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)

Renal cell carcinoma exhibits chemoresistance attributable in part to the P-glycoprotein drug efflux mechanism. Acrivastine is a hydrophylic antihistamine that has been shown in vitro to reverse this form of resistance. After five patients were treated on a dose-finding study, seventeen patients with metastatic or unresectable renal cell carcinoma were entered into a phase II study of vinblastine in combination with acrivastine. Patients received oral acrivastine at doses of 400 mg every 4 hours for 6 days and a 96-hour continuous infusion of vinblastine at a dose of 1.6 mg/m2/24 h. Of 15 evaluable patients, no tumor responses were seen. The regimen was well-tolerated with the majority of toxicities being gastrointestinal and hematologic. Serum levels of acrivastine, its principal metabolite (270C81) and vinblastine were measured during the study. Based on in vitro data, the plasma levels of acrivastine were within a range adequate to block P-glycoprotein activity. High doses of acrivastine were well-tolerated clinically, however, the combination of acrivastine and vinblastine was not active against renal cell carcinoma.
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PMID:A phase II study of vinblastine in combination with acrivastine in patients with advanced renal cell carcinoma. 786 Feb 31

We have established a model of human renal cell carcinoma, Kgg2, transplanted into athymic nude mice which expressed P-glycoprotein (P-gp) (detected by flow cytometry) and a high level of mRNA transcript of mdr1 gene (Northern blot analysis). We have evaluated the antitumor activity of a new highly potent vinca-alkaloid derivative, S 12363, in comparison with the activity of the reference compound vinblastine (VLB), when used alone or in combination with verapamil (VRP). The influence of the calcium influx blocker verapamil on the activity of the combination of S 12363 with adriamycin (ADR) was also determined. The results showed that S 12363 at a dose of 0.05 mg/kg/day, administered alone by intraperitoneal route daily on days 1 to 5, induced a tumoral regression of 50% during the first days after treatment. This effect was potentialized by simultaneous treatment with verapamil at 20 mg/kg/day for 5 days, leading to a long-term reduction of 70% of tumor growth. Vinblastine at a dose of 0.4 mg/kg/day administered alone or in combination with verapamil, using the same protocol, was less efficient. The association of S 12363 at 0.075 mg/kg/day (on days: 1-5, 11, 21 and 31), adriamycin at 2 mg/kg/day (on days: 11, 21 and 31) and verapamil at 20 mg/kg/day (on days: 0-5, 11, 21 and 31) induced an important reduction of tumor growth of 80% at the end of the experiment. In conclusion, the new vinca-alkaloid derivative S 12363 could present a therapeutic advantage over the reference compound vinblastine in the treatment of renal cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antitumor activity of the new vinca-alkaloid S 12363 alone or in combination with verapamil on a human multidrug resistant renal carcinoma xenograft. 790 53

We evaluated 28 patients with advanced renal cell carcinoma for the initial expression of P-glycoprotein (MDR1 gene product) employing immunocytochemistry. Tumor specimens were obtained upon primary tumor nephrectomy. In all patients, progression-free survival time following nephrectomy was evaluated and correlated statistically with the staining results. Progression-free survival of patients with no or very few (< 1%) P-glycoprotein-positive tumor cells (n = 8, median survival 27.0 months) was significantly extended (p < 0.04) as compared to patients with 1% or more P-glycoprotein-positive tumor cells (n = 20, median survival 4.0 months). Correlations with histopathological tumor characteristics were insignificant. These results suggest a potential role for P-glycoprotein as a biologic parameter predictive of tumor progression in renal cell carcinoma patients.
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PMID:Immunocytochemical detection of P-glycoprotein: initial expression correlates with survival in renal cell carcinoma patients. 791 63

The expression of the multidrug-resistance gene product, P-glycoprotein was examined immunohistochemically in 31 untreated human renal cell carcinomas. In 17 of these, chemosensitivity to Adriamycin and vinblastine was also assessed by a microtiter succinate dehydrogenase inhibition test and the correlation between the expression of P-glycoprotein and intrinsic multidrug resistance was investigated. P-glycoprotein was detected in 16 (51.6%) of the 31 carcinomas. In the chemosensitivity test, 14 (82.4%) of the 17 carcinomas were estimated to be resistant to both drugs (multidrug resistant; MDR). Eight (72.7%) of the 11 carcinomas with a positive expression of P-glycoprotein were MDR, and none of them were sensitive of both drugs. On the other hand, MDR carcinomas were not necessarily associated with the expression of P-glycoprotein. Eight (61.5%) of the 13 MDR carcinomas showed a positive expression of P-glycoprotein while the remaining 5 (38.5%) were negative. These results suggest that the expression of P-glycoprotein is an important factor responsible for the intrinsic MDR phenotype of renal cell carcinoma, however, there are probably other factors involved as well which have yet to be fully elucidated.
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PMID:Expression of P-glycoprotein and multidrug resistance in renal cell carcinoma. 810 56

The expression of alkaline phosphatase (AP) was analyzed in multidrug-resistant (MDR) tumor cells (sarcoma 180, lung carcinoma, and renal cell carcinoma cell lines) by means of immunocytochemistry. MDR cell cultures showed an overexpression of AP and a cross-resistance to 6-thioguanine (6-TG, CAS 154-42-7). Significant correlations between AP expression and doxorubicin or vincristine resistance and P-glycoprotein (P-170) expression were found in these cell cultures. A specific AP inhibitor, levamisole, reversed resistance to 6-TG, but not to doxorubicin. This indicates that 6-TG resistance is certainly associated to P-170 but a causal function of AP for the development of MDR does not exist.
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PMID:Increase of alkaline phosphatase in multidrug-resistant tumor cells and their cross-resistance to 6-thioguanine. 826 80

One potential explanation for why renal cell carcinoma is usually poorly responsive to chemotherapy is intrinsic multidrug resistance. Dipyridamole (DP) is one of several agents known to bind to P-glycoprotein and potentially reverse multidrug resistance in vitro, and dosages needed to obtain appropriate levels in vivo appear to be well tolerated. The current study was undertaken to evaluate the combination of vinblastine (VLB) and DP in patients with advanced renal cell carcinoma and no prior chemotherapy. From August 1989 through December 1989, 15 patients with inoperable recurrent or metastatic renal cell carcinoma were treated with VLB 0.2 mg/kg (i.v. slow push) and concurrently received DP75 mg p.o. q.i.d. starting 48 hours before and continuing 48 hours after VLB administration. Courses were repeated every 3 weeks for a maximum of 8 weeks, or until disease progression or undue toxicities ensued. The predominant toxicities seen were mild neurotoxicity and leukopenia. Only 1 patient had grade IV leukopenia, and no lethal toxicities occurred. No objective responses were seen; 2 patients had stable disease for 29 and 30+ months. The median survival was 9 months (range: 2.5-30+). We conclude that at the dose and schedule used in this study, the combination of VLB and DP may be administered with acceptable toxicities, but is ineffective in the treatment of advanced renal cell carcinoma.
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PMID:A phase II trial of vinblastine plus dipyridamole in advanced renal cell carcinoma. A Hoosier Oncology Group Study. 831 Oct

Using renal carcinoma and prostate carcinoma cell lines, we investigated the concept of targeting and killing multidrug resistant cells in urogenital cancers. Renal carcinoma lines HTB44, 45, 46, and 47 expressed a relatively low, but detectable level of multidrug resistance (MDR)1 mRNA as indicated by Northern blot analysis, whereas prostate lines LNCaP and DU145 were found to be MDR1-negative. Anti-P-glycoprotein monoclonal antibody MRK16 was conjugated to Pseudomonas exotoxin (PE) by a stable thioether bond. Treatment with MRK16-PE resulted in a dose-dependent killing of multidrug resistant renal carcinoma cells, while non-MDR expressing prostate carcinoma cells were not affected. Addition of excess MRK16 blocked the effect of MRK16-PE. Furthermore, MOPC-PE, a non-MDR associated monoclonal antibody control conjugate, did not target and kill multidrug resistant renal carcinoma cells. Having established that MRK16-PE was active against and specific for multidrug resistant cells in culture, we also tested bioactivity in MDR-transgenic mice, whose bone marrow cells express the human MDR1 gene at a level approximately equal to that found in many human cancers. Again, MRK16-PE killed multidrug resistant bone marrow cells with high efficiency in an intact animal, and killing was blocked by unconjugated MRK16.
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PMID:Pseudomonas exotoxin conjugated to monoclonal antibody MRK16 specifically kills multidrug resistant cells in cultured renal carcinomas and in MDR-transgenic mice. 841 4

Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined-treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 microM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil.
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PMID:Dexverapamil to modulate vinblastine resistance in metastatic renal cell carcinoma. 869 36

The multidrug resistant (MDR) phenotype is a well-studied subject that has been recognized as a determinant underlying specific types of drug resistance in human cancer. Although it is clear that the P-glycoprotein plays a major role in MDR, it is not clear whether post-translational modifications such as phosphorylation have any major impact on its modulation. The laboratory of Dr. Bruce Chabner was one of the first to describe increased expression and activity of protein kinase C (PKC) associated with the MDR phenotype. Since that time, a similar correlation has been observed in many other MDR cell lines. Most of these studies have been performed with doxorubicin-selected cells that have acquired MDR and have shown increased PKC activity, mainly for PKC-alpha isoenzyme. Intrinsic MDR in human renal cell carcinoma lines has been shown to correlate directly with PKC activity, but further studies with intrinsic MDR cell lines are needed before any conclusions can be drawn. More recent evidence suggests that there is a complex biochemical process by which PKC isoenzymes differentially phosphorylate specific serine residues in the linker region of P-glycoprotein which may lead to alterations in P-glycoprotein ATPase and drug-binding functions. To further complicate matters, PKC plays an important role in anti-apoptotic pathways, which can confound the dissection and elucidation of drug-resistance mechanisms. However, these areas are still under active investigation and not fully answered. Further studies are needed to specifically answer the question of whether PKC directly modulates basal and/or drug-stimulated P-glycoprotein function. This manuscript reviews the majority of the literature on PKC and MDR, as well as offers caveats for interpretation of these studies to answer the above questions.
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PMID:P-glycoprotein, multidrug resistance and protein kinase C. 882 Sep 51

Solitary stroma-invading tumor cells expressing the ATP-binding cassette transporter P-glycoprotein have been reported to be associated with a significantly higher incidence of vessel invasion and lymph node metastases. In contrast to P-gp-mediated multidrug resistance (MDR) which has become well characterized over the last decade, little is known about further morphological and functional alterations in drug-resistant tumor cells. Binding of malignant cells to components of the extracellular matrix mediated by beta 1 integrins has been suggested to play a substantial role in the metastatic cascade. We studied alterations of beta 1 integrin expression and in vitro adhesiveness to extracellular matrix proteins of the human renal carcinoma line Caki-1 in comparison to the vinblastine resistant sublines Caki-1/V1 and Caki-1/V10 (cultured in the presence of 1 ng/ml and 10 ng/ml vinblastine, respectively). Both VLA-1 and VLA-2 receptors were acquired by the Caki-1/V10 subline, whereas untreated and Caki-1/VI cells lacked surface expression of these antigens. VLA-6 was found to be decreased in the vinblastine-resistant sublines. Attachment of drug-resistant Caki-1/V1 and Caki-1/V10 cells to collagen type I was significantly increased when compared to parental cells (p < or = 0.005). Significant differences in the attachment to type IV collagen were observed between Caki-1/V10 and untreated cells (p < or = 0.045). Both Caki-1/V1 and Caki-1/ V10 cells exhibited increased adhesion to fibronectin when compared to cells of the untreated line (p < or = 0.04). Whether an aberrant expression of beta 1 integrin receptors in resistant cells in combination with altered tumor cell adhesiveness is caused by MDR induction or whether it is an epiphenomenon of cytotoxic stress is unknown. Future studies will be needed to characterize the clinical relevance of MDR-associated changes in tumor cells.
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PMID:Exposure to vinblastine modulates beta 1 integrin expression and in vitro binding to extracellular matrix molecules in a human renal carcinoma cell line. 903 Feb 41


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