-resistant tumor cell lines. In this study, fresh tumor tissues from patients with multiple myeloma, malignant lymphoma, or metastatic breast cancer were studied immunohistochemically for P-glycoprotein expression and for in vitro sensitivity to doxorubicin. Twenty-six patients who were either previously untreated or in relapse after chemotherapy had tumor specimens submitted that could be evaluated in both assays. The testing was done independently and blindly in separate laboratories instead of our being provided relevant clinical data on the patients. Tumor cells from 12 of the 26 patients (46%) stained positively for P-glycoprotein. Fifteen of the 26 specimens (58%) exhibited drug resistance in vitro. Although only three (21%) of the 14 P-glycoprotein-negative tumors exhibited in vitro resistance to doxorubicin, all 12 fresh tumors that stained positively for P-glycoprotein were resistant to doxorubicin. The difference in frequency of intrinsic doxorubicin resistance between P-glycoprotein-negative and -positive tumors was highly significant (P less than .001). Similar trends were observed in each of the individual tumor categories and were statistically significant in myeloma and breast cancer. Four of the biopsy specimens that stained positively for P-glycoprotein and exhibited doxorubicin resistance were from patients who had not received prior cytotoxic chemotherapy. Similar conclusions were reached when results of drug sensitivity tests were ranked in relation to the median infective dose rather than by criteria based on correlations with clinical drug resistance. Our findings indicate that positive staining for P-glycoprotein associated with multidrug resistance predicts intrinsic cellular resistance of human cancers to doxorubicin. We anticipate that immunohistochemical staining for P-glycoprotein will prove useful in clinical oncology.
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PMID:Prediction of doxorubicin resistance in vitro in myeloma, lymphoma, and breast cancer by P-glycoprotein staining. 256 3

Paclitaxel is a highly active single agent as therapy for previously untreated as well as doxorubicin-refractory metastatic breast cancer, with associated response rates of 62% and 20-48%, respectively. Complete responses with paclitaxel occur chiefly in breast cancer patients whose metastatic disease has not been previously treated with chemotherapy. Early data suggest a possible dose-response relationship for paclitaxel in metastatic breast cancer, but the optimal dose has not yet been defined. The optimal duration of infusional paclitaxel treatment is also not yet known. A study of 96-hour infusional paclitaxel in the treatment of doxorubicin- or mitoxantrone-refractory metastatic breast cancer patients has demonstrated a 48% response rate suggesting that prolonged exposures to paclitaxel may offer a therapeutic advantage. Randomized trials of 3- vs 96-hour paclitaxel are ongoing or planned. The relative efficacy of paclitaxel versus standard chemotherapy as front-line or salvage therapy for metastatic breast cancer is currently under study. In addition, two randomized trials are under way in node positive breast cancer patients to study whether treatment with paclitaxel following standard or high dose doxorubicin and cyclophosphamide adjuvant therapy results in improved patient benefit. Combining paclitaxel with other active agents in the treatment of metastatic breast cancer is an area of active investigation. Combined paclitaxel and doxorubicin, administered concurrently or sequentially, is associated with modest complete response rates in metastatic breast cancer patients. Sequential paclitaxel-->doxorubicin administration is associated with more mucositis than is doxorubicin-->paclitaxel when paclitaxel is administered over 24 hours. High doses of cyclophosphamide can be combined with 24- or 72-hour infusional paclitaxel, and phase II studies of this combination are warranted. Early data suggest that administering biweekly paclitaxel and cisplatin to previously untreated metastatic breast cancer patients is associated with high response rates, and confirmatory studies of this combination and schedule are planned. Preclinical data suggest that cell cycle considerations may be important in combining doxorubicin and possibly other agents with paclitaxel. Paclitaxel is an excellent substrate for P-glycoprotein, the protein product of the multidrug resistance-1 (mdr-1) gene, and phase I trials are under way combining paclitaxel with several known blockers of Pgp function. Finally, pilot studies are under way to determine whether the radiation sensitizing effects of paclitaxel can be exploited as part of radiation therapy for patients with locally advanced breast cancer.
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PMID:Current status of paclitaxel in the treatment of breast cancer. 774 30

The search for new active agents and strategies to improve the prognosis for patients with stage IV breast cancer has led to examination of paclitaxel. Several clinical trials have been undertaken to determine its optimal use and clarify its role in the treatment of breast cancer and other malignancies. Several phase II trials involving breast cancer patients with limited prior therapy have yielded overall response rates (complete response and partial response) of 44% to 62% among women receiving paclitaxel. Treatment was generally well tolerated, with febrile neutropenia the most common side effect. An interim analysis of the European-Canadian Randomized Trial in Metastatic Breast Cancer demonstrated safety and efficacy of paclitaxel in a multicenter setting. Among the 234 patients evaluable for response, 29% (34/117) responded at 175 mg/m2 paclitaxel and 22% responded (26/117) at 135 mg/m2. Treatment was well tolerated at both dose levels; responses continue to evolve in patients who remain on study. Among patients with extensive prior therapy (> 2 prior regimens for stage IV disease), paclitaxel also has demonstrated safety and efficacy. At Memorial Sloan-Kettering Cancer Center, responses were noted among 36% of patients who had received two prior treatments and 21% of those who had received 3 or more. Paclitaxel was administered at 200 mg/m2 plus G-CSF. Other studies involving heavily pretreated patients yielded overall response rates as high as 53%. The concerns about cross-resistance between paclitaxel and doxorubicin (or other agents for which resistance is thought to be at least partly due to P-glycoprotein-mediated pleiotropic drug resistance) also are addressed.
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PMID:Single-agent use of Taxol (paclitaxel) in breast cancer. 786 28

Paclitaxel (Taxol) is a new cytotoxic agent with considerable activity in phase II studies on metastatic breast cancer. Paclitaxel for clinical use is dissolved in the solvents cremophor EL and ethanol. In this study, we added paclitaxel, formulated either in cremophor EL and ethanol or only in ethanol, in increasing concentrations to two parental human breast cancer cell lines (ZR 75-1 and HS 578T) and their corresponding sublines with acquired doxorubicin resistance and P-glycoprotein expression. Paclitaxel dissolved either in ethanol or ethanol plus cremophor EL, resulted in steep and almost identical dose-response curves for the parental lines ZR 75-1 and HS 578T, respectively, independent of the solvent used. When paclitaxel was formulated only in ethanol the effects on the corresponding doxorubicin-resistant sublines were significantly reduced compared with paclitaxel dissolved in ethanol plus cremophor EL. These effects by cremophor EL may partly explain some of the antitumoral effects observed by paclitaxel in anthracycline failing patients.
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PMID:Paclitaxel-induced cytotoxicity--the effects of cremophor EL (castor oil) on two human breast cancer cell lines with acquired multidrug resistant phenotype and induced expression of the permeability glycoprotein. 791 8

Resistance to cytotoxic chemotherapy is a major problem in the management of patients with metastatic breast cancer. Various data suggest P-glycoprotein-associated multidrug resistance (MDR) to be a relevant resistance mechanism in this tumor. The purpose of this study was to evaluate feasibility and activity of combining oral dexverapamil, a second-generation chemosensitizer currently in clinical development for MDR reversal, with epirubicin in patients with epirubicin-refractory high-risk metastatic breast cancer. Patients first received epirubicin alone at 120 mg/m2. In cases of clinical refractoriness, epirubicin was continued at the same dose and schedule but supplemented with oral dexverapamil. Dexverapamil was given at 300 mg every 6 h for a total of 13 doses and commenced 2 days prior to epirubicin administration. At the time of this interim analysis, 41 patients had received epirubicin alone and 20 proceeded to treatment with epirubicin plus dexverapamil. Of the 20 patients, 14 were considered evaluable for toxicity and activity. Addition of dexverapamil resulted in a significant decrease in mean heart rate and blood pressure as well as prolongation of PQ time as compared to epirubicin alone. However, these cardiovascular effects of dexverapamil were usually mild, and subjective tolerance of treatment was good. In 7/14 patients, dose escalation of dexverapamil was feasible. Dexverapamil had no effect on epirubicin toxicities and did not require reduction of the epirubicin dose. In 2/14 patients, the addition of dexverapamil to epirubicin was able to convert progressive disease and no changes respectively, into partial responses. In 3 patients with progressive disease, addition of dexverapamil temporarily prevented further tumor progression. Analyses of dexverapamil and nor-dexverapamil plasma levels, of in vitro reversal activity of patient sera containing dexverapamil, and of epirubicin pharmacokinetics without and with dexverapamil are currently in progress. Addition of oral dexverapamil to epirubicin 120 mg/m2 proved to be feasible in a multiinstitutional setting. Patient accrual is continuing to determine whether dexverapamil is capable of overcoming epirubicin refractoriness in a significant number of patients with metastatic breast cancer.
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PMID:Dexverapamil to overcome epirubicin resistance in advanced breast cancer. 869 40

Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase II trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m(-2) i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 microg ml[-1] h[-1], P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 microM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, CI 5-39%, s.e.P 0.079). The remissions lasted 3, 8, 11 and 11+ months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.
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PMID:Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer. 956 55

The purpose of this study is to evaluate whether metastatic breast cancer that has progressed on an anthracycline-containing drug regimen will subsequently respond to that identical regimen if dexverapamil, a modulator of P-glycoprotein-mediated drug resistance, is given concomitantly. Eligible patients received 180 mg/m2 dexverapamil every 6 h for 15 doses with the anthracycline administered 30 min after the seventh dose. Blood for dexverapamil levels was drawn before and 30 min after this dose. When possible, biopsies were obtained to measure mdr-1 expression by reverse transcription-PCR and by image cytometry. Of the 21 patients entered onto the trial, 20 were evaluable for response. There were two partial responses (10%) that both lasted for 6 months, and two additional patients had stable disease. Seven patients had asymptomatic cardiotoxicity consisting of hypotension (24%), bradycardia (5%), or prolongation of the P-R interval (14%). Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days after stopping it. Dexverapamil did not seem to increase anthracycline toxicity. The median trough dexverapamil plus norverapamil level on day 3 was 1110 ng/ml (range, 186-3385 ng/ml), and the median peak level was 2164 ng/ml (range, 964-8382 ng/ml). There was poor correlation between reverse transcription-PCR and image cytometry for the level of mdr-1 expression. Because dexverapamil has been shown to affect doxorubicin pharmacokinetics subsequent to the initiation of this trial, it cannot be concluded that the responses seen were necessarily due to P-glycoprotein inhibition. Additional studies are necessary to determine whether mdr-1 modulators can reverse clinical drug resistance in breast cancer patients. The intrinsic cardiotoxicity of dexverapamil makes it less suitable for such studies than several other available agents.
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PMID:Phase II study of dexverapamil plus anthracycline in patients with metastatic breast cancer who have progressed on the same anthracycline regimen. 962 62

Chemotherapy resistance is a major problem in the management of patients with breast cancer. Clinical resistance of solid tumors such as breast cancer is likely to be multifactorial and heterogeneous. Usually, patients refractory to chemotherapy exhibit resistance to multiple cytotoxic agents of different structure (and often function). A comparable experimental phenomenon has been termed multidnug resistance or MDR. MDR can be caused by various molecular mechanisms. One of these mechanisms is overexpression of MDR1/P-glycoprotein, which cna be expected in around 30-40% of primary and 50% of metastatic breast cancers. Preliminary evidence suggests that P-glycoprotein-positivity is associated with poor treatment outcome in both primary and advanced breast cancer. Studies of MDR reversal in metastatic breast cancer have generally yielded negative results. Recently, however, we found dexverapamil to be able to induce partial remissions to epirubicin in 4/23 patients (17%) with metastatic breast cancer refractory to the same dose and schedule of epirubicin alone. Dexverapamil did not increase the toxicity or the area under the plasma concentration-time curve of epirubicin. More carefully designed and conducted studies are needed to conclusively determine the clinical relevance of various resistance mechanisms in breast cancer and whether chemosensitizers such as dexverapamil or cyclosporins are able to enhance chemotherapy efficacy in this tumor.
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PMID:Chemotherapy resistance in breast cancer. 970 89

Clinical studies of agents capable of reversing P-glycoprotein (Pgp)-mediated multidrug resistance have attracted much attention in recent years. One question of interest in such studies is whether the concentrations achieved by chemosensitizers are sufficient to inhibit Pgp function. The goal of the present study was to develop a reliable ex vivo bioassay for analysis of the Pgp-inhibiting activity of chemosensitizer-containing patient serum. The fluorescent Pgp substrates daunorubicin (DNR) and rhodamine 123 (R123) were used as probes for Pgp function. The 8226/DOX6 human myeloma cell line, which expresses Pgp at levels that can be detected in clinical cancers, was used as a model system. The index chemosensitizers tested were dexverapamil (DVPM) and cyclosporin A, with particular focus on DVPM. Using flow cytometry, chemosensitizer effects on 1-h drug accumulation and on drug retention at 30 min were evaluated. In the studies using pooled human serum spiked in vitro with graded chemosensitizer concentrations, the order of assay sensitivity was R123 retention >>> R123 accumulation > DNR retention equal to DNR accumulation. Keeping serum spiked with DVPM for several hours at room temperature or 4 degreesC or for several months at -80 degreesC had no effect on Pgp-blocking activity. Sixteen blood samples from patients with metastatic breast cancer receiving DVPM to overcome epirubicin resistance were analyzed for Pgp-inhibiting activity and for levels of DVPM and nor-DVPM, the major metabolite of verapamil. Each patient sample was found capable of increasing R123 retention in the 8226/DOX6 cells, with activity factors of 3- to 8-fold and good agreement between DVPM blood levels and bioassay activity (r = 0.7168; two-sided P = 0.0018). The R123 retention assay developed and validated in this study seems to be a sensitive, reproducible, and easy-to-use method for analysis of Pgp-inhibiting activity of chemosensitizer-containing human serum. The assay seems capable of estimating DVPM blood levels and could prove to be a valuable tool for monitoring chemosensitizer treatment in cancer patients.
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PMID:Sensitive and rapid bioassay for analysis of P-glycoprotein-inhibiting activity of chemosensitizers in patient serum. 981 84

The management of breast cancer requires the judicious use of cytotoxic therapy, hormone therapy, radiotherapy, analgesics, and other forms of physical and psychological support for optimal palliation of symptoms and prolongation of survival. Patients with low-risk metastatic breast cancer often benefit from hormone therapy as initial management; other patients are best treated with early introduction of cytotoxic therapy. Combination chemotherapy is superior to single-agent treatment, and anthracycline-containing regimens are more effective than the rest. The development of primary or secondary resistance to anthracycline therapy represents an adverse prognostic indicator, associated, until recently, with poor response to subsequent cytotoxic therapy and short survival. Prior to the development of taxanes, response to second- and third-line chemotherapy for patients with primary anthracycline resistance was observed in 5% of patients. Paclitaxel and docetaxel retain substantial antitumor activity in anthracycline-resistant breast cancer, and vinorelbine is also moderately effective in this subset of patients. Attempts to reverse P-glycoprotein-related drug resistance, while encouraging in the laboratory, have not been successful in the clinic. A number of novel therapeutic interventions, many that bypass traditional mechanisms of drug resistance, are currently in clinical developments, with encouraging preliminary results.
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PMID:Anthracycline-Resistant Breast Cancer. 1109 3


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