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

To investigate the possible role of the multidrug resistance phenotype to chemoresistance in human ovarian carcinoma, we have analyzed human multidrug resistance gene (mdr 1) expression in 8 human ovarian adenocarcinoma cell lines. An increase in P-glycoprotein level specific to multidrug-resistant tumor cells was not apparently associated with the increase in resistance to vincristine (VCR) or doxorubicin (Adriamycin). Mdr 1 transcripts (4.5 kilobases) were observed in the RNA preparation obtained from only one cell line (SHIN-3) that showed the highest resistance to both drugs in vitro and in vivo. No cell lines showed mdr 1 DNA amplification. These results suggest that the insensitivity of human ovarian carcinoma to chemotherapy could be partly explained by the expression of mdr 1.
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PMID:Expression of a human multidrug resistance gene in human ovarian carcinoma cell lines. 134 3

Presentation of doxorubicin in liposomes has shown to enhance the sensitivity of multidrug resistant CH LZ cells to the drug (Thierry et al. Cancer Commun. 1:311-316, 1989). We confirmed that liposomally encapsulated doxorubicin may partially overcome multidrug resistance in the human ovarian carcinoma SKVLB cell line and that this effect is, at least in part, due to an increase of cellular drug accumulation. When used at high concentration, empty liposomes appear to be specifically cytotoxic in the MDR SKVLB and CH LZ cells. As observed with certain multidrug resistance modulators, empty liposomes inhibited the specific [3H]-vincristine binding to P-glycoprotein-enriched membranes isolated from CH LZ cells (60% at 0.2 mg lipid/ml). Our data suggest that liposomes may alter the P-glycoprotein function by direct interaction.
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PMID:Effect of liposomes on P-glycoprotein function in multidrug resistant cells. 135 35

Human ovarian carcinoma cell line (NOS2), established from a patient with serous cystadenocarcinoma of the ovary, has been exposed to a stepwise increase in cis-diamminedichloroplatinum (II) (CDDP) concentration to produce a CDDP-resistant cell line NOS2CR) as an experimental model for resistance to CDDP. NOS2CR cells showed a 7-fold resistance to CDDP and a lesser degree of cross-resistance to diammine (1,1-cyclobutanedicarboxylato)-platinum (II) (CBDCA) and (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato) platinum (II) (DWA2114R). In the absence of CDDP, cross-resistance to DWA2114R was reduced to the original level by 2 months, although 83% resistance to CDDP remained up to 6 months. To investigate CDDP-resistant mechanisms, alterations in the intracellular accumulation of CDDP and analogues were assayed by atomic absorption. In both NOS2 and NOS2CR cells, accumulation of CDDP increased linearly with time and was concentration-dependent. NOS2CR cells demonstrated 71, 52 and 12% reduction in accumulation of CDDP, CBDCA, and DWA2114R, respectively. These reductions did not seem to be due to P-glycoprotein, because expression of multidrug-resistant 1 gene was not detected in either NOS2 or NOS2CR cells. These studies indicate that the mechanisms of resistance to CDDP and analogues in NOS2CR cells are related in the main to reduced intracellular accumulation of drugs. DWA2114R might be helpful to treat CDDP-resistant and recurrent tumors which were treated by CDDP.
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PMID:Accumulation of cis-diamminedichloroplatinum (II) and its analogues in sensitive and resistant human ovarian carcinoma cells. 149 42

Newly synthesized quinoline derivatives were investigated for their efficacy to reverse multidrug resistance (MDR). In this study, one of the most effective quinoline derivatives, MS-073, was compared with verapamil with regard to its ability to overcome MDR in vitro and in vivo. MS-073 at 0.1 microM almost completely reversed in vitro resistance to vincristine (VCR) in VCR-resistant P388 cells. The compound also reversed in vitro VCR, adriamycin (ADM), etoposide, and actinomycin D resistance in ADM-resistant human myelogenous leukemia K562 (K562/ADM) cells, ADM-resistant human ovarian carcinoma A2780 cells, and colchicine-resistant human KB cells. MS-073 administered i.p. daily for 5 days with VCR enhanced the chemotherapeutic effect of VCR in VCR-resistant P388-bearing mice. Increases in life span of 19-50% were obtained by the combination of 100 micrograms/kg of VCR with 3-100 mg/kg of MS-073, as compared to the control. The ability of MS-073 to reverse MDR was remarkably higher, especially at low MS-073 doses, than that of verapamil, both in vitro and in vivo. MS-073 enhanced accumulation of [3H]VCR in K562/ADM cells. Photolabeling of P-glycoprotein with 200 nM [3H]azidopine in K562/ADM plasma membranes was completely inhibited by 10 microM MS-073, indicating that MS-073 reverses MDR by competitively inhibiting drug binding to P-glycoprotein.
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PMID:Circumvention of multidrug resistance by a newly synthesized quinoline derivative, MS-073. 167 87

Forskolin and 1,9-dideoxyforskolin, an analogue that does not activate adenylyl cyclase, were tested for their ability to enhance the cytotoxic effects of adriamycin in human ovarian carcinoma cells, SKOV3, which are sensitive to adriamycin and express low levels of P-glycoprotein, and a variant cell line, SKVLB, which overexpresses the P-glycoprotein and has the multidrug resistance (MDR) phenotype. Forskolin and 1,9-dideoxyforskolin both increased the cytotoxic effects of adriamycin in SKVLB cells, yet had no effect on SKOV3 cells. Two photoactive derivatives of forskolin have been synthesized, 7-O-[[2-[3-(4-azido-3- [125I]iodophenyl)propionamido]ethyl] carbamyl]-7-deacetylforskolin, 125I-7-AIPP-Fsk, and 6-O-[[2-[3-(4-azido-3- [125I]iodophenyl)propionamido]ethyl]carbamyl]forskolin, 125I-6-AIPP-Fsk, which exhibit specificity for labeling the glucose transporter and adenylyl cyclase, respectively (Morris et al., 1991). Both photolabels identified a 140-kDa protein in membranes from SKVLB cells whose labeling was inhibited by forskolin and 1,9-dideoxyforskolin. There was no specific labeling of proteins in membranes from the SKOV3 cells. The overexpressed 140-kDa protein in SKVLB membranes was identified as the P-glycoprotein by immunoblot analysis and immunoprecipitation using anti-P-glycoprotein antiserum. Total inhibition of photolabeling of the P-glycoprotein was observed with verapamil, nifedipine, diltiazem, and vinbalastine, and partial inhibition was observed with colchicine and cytochalasin B. Forskolin was less effective at inhibiting the photolabeling of the P-glycoprotein than 1,9-dideoxyforskolin or a lipophilic derivative of forskolin. The data are consistent with forskolin binding to the P-glycoprotein analogous to that of other chemosensitizing drugs that have been shown to partially reverse MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of forskolin with the P-glycoprotein multidrug transporter. 167 46

The cyanomorpholino derivative of doxorubicin (MRA-CN) is a DNA intercalator and alkylator that is a highly potent cytotoxin, non-cross-resistant in multidrug-resistant cells, and noncardiotoxic in comparison with doxorubicin. To further examine mechanisms of action and resistance to MRA-CN, a cell line resistant to MRA-CN, ES-2R, was established by growing a human ovarian carcinoma cell line, ES-2, in increasing concentrations of the drug. The resistant subline was 4-fold resistant to MRA-CN and cross-resistant to other DNA cross-linking agents, cisplatin (7-fold) and carmustine (3-fold), as well as to the DNA strand-breaking agents etoposide (6-fold), doxorubicin (2-fold), bleomycin (5-fold), and ionizing radiation (2-fold). In contrast, ES-2R cells were not cross-resistant to vinblastine. Several months of additional growth of ES-2R cells in MRA-CN did not yield higher, stable levels of drug resistance. A low level of P-glycoprotein was detectable in the ES-2R cells. However, the extent of intracellular accumulation of [3H]MRA-CN by this resistant cell line was identical to that of the sensitive line. The number of DNA cross-links formed by cisplatin in ES-2R was only 50% of that of the ES-2 cells and was associated with a 50% increase in the rate of repair of these cross-links in the resistant cells. Ionizing radiation induced similar amounts of single- and double-strand breaks in the ES-2 line as well as in the ES-2R cells. There was no apparent difference between the two cell lines in the rate and extent of repair of these DNA breaks. Thus, enhanced DNA repair cannot explain the phenomenon of cross-resistance to radiation. Comparisons of glutathione (GSH) content and the enzymes involved in GSH homeostasis showed significant differences. Resistant cells contained 1.5-fold more GSH, a 2.2-fold increase in gamma-glutamyltranspeptidase activity, and a 2.4-fold increase in GSH reductase compared with ES-2 cells (all P less than 0.05). Total glutathione-S-transferase (GST) activity was 2.6-fold higher (P less than 0.01) in the ES-2R line. The pi-class GST subunit by Western blotting and GST activity toward ethacrynic acid were increased 2-fold in the resistant cells. Depletion of GSH levels in ES-2R cells by buthionine sulfoximine restored the sensitivity of ES-2R to MRA-CN. These findings implicate a role for GSH metabolism in the resistance phenotype of ES-2R cells. We have previously reported that these cells have an increased generation time and decreased topoisomerase II content. Thus, the ES-2R cell line exhibits a complex phenotype of broad cross-resistance, which is likely to involve multiple mechanisms, and includes enhanced DNA repair and increased GSH content and GST activity.
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PMID:Multifactorial mechanisms associated with broad cross-resistance of ovarian carcinoma cells selected by cyanomorpholino doxorubicin. 171 40

Following EMS mutagenesis, three estramustine (EM) resistant DU 145 human prostatic carcinoma cell lines were clonally selected by exposure to incrementally increasing concentrations of the drug. Although only low levels of resistance (approximately 3-fold) were attainable, this resistance was stable in the absence of continuous drug exposure. These EM-resistant clones (EMR 4,9,12) did not exhibit cross resistance to vinblastine, taxol, or adriamycin, and had collateral sensitivity to cytochalasin B. None of the lines had elevated expression of P-glycoprotein mRNA or glutathione S-transferase activity, suggesting a phenotype distinct from the classic multi-drug resistance phenotype. This conclusion was supported further by the observation that two MDR cell lines (FLC mouse erythroleukaemic and SKOV3 human ovarian carcinoma cells) showed sensitivity to EM. Fluorescent activated cell sorting analysis of the effects of EM on cell cycle traverse revealed that at EM concentrations up to 20 microM an increasing percentage of wild type cells were blocked in G2/M; no such effect occurred in EMR lines. Differential interference contrast microscopy was employed to study EM's effect on mitosis. EMR lines were able to form functional, albeit smaller, spindles at EM concentrations that resulted in chromosomal disorganisation and inhibition of mitotic progression in wild type cells. EMR lines were able to progress through mitosis and cytokinesis at the same rate as untreated cells. Tritiated EM was used to evaluate potential drug uptake/efflux mutations in ERM clones. EMR 4 and 9 incorporate less EM than wild type cells; however, they have significantly decreased cellular volumes. The initial efflux rate constants for EMR clones were greater than for wild type cells. Within 5 min greater than 70% of the drug was lost from resistant cells compared to a 50% loss by the wild type. Although the specific mechanisms of resistance have yet to be defined, the lack of collateral resistance to other MDR/anti-microtubule agents could serve as the basis for the clinical use of EM in combination chemotherapy.
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PMID:Resistance to the antimitotic drug estramustine is distinct from the multidrug resistant phenotype. 189 55

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

Cyclosporin A (Sandimmune) rapidly induced an increase in daunorubicin accumulation in multidrug-resistant human ovarian carcinoma cells (2780AD) and was more potent than verapamil. Steady-state 3H-cyclosporin A accumulation at 37 degrees C in 2780AD cells was 60-70% of that in the sensitive A2780 cells. A rapid increase of ATP consumption and lactate production was induced in 2780AD cells by verapamil, but not by cyclosporin A. These results suggest that the interactions of cyclosporin A and verapamil with P-glycoprotein, which leads to inhibition of drug transport, have a different mechanistic basis.
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PMID:Cyclosporin A and verapamil have different effects on energy metabolism in multidrug-resistant tumour cells. 239 Apr 89


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