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)

A cell line (GZL-8) was established by cloning from ascitic fluid of an untreated ovarian carcinoma patient. The cells grew rapidly, accumulated lipids and showed chromosomal alterations. One of the marker chromosomes showed characteristics of a Y-like chromosome. This unusual finding was confirmed by DNA hybridisation using specific probes to the Y chromosome. The cells stained with fluorescent antibodies to desmoplakin and cytokeratins 8, 18, 19, and weakly with vimentin but not with desmin. The presence of epithelial membrane antigen, human milk fat globulin, alpha-lactalbumin, alpha-fetoprotein, placental alkaline phosphatase and oestrogen receptor-related antigen was demonstrated by indirect immunoperoxidase staining, but no CA-125 antigen could be detected. The cells showed positive reaction with antibodies to P-glycoprotein. The function of the P-glycoprotein transport system was demonstrated by the rhodamine-123 release test. The cells were initially responsive to doxorubicin, and to high concentrations of cisplatin. Growth inhibition by doxorubicin, especially at low doses was enhanced by the addition of verapamil or tamoxifen. This was shown by the soft agar clonogenic assay, by direct cell counting and by the MTT reducing test. Our results show that combination between drug and sensitivity modulators may be of potential clinical value in ovarian cancer.
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PMID:A cell line with unusual characteristics from an ovarian carcinoma patient: modulation of sensitivity to antitumour drugs. 134 52

FK-506, a novel immunosuppressive agent, was examined for its reversing effect on multidrug-resistant tumor cells. FK-506 at 3 microM completely reversed the resistance against vincristine (VCR) in vitro in VCR-resistant mouse leukemia P388 cells (P388/VCR). FK-506 also enhanced the cytotoxicity of VCR in Adriamycin(ADM)-resistant human ovarian cancer A2780 cells (AD10) and ADM-resistant human myelogenous leukemia K562 cells (K562/ADM) in vitro. FK-506 was also effective in modulating sensitivity to ADM in AD10 cells in vitro. FK-506 enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When 20 mg/kg FK-506 was combined with 200 micrograms/kg VCR, a T/C value of 151% was obtained. Under the protocol used in this study, FK-506 was more potent than cyclosporin A (CsA) and verapamil. FK-506 inhibited [3H]azidopine binding to P-glycoprotein efficiently. The binding of VCR to K562/ADM plasma membrane was inhibited by FK-506 as effectively as by CsA. Moreover, the accumulation of VCR in AD10 cells was increased by FK-506 as efficiently as that of CsA and verapamil. These results indicate that FK-506 directly interacts with P-glycoprotein like CsA and verapamil, inhibits the active efflux of vincristine from resistant cells, increases the vincristine accumulation in resistant cells, and thus overcomes multidrug resistance in vitro and in vivo.
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PMID:Reversal of multidrug resistance by an immunosuppressive agent FK-506. 137 Jul 65

The major limitation to curative therapy for ovarian cancer is the development of drug resistance. Cyclosporin A (CsA), an immunosuppressive agent that has been used extensively in organ transplantation, also has been shown to decrease the resistance of cancer cells to some chemotherapeutic agents. Since cisplatin (CDDP) is the most common drug used for the treatment of ovarian cancer, we evaluated the potential of CsA to decrease resistance to CDDP in ovarian cancer cells selected for resistance to CDDP (A2780-CDDP). Although CsA significantly increased the sensitivity of A2780-CDDP cells to cytolysis by CDDP it did not increase CDDP sensitivity in the CDDP-sensitive parent cells (A2780), that is, CsA did not decrease basal resistance to CDDP. Both A2780-CDDP and A2780 are sensitive to cytolysis by Adriamycin (ADR). CsA significantly decreased the basal resistance of both cell lines to ADR. Interestingly, the effect of the protein synthesis inhibitors, emetine and cycloheximide, was similar to that of CsA, suggesting that CsA decreased selected resistance to CDDP and decreased basal resistance to ADR by affecting a protein synthesis-dependent resistance mechanism(s). In contrast to CsA and protein synthesis inhibitors, buthionine sulfoximine, an inhibitor of glutathione synthesis, decreased basal resistance of both cell lines to cytolysis by CDDP but not ADR, while verapamil, an inhibitor of P-glycoprotein, had no effect on cytolysis in either cell line. These results suggest that CsA may not decrease resistance to CDDP or ADR-mediated cytolysis by reducing glutathione or by inhibiting P-glycoprotein.
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PMID:The effects of cyclosporin A on the lysis of ovarian cancer cells by cisplatin or adriamycin. 142 96

We studied the resistance of colon tumors to anticancer agents in vitro. Using daunorubicin (DN), a number of cellular parameters which normally indicate acquired or multidrug resistance (MDR), were compared for several human wild-type colon cell lines, i.e. HT29, SW1116 and COLO 320, and the murine colon cell line C-26. The sensitive/MDR human ovarian cancer cell line couple A2780/2780AD was used as a reference. The amount of P-glycoprotein (P-gp) was in the order HT29, A2780 less than or equal to SW1116 less than C26 less than or equal to COLO 320 less than 2780AD. The MDR modifiers verapamil, Cremophor EL, cyclosporin A and Ro 11-2933/001 had significant effects on DN cytotoxicity, total DN accumulation and efflux, only if P-gp was present. A flow-through system was used to study the mechanism of DN transport. For the first time, evidence for saturation of an active transport of DN from the cells is reported. We discussed the possible presence of cooperative activity between at least two binding sites on the protein responsible for DN efflux, likely to be P-gp.
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PMID:P-glycoprotein drug efflux pump involved in the mechanisms of intrinsic drug resistance in various colon cancer cell lines. Evidence for a saturation of active daunorubicin transport. 167 38

P-glycoprotein (P-gp) expression and DNA topoisomerase (Topo) II are important variables in multidrug resistant tumor cell lines. The aim of this study was to evaluate P-gp expression and Topo I and II activity in benign and malignant epithelial ovarian tumors. P-gp expression was analyzed immunohistochemically in cryostat sections of fresh tumor specimens. In the same specimens Topo I and II activity were measured by, respectively, relaxation of supercoiled plasmid pBR322 DNA and decatenation of kinetoplast DNA. P-gp expression (range, 5-100% positive staining cells) was found in 3 of 6 cystadenomas, 0 of 2 borderline tumors, 15 of 21 untreated ovarian cancers, and 8 of 13 platinum/cyclophosphamide treated ovarian cancers. Median Topo I and II activity were elevated in malignant ovarian tumors compared to benign and borderline tumors. No difference was found between median Topo I activity in untreated ovarian cancer and platinum/cyclophosphamide treated ovarian cancer. High Topo II activity (greater than or equal to 8 x 10(2) units/mg protein) was more frequent in untreated compared to platinum/cyclophosphamide treated samples. Respectively, 8- and 16-fold differences in Topo I and II activity were found in the malignant tumors. Topo II activity in malignant tumors correlated with Topo I activity (r = 0.36, P less than 0.05) and the tumor volume index (r = 0.35, P less than 0.05). However, this last weak correlation cannot explain the 16-fold differences in Topo II activity in malignant tumors. Mitotic index and P-gp expression did not correlate with Topo I or II activity. A large variability in P-gp expression and Topo I and II activity was observed in patients with ovarian cancer.
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PMID:P-glycoprotein expression and DNA topoisomerase I and II activity in benign tumors of the ovary and in malignant tumors of the ovary, before and after platinum/cyclophosphamide chemotherapy. 168 37

We investigated the capabilities of flow cytometry in the analysis of a multidrug resistant (MDR) human ovarian cancer cell line 2780AD and its drug sensitive parental A2780. A functional assay using daunorubicin (DNR) as a fluorescent probe was combined with an immunofluorescence assay of P-glycoprotein (P-gp) using the monoclonal antibody MRK-16. Functionally MDR could be demonstrated by the lower DNR-content of MDR cells compared to DNR-content of drug sensitive cells. When incubation was performed with DNR in the presence of verapamil, DNR-content increased in the MDR cells. However the content of the A2780 cells was never attained. Differences in DNR-content were not related to differences in DNA-content. In experimental cell lines immunofluorescence data were inversely related with those of DNR-content: MDR cells had high levels of P-gp expression and low levels of DNR-content (and vice versa in drug sensitive cells). Both assays can be easily combined in a multiparametric flow cytometric procedure to evaluate both parameters simultaneously in the same cells. Analysis of clinical samples demonstrates the existence of aberrant subpopulations which would not be detected by using a single parameter assay.
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PMID:Flow cytometric double labeling technique for screening of multidrug resistance. 168 85

The multidrug-resistance gene, MDR1, encodes a plasma membrane glycoprotein termed P-glycoprotein that mediates active cellular efflux of certain chemotherapeutic agents. P-Glycoprotein expression was evaluated in 98 frozen tumor specimens from 57 patients with epithelial ovarian cancer by the indirect immunoperoxidase technique with monoclonal antibodies C219 and JSB-1 used for detection. Tumor specimens were further characterized antigenically with a panel of monoclonal antibodies representing a variety of epithelial cell antigens. Included were 57 specimens from 33 previously untreated patients; 11 specimens were also available from eight patients in this group after chemotherapy. An additional 30 specimens were studied from 24 other patients after chemotherapy. In only four of the 57 patients with ovarian cancer (7%) did one or more of the specimens express P-glycoprotein. Two of these patients had tumors that were considered clinically drug resistant. No increase in P-glycoprotein expression was noted after exposure to chemotherapy, including the eight individuals for whom specimens were available both before and after treatment. Although drug resistance is a major problem in treatment of ovarian cancer, resistance to the drugs most active against these tumors probably occurs through a mechanism other than expression of the MDR1 gene product.
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PMID:Expression of P-glycoprotein in epithelial ovarian cancer: evaluation as a marker of multidrug resistance. 197 72

A 2780 human ovarian cancer cells, obtained from an untreated patient, have been exposed to a relatively low, clinically maintainable dose (10 nmol/l) of the anthracycline doxorubicin (DX) to derive a low-degree (5-fold) drug-resistant subline (A2780-DX1). Compared to parental cells, these DX-resistant cells have increased size (+60% of cell volume) and contain a greater number of cytoplasmic vacuoles as determined by electron microscopy. When exposed to several other antiproliferative drugs, A2780-DX1 cells were highly cross-resistant (greater than 10-fold) to epirubicin, mafosfamide and cisplatin and slightly cross-resistant (2- to 3-fold) to navelbine and bleomycin, while they retained the original sensitivity to vinblastine, Ara-C and fluorouracil. Gel electrophoresis of cytoplasmic membrane proteins showed differences between the pattern of parental A2780 sensitive and A2780-DX1 cells as far as low-molecular-weight proteins (less than 45 kD) are concerned, while no clear overexpression of P-glycoprotein (P-170) could be detected. Membrane modifications yielding a decrease of both DX uptake and retention, increased content of intracellular glutathione (+32%) and reduced DNA double-strand breaks seem to be involved in the resulting multidrug-resistant phenotype of A2780-DX1 cells.
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PMID:Generation and characterization of a low-degree drug-resistant human tumor cell line. 224 68

In an effort to devise an effective treatment for human drug-resistant cancers, we have developed monoclonal antibodies, MRK16 and 17, reactive to the multidrug transporter protein, P-glycoprotein. The monoclonal antibodies given intravenously effectively prevented tumor development in athymic mice inoculated subcutaneously with drug-resistant human ovarian cancer cells 2780AD. Treatment with MRK16 induced rapid regression of established subcutaneous tumors and apparent cures of some animals. Complement-dependent cytotoxicity (MRK16) and antibody-dependent cell-mediated cytolysis (MRK16 and 17) were observed with these antibodies. These monoclonal antibodies may have potential as treatment tools against multidrug resistant human tumors possessing the P-glycoprotein.
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PMID:Inhibition of multidrug-resistant human tumor growth in athymic mice by anti-P-glycoprotein monoclonal antibodies. 257 2

Drug-resistant cancer cells with the multidrug-resistance phenotype show overexpression of P-glycoprotein, and we therefore tested carcinoma tissue from five patients with stage III or IV ovarian cancer for P-glycoprotein using 265/F4 and C 219 monoclonal antibodies, prepared against membrane glycoproteins in colchicine-resistant CHO cells. Using immunofluorescence and immunoblotting techniques, one of the tumors showed a positive reaction. Using the pcDR 1.5 clone we found that the same cancer tissue had elevated expression of the genes responsible for multidrug resistance. The demonstration of elevated P-glycoprotein in ovarian carcinomas indicates that P-glycoprotein overexpression is not limited to experimental tumor models.
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PMID:Detection of drug resistance in human ovarian carcinoma. 265 33


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