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)

Adult renal cell carcinoma (RCC) is clinically resistant to chemotherapy. However, in nephroblastoma (NBL) chemotherapy has increased survival dramatically. We studied the P-glycoprotein (P-gp) expression of 18 RCC and 9 NBL as well as 1 benign renal adenoma and fetal renal tissue using three different monoclonal antibodies (MRK-16, C-219, JSB-1). P-gp was found positive with all three antibodies in 12/18 RCC, while only 2 tumors were completely negative. Staining varied with respect to intensity and number of positive cells [5%-90%]. Intense staining was seen at the apical side of malignant tubules in well differentiated parts of RCC and in tubular structures of the benign renal adenoma. Poorly differentiated parts of the tumors showed less staining. In NBL blastemal parts were negative. In 4/8 specimens showing focal epithelial differentiation, however, the luminal side of more differentiated tubular structures did stain, strongly resembling P-gp staining in the developing fetal human kidney. These results indicate that P-gp expression in normal (fetal) human kidney as well as in benign and malignant tumors derived from this organ depends on the degree of differentiation of tubules, which may have implications for chemotherapy sensitivity in both malignant tumors.
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PMID:Differentiation dependent expression of P-glycoprotein in the normal and neoplastic human kidney. 167 98

Multidrug resistance in human renal cell carcinoma is mainly caused by expression of the MDR1 gene and is characterized by a broad spectrum cross resistance to many natural product chemotherapeutic agents. This resistance can be overcome by applying chemosensitizers which inhibit the function of the MDR1 gene product P-glycoprotein. The development of new reversing agents with fewer side effects and a higher potency in modifying resistance is a high priority of research on drug resistance. We have evaluated four new verapamil derivatives on 21 primary human renal cell carcinomas in vitro, and also tested them in an MDR-transgenic mice model. These mice express the human MDR1 gene in their bone marrow cells and measurement of their white blood counts provides a simple, rapid and reliable system to screen for the potency of MDR-reversing agents in vivo. We demonstrate here that all four drugs are effective in reversing multidrug resistance in primary cultures of human renal cell carcinomas when used in combination with vinblastine chemotherapy, and to a lesser extent with doxorubicin or daunomycin chemotherapy. Our in vivo data indicate that two of these reversing agents display low toxicity at high concentrations and are more effective at low, clinically achievable concentrations, than the other two drugs and R-verapamil. These results make the two new drugs attractive candidates to be taken into clinical trials.
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PMID:New potent verapamil derivatives that reverse multidrug resistance in human renal carcinoma cells and in transgenic mice expressing the human MDR1 gene. 167 34

The multidrug transporter, initially identified as a multidrug efflux pump responsible for resistance of cultured cells to natural product cytotoxic drugs, is normally expressed on the apical membranes of excretory epithelial cells in the liver, kidney, and intestine. This localization suggests that the multidrug transporter may have a normal physiological role in transporting cytotoxic compounds or metabolites. In the liver, hepatectomy or treatment with chemical carcinogens increases expression of the MDR1 gene which encodes the multidrug transporter. To evaluate conditions which increase MDR1 gene expression, we have investigated the induction of the MDR1 gene by physical and chemical environmental insults in the renal adenocarcinoma cell line HTB-46. There are two strong heat shock consensus elements in the major MDR1 gene promoter. Exposure of HTB-46 cells to heat shock, sodium arsenite, or cadmium chloride led to a 7- to 8-fold increase in MDR1 mRNA levels. MDR1 RNA levels did not change following glucose starvation or treatment with 2-deoxyglucose and the calcium ionophore A23187, conditions which are known to activate the expression of another family of stress proteins, the glucose-regulated proteins. The levels of the multidrug transporter, P-glycoprotein, as measured by immunoprecipitation, were also increased after heat shock and sodium arsenite treatment. This increase in the level of the multidrug transporter in HTB-46 cells correlated with a transient increase in resistance to vinblastine following heat shock and arsenite treatment. These results suggest that the MDR1 gene is regulatable by environmental stress.
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PMID:Heat shock and arsenite increase expression of the multidrug resistance (MDR1) gene in human renal carcinoma cells. 196 74

This paper describes the cellular and tissue distribution of P-glycoprotein (P-GP) (mdr1 gene product), the role of P-GP in vivo and immunodiagnosis of multi-drug-resistant cancers. We mainly used MRK 16 monoclonal antibody (MAb) reactive with P-GP. P-GP was found to be expressed very strongly in the adrenal cortex of adults and strongly in the renal tubules of the kidney, capillary blood vessels of the brain, and also in placenta. Interestingly, P-GP was not distributed in fetal and neonatal adrenals, and thus may be closely related to adrenal maturation. A high level of P-GP expression was also seen in all cases of functional hormone-producing adrenal tumor, one case of insulinoma, two cases of untreated colonic cancer, one case each of untreated lung cancer, gastric cancer and breast cancer, six cases of renal cell carcinoma and 17 cases of bladder cancer. Using flow cytometry and immunocytochemistry, we investigated the reactivity of MRK 16 MAb with peripheral human mononuclear cells (mainly blastic cells and lymphocytes) from 31 patients with leukemia or malignant lymphoma. Reactivity with MRK 16 MAb was observed in five cases. Some cases reflected the prior administration of adriamycin, vincristine and VP-16, which are known to induce P-GP expression. P-GP-MRK 16-protein A-Sepharose complex derived from human adrenal possessed marked ATPase activity. These data suggest that P-GP may play a physiological role in the human adrenal. Finally, diagnostic criteria of multi-drug-resistant cancers are presented.
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PMID:Expression and functions of P-glycoprotein (mdr1 gene product) in normal and malignant tissues. 197 61

The natural resistance to doxorubicin of 15 human renal carcinoma cell lines was analyzed and compared to proliferative activity and expression of P-glycoprotein. We found a significant negative correlation between proliferative activity and natural resistance to doxorubicin, as well as between proliferative activity and the expression of P-glycoprotein. A positive correlation between resistance and expression of P-glycoprotein was found.
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PMID:Correlations between natural resistance to doxorubicin, proliferative activity, and expression of P-glycoprotein 170 in human kidney tumor cell lines. 197 57

The expression of MDR1 gene was investigated in human solid tumors with respect to adriamycin resistance. Forty fresh human surgical specimens were analyzed by RNA dot blot assay for their expression of the human MDR1 gene and by immunohistological staining using a monoclonal antibody against P-glycoprotein (MDR1 gene product). The MDR1 mRNA level was increased in 11 cases of 40 cancer patients, including three rectal cancers, two breast cancers, two gastric cancers, one colon cancer, one renal cell carcinoma, one gall bladder cancer and one malignant lymphoma of stomach. However, considerable variation of the MDR1 mRNA level was noted among cancers of a specific type. Immunohistochemical studies with the monoclonal antibody were shown to be positive in 18 tumors. In all tumors tested, the MDR1 mRNA level and the immunohistochemical analysis showed a significant correlation. However, two of five tumors which resisted adriamycin treatment were found to be negative in MDR1 transcript, but positive in immunohistological analysis. These results indicate that immunohistochemical analysis would be more sensitive for detecting P-glycoprotein-expression, and that resistance to adriamycin, being multifactorial, can be associated at least, in part with the increased amount of MDR1 gene product.
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PMID:Expression of the multidrug resistance gene in human tumors. 198 Sep 15

We report the immunohistochemical detection of the 170-180 kDa multi-drug-resistance-related P-glycoprotein in human tumor cells with a low level of resistance. A series of human squamous lung cancer cell lines with increasing levels of resistance to doxorubicin (DOX) was developed and stained for P-glycoprotein, using the JSB-IMAb. Subline SW1573/50A with a 4- to 6-fold cross-resistance to daunorubicin (DNR) and vincristine (VCR) showed rather uniform positive staining for P-glycoprotein apparently at cytoplasmic sites. Only in cells with higher degrees of resistance (greater than 10-fold) could plasma-membrane-associated P-glycoprotein be made visible. DNR efflux was increased in SW1573/50A as compared to the parent line SW1573 (52 and 70% DNR were retained during 3 min efflux respectively). Verapamil partially reversed DNR and VCR resistance in SW1573/50A. Cells obtained from a metastasized renal cell carcinoma and cultured in vitro stained in a similar way to SW1573/50A and showed some sensitivity to verapamil modulation of VCR cytotoxicity. Our results suggest that weakly resistant cancer cells obtained from patients can be routinely detected with JSB-I on cytospins, and implicate that in such weakly resistant cells P-glycoprotein may be present, while plasma membrane expression is not yet readily detectable.
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PMID:Immunohistochemical detection of P-glycoprotein in human tumor cells with a low degree of drug resistance. 256 22

We examined the distribution of RNA levels expressed by the multidrug-resistance gene (MDR1, also known as PGY1) in 42 renal cell carcinoma (RCC) samples (38 primary and four metastatic lesions). The median MDR1 RNA level for the 38 primary lesions, expressed relative to the level for KB-3-1 cells, was approximately one-half of the level in multidrug-resistant KB-8-5 cells. Elevated MDR1 RNA levels were also observed in three of the four metastatic lesions. The mean MDR1 RNA level was higher in well-differentiated RCCs than in those that were poorly differentiated, suggesting that the increased expression of the MDR1 gene in RCCs originates from the increased expression in renal proximal tubule cells. To clarify the association of the MDR1 protein product P-glycoprotein with natural resistance to doxorubicin (ADR) in RCCs, we evaluated the effects of quinidine on in vitro sensitivity to ADR in 16 RCC samples, using a [3H]thymidine incorporation assay. The enhancing effect of quinidine (7.5 micrograms/mL) on sensitivity to ADR was statistically significant only in the group with high MDR1 RNA levels. Similar enhancement by quinidine of sensitivity to ADR was also observed in the established RCC cell lines in which MDR1 RNA levels were high. These results suggest that P-glycoprotein is active in the natural resistance of RCCs to ADR.
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PMID:MDR1 RNA levels in human renal cell carcinomas: correlation with grade and prediction of reversal of doxorubicin resistance by quinidine in tumor explants. 272 49

The lipophilic antitumor alkaloid acronycine (ACRO) was solubilized in the cosolvent system used for etoposide. ACRO in this etoposide diluent (VPD) was found to be cytotoxic (less than or equal to 50% colony formation in soft agar) in fresh human tumors from patients with renal cell cancer, ovarian cancer, uterine cancer, and metastatic tumors of unknown primary. In P-glycoprotein-positive, multidrug-resistant (MDR) cell lines, ACRO in VPD was active in MDR Chinese hamster ovary cells but not against MDR L1210 murine leukemia cells, 8226 human myeloma cells, or human CCRF-CEM lymphoblasts. In mice, ACRO in VPD was active in two solid tumor models and an i.p. MOPC-315 plasmacytoma model. ACRO i.p. in 10% VPD (v/v%) produced significant tumor growth delays in (a) nude mice bearing human MCF-7 breast cancer xenografts and (b) C57BL mice bearing colon 38 tumor. In MOPC-315-bearing mice, a single i.p. ACRO dose of 25 mg/kg was as effective as melphalan (15 mg/kg) at prolonging life span. Finally, ACRO pharmacokinetics was evaluated in mice given single 25-mg/kg doses i.p. or p.o. The oral bioavailability of an ACRO solution in VPD was only 50% but both i.p. and p.o. regimens achieved plasma levels greater than 1.0 micrograms/ml. The plasma half-life was just under 2 h. These results show that parenteral ACRO in VPD comprises a cytotoxic antitumor agent with improved bioavailability over p.o. administration. ACRO is active in vitro against several human solid tumors but is cross-resistant in 3 of 4 MDR tumor cell lines. The prior clinical activity of p.o. ACRO in myeloma and the new results in MOPC-315 plasmacytomas in mice suggest that ACRO in VPD could have activity against human multiple myeloma.
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PMID:Antitumor activity and murine pharmacokinetics of parenteral acronycine. 291 Apr 53

Multidrug resistance (MDR) in a variety of human tumors such as renal cell carcinoma (RCC) is thought to be caused by expression of the mdr1 gene and may be reversed by applying chemosensitizers such as Dexverapamil that inhibit the mdr1 gene product P-glycoprotein. On the basis of our preclinical analysis, we initiated a clinical (GCP) study with vinblastine (VBL), the most effective--if at all--chemotherapeutic agent; dexverapamil; and dexamethasone in patients with RCC. All patients had histologically proven RCC that was metastatic and progressive at study entry. The statistical design featured a preliminary study of two cycles of VBL alone followed by tumor evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for a minimum of three cycles of combination therapy. Having obtained institutional permission by the ethical review committee (MEC 124, 106-1993/12), we enrolled 24 patients on this protocol starting on May 3, 1993. In the preliminary study, 1 complete response (CR) was achieved with VBL alone, and myelotoxicity led to an adequate dose reduction from 2 mg/m2 VBL per day given as a 5-day continuous infusion (days 1-5) in 6/10 yet evaluable patients to 1.4 mg/m2 per day. In 8/11 yet evaluable patients, dexverapamil doses reached > or = 3000 mg/day by 7-day oral uptake (days 0-6, supported by 20 mg dexamethasone given twice daily), which is significantly higher than those previously reported. The combination of VBL given at 1.4 mg/m2 per day plus, dexverapamil given at 3000 mg per day was felt to be safe and well tolerated. Nine patients were yet evaluable for response. One partial response and three minor responses were noted in this heavily pretreated study population. It appears that this innovative approach may have some activity in RCC and may eventually lead to a rational treatment modality. Careful evaluation in ongoing studies is warranted.
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PMID:Chemoresistance of renal cell carcinoma: 1986-1994. 782 Jan 44


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