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)

The (-)-isomer of verapamil is 10-fold more potent as a calcium antagonist than the (+)-isomer. However, both enantiomers are equally effective in increasing cellular accumulation of anticancer drugs [Gruber et al., Int J Cancer 41: 224-226, 1988]. In addition to verapamil, there exists a wide variety of stereoisomers with phenylalkylamines and dihydropyridine structures which markedly differ in their potency as calcium antagonists. We have tested these drugs for their ability to increase intracellular accumulation of [3H]vinblastine ([3H]VBL) in a doxorubicin-resistant cell line (F4-6RADR) derived from the Friend mouse leukemia cell line (F4-6P) and in COS-7 monkey kidney cells. Both cell types express substantial amounts of multidrug resistance gene 1 mRNA and P-glycoprotein as revealed by RNA and immuno blot analysis. The enantiomers with phenylalkylamine structures [(+/-)-verapamil; (+/-)-devapamil; (+/-)-emopamil)] and with dihydropyridine structures [(+/-)-isradipine; (+/-)-nimodipine; (+/-)-felodipine; (+/-)-nitrendipine; (+/-)-niguldipine] increased [3H]VBL accumulation in both cell lines at micromolar concentrations. Although the stereoisomers of these drugs differ markedly in their potency as calcium channel blockers they were about equally effective in increasing VBL levels in the cells. There was no substantial difference in the potencies of the phenylalkylamine drugs in affecting cellular [3H]VBL transport. Major potency differences, however, were observed in the dihydropyridine drug series with the niguldipine isomers as the most effective drugs. Moreover, the niguldipine enantiomers were equally as effective in reversing VBL resistance in F4-6RADR cells as were the verapamil enantiomers. Since (-)-niguldipine (B859-35) displays a 45-fold lower affinity for calcium channel binding sites than (+)-niguldipine, but is equally potent in inhibiting drug transport by P-glycoprotein and in reversing drug resistance, it may be, in addition to (+)-verapamil, another useful candidate drug for the treatment of multidrug resistance in cancer patients.
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PMID:Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. 135 73

In an attempt to determine the incidence and clinical relevance of mdr1 gene expression in acute myeloid leukemia (AML), we examined 126 specimens obtained from adult patients with de novo AML by slot blot and immunocytochemistry. We found a high incidence of mdr1 gene expression in newly diagnosed patients (27% by immunocytochemistry and 43% by slot blot). No difference was observed between newly diagnosed patients and relapsed patients. However, patients with resistant disease showed statistically higher incidence of mdr1 gene expression compared to the untreated and relapsing patients (60% versus 27% by immunocytochemistry, p 0.005; and 73% versus 45% by slot blot, p less than 0.05). The expression of mdr1 gene correlated significantly with clinical drug resistance: 62% of patients positive for mdr1-mRNA and 68% of patients positive for P-glycoprotein (P-gp) eventually developed resistance to chemotherapy, while this was the case for a lower percentage of patients who did not express mdr1 gene (only 23% by slot blot analysis, p = 0.0052, or 24% by immunocytochemistry, p = 0.0009). A combined parameter, mdr1-mRNA/P-gp, had a very high prognostic value in terms of specificity and sensitivity. All nine patients (100%) who were mdr1-mRNA+/P-gp+ progressed to clinical drug resistance afterward, whereas 11 of 13 (85%) patients who were mdr1-mRNA-1 P-gp- entered complete remission and only two patients later developed drug resistance (p = 0.0005). It could thus be used as a reliable parameter in clinical settings.
Leukemia 1992 Sep
PMID:Relevance of mdr1 gene expression in acute myeloid leukemia and comparison of different diagnostic methods. 135 75

A vincristine resistant cell line was obtained from mouse leukemia cells L1210 by long-term adaptation in a medium with stepwise increasing concentrations of vincristine. By Western blotting using monoclonal antibody C219, positive signal on the presence of P-glycoprotein was observed in the resistant cells. Moreover, hybridization of mRNA from vincristine resistant cells with radiolabeled MDR1 cDNA probe gave evidence about the expression of MDR1 gene. The observed resistance may be depressed by application of "chemosensitizers" such as (1) calcium entry blockers (verapamil and nifedipine); (2) neuroleptics (trifluorperasine) and (3) local anesthetics (lidocaine) directly to the grow medium. Any significant effect in O2 consumption as well as incorporation of [U-14C]-glucose by the sensitive or resistant cells was not detected in the absence of vincristine. Presence of vincristine induced increasing velocity of O2 consumption by resistant cells from 2.5 +/- 0.3 to 3.3 +/- 0.2 microliters/min.10(6) cells, and, on the other hand, decreasing O2 consumption by sensitive cells from 2.3 +/- 0.2 to 1.7 +/- 0.1 ml/min.10(6) cells. The presence of vincristine induced less potent decrease in glucose incorporation by resistant cells in comparison with values which were observed in sensitive cells.
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PMID:Adaptation of mouse leukemia cells L1210 to vincristine. Evidence for expression of P-glycoprotein. 135 38

A newly synthesized dihydropyridine analogue, 2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorina n-2-yl)-1- (2-morpholinoethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate (PAK-200), at 1 microM completely reversed the resistance to vincristine in vincristine-resistant P388 mouse leukemia cells (P388/VCR), in vitro. PAK-200 at 2 microM inhibited the efflux of [3H]vincristine from P388/VCR and increased the accumulation of [3H]vincristine in P388/VCR to a level similar to that in P388 cells. P-Glycoprotein in membrane vesicles from P388/VCR cells was photolabeled with [3H]azidopine. The labeling was completely inhibited by 10 microM PAK-200. The calcium antagonistic activity of PAK-200 was about 1000 times lower than that of another dihydropyridine analogue, nicardipine. Experiments with P388 and P388/VCR-bearing mice showed that PAK-200 enhanced the effect of vincristine on both leukemia cells in vivo. These results suggest that PAK-200 interacts with P-glycoprotein and reverses drug resistance in P388 mouse leukemia cells in vitro, and that PAK-200 has an ability to potentiate the effect of vincristine on P388 mouse leukemia cells in vivo.
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PMID:Potentiation of the vincristine effect on P388 mouse leukemia cells by a newly synthesized dihydropyridine analogue, PAK-200. 142 98

Tumor cell resistance due to enhanced efflux of drugs with diverse structures and/or mechanisms of action is termed multidrug resistance (MDR), and modulation of the MDR phenotype by calcium blockers or calmodulin inhibitors is suggested to involve P-glycoprotein. In drug-sensitive (S) and 5-fold doxorubicin (DOX)-resistant (R0) L1210 mouse leukemia cells, no obvious differences in mdr mRNA or P-glycoprotein expression or alterations in cellular uptake, retention, or cytotoxicity of vincristine (VCR) were observed. However, in the 10-fold (R1) and 40-fold (R2) DOX-resistant sublines, expression of P-glycoprotein was correlated with the level of resistance (R2 greater than R1). An RNase protection assay revealed that elevated levels of mdr1 and mdr2 mRNA were detected in R1 and R2 cells, with an additional increase in mdr3 mRNA in the R2 subline. Further, in the R1 and R2 sublines, no VCR dose-dependent cytotoxicity was apparent, and cell kill of greater than 40% was not achievable following a 3-hr drug exposure. Cellular uptake and retention of VCR were 2- to 4-fold lower in the R1 and R2 sublines, compared with similarly treated S or R0 cells. Potentiation of VCR cytotoxicity by a noncytotoxic concentration of 5 microM trifluoperazine (TFP) was greater than 2-fold in S and R0 cells and less than 1.3-fold in the R1 and R2 sublines. Modulation of VCR uptake by 5 microM TFP in the S and R0 cells was 2-fold and it was 4- to 7-fold in the R1 and R2 sublines. The presence of 5 microM TFP, by competing for efflux, enhanced VCR retention 1.5-fold in S and R0 cells and 2- to 4-fold in the R1 and R2 sublines. In contrast to these results with VCR, dose-dependent cytotoxicity of DOX was apparent in all the resistant sublines, and modulation of DOX cytotoxicity by 5 microM TFP was dependent on the level of resistance. Cellular accumulation of DOX was 20 and 50% lower in the R1 and R2 sublines, respectively, compared with similarly treated S or R0 cells. Marked increases (greater than 1.5-fold) in cellular accumulation of DOX by TFP were apparent only in the R2 subline. Results suggest that a relationship between overexpression of P-glycoprotein isoforms and their role in affecting cellular drug levels and consequent cytotoxicity in MDR L1210 cells determines resistance to VCR but not DOX.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Relationship between expression of P-glycoprotein and efficacy of trifluoperazine in multidrug-resistant cells. 167 Sep 62

The expression of the P-glycoprotein which is associated with the development of multidrug resistance in various cell lines was investigated in 87 fresh acute leukaemia and multiple myeloma samples using the specific mouse monoclonal antibody MRK16 in an indirect immunofluorescence assay. Considering a 10% positive cell cut-off value, a heterogeneous expression of P-glycoprotein was observed in 5/22 (22.7%) de novo acute leukaemias, 7/22 (31.8%) relapse or secondary acute leukaemias, 14/27 (51.8%) acute transformation of myeloproliferative or myelodysplastic syndromes and 5/16 (31.2%) multiple myelomas. This expression was not associated with specific cytogenetic abnormalities, especially alterations of chromosome 7q. Verapamil, a calcium channel blocker, has been demonstrated to circumvent the multidrug resistance in cell lines, possibly by interfering with P-glycoprotein function. Using the microculture tetrazolium assay, verapamil was demonstrated to increase the sensitivity of fresh leukaemic or myeloma cells to doxorubicin in 19/43 (43.1%) samples. The doxorubicin IC50 level and the capacity of verapamil to increase the sensitivity of blast cells to doxorubicin in vitro did not correlate with the expression of P-glycoprotein. We conclude that high non-cytotoxic concentrations of verapamil were able to increase the in vitro doxorubicin sensitivity of fresh acute leukaemia and myeloma cells without detectable expression of the P-glycoprotein.
Leukemia 1991 Jul
PMID:P-glycoprotein expression and in vitro reversion of doxorubicin resistance by verapamil in clinical specimens from acute leukaemia and myeloma. 167 57

The ability of cyclosporin to modify drug accumulation in vitro, measured by the cellular accumulation of daunorubicin, was examined. In 42 patients with chronic lymphatic leukaemia this correlates well with the levels of P-glycoprotein (Pgp) measured by immunofluorescent labelling of Pgp after treatment of the cells with neuraminidase to unmask the epitope recognized by the monoclonal antibody MRK 16. It is shown that flow cytometric analysis using MRK 16 to detect Pgp expression levels together with drug accumulation studies can rapidly assess the multidrug-resistant phenotype of patients' cells, and enable selection of those suitable for therapy with agents known to circumvent mdr-1 mediated drug resistance.
Leukemia 1991 Dec
PMID:Increased drug accumulation ex vivo with cyclosporin in chronic lymphatic leukemia and its relationship to epitope masking of P-glycoprotein. 168 51

We studied blood and bone marrow cells from 42 patients with Ph-chromosome positive chronic myeloid leukemia (CML) and 20 normal subjects for amplification of the multidrug resistance gene (MDR-1) by Southern blotting and for overexpression of P-glycoprotein (P-170) by immunocytochemistry on intact cells with the monoclonal antibody C219. No P-170 could be detected in normal bone marrow or buffy coat. Overexpression of P-170 without amplification of MDR-1 was found in four of 11 patients with chronic phase CML at diagnosis, seven of 16 patients treated with busulfan or hydroxyurea in chronic phase and four of 15 patients in blast crisis. The P-170 overexpression involved only cells of the granulocyte lineage and varied from weak to strong in individual patients. It did not correlate with duration of or response to treatment during chronic phase. In transformation P-170 expression was seen in differentiated cells of the granulocyte lineage but not in blast cells, although three patients had been treated intensively with lipophilic and other cytotoxic drugs to which they had become resistant. We conclude that resistance to busulfan and hydroxyurea in chronic phase and resistance of blast cells to other cytotoxic drugs in transformation are not mediated primarily through the MDR-1/P-170 pathway.
Leukemia 1990 Oct
PMID:The role of the MDR-1/P-170 mechanism in the development of multidrug resistance in chronic myeloid leukemia. 197 71

Cells selected for resistance to doxorubicin (DOX) express the multidrug resistance (MDR) phenotype, and resistance has been suggested to be due primarily to enhanced cellular efflux of drug. A progressively DOX-resistant (10- and 40-fold) L1210 mouse leukemia model system, which does not exhibit enhanced DOX efflux as a primary mechanism of resistance, was found to display the MDR phenotype, based on overexpression of P-glycoprotein in western blots and cross-resistance to vinca alkaloids. Cross-resistance to another topoisomerase II inhibitor, etoposide (VP-16), was similar to that of DOX (10- and 40-fold), whereas resistance to N-[4-(9-acridinylamino)-3-methoxyphenyl]methanesulfonamide (m-AMSA) was 5-fold lower. In contrast, no cross-resistance to camptothecin, an inhibitor of topoisomerase I, was observed. Topoisomerase II decatenation activity in nuclear extracts from 10- and 40-fold DOX-resistant cells was 2- and 4-fold lower, respectively, when compared to sensitive cells. In these cells, however, marked reductions in m-AMSA- and VP-16-induced topoisomerase II mediated DNA cleavage were found to exceed decreases in the catalytic activity of the enzyme. Results from this study demonstrated that, in progressively DOX-resistant L1210 mouse leukemia cells with the MDR phenotype, a better relation existed between the degree of resistance and reduced VP-16- and m-AMSA-induced topoisomerase II mediated DNA cleavage, than between increases in P-glycoprotein and concomitant reduction in DOX accumulation.
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PMID:Progressive resistance to doxorubicin in mouse leukemia L1210 cells with multidrug resistance phenotype: reductions in drug-induced topoisomerase II-mediated DNA cleavage. 257 73

Mouse macrophage-like J774.2 cells were selected for resistance to colchicine and examined by molecular/cytogenetic analysis to determine whether the acquisition of the multidrug resistant (mdr) phenotype was associated with specific chromosomal rearrangements. Cytogenetic studies of the J774.2 parental and two colchicine-resistant (CLCR) sublines--J7.Cl-30 (770-fold CLCR) and J7.Cl-100 (2500-fold CLCR)--demonstrated specific numeric and structural karyotypic alterations accompanying the emergence of mdr. The parental cells demonstrated a modal chromosome number of 63, while the modal number of the J7.Cl-30 subline was 53. The most striking difference between the parental and J7.Cl-30 subline was the presence of an average of 60 double minutes (DMs) per cell in the CLCR cells. The 2500-fold resistant J7.Cl-100 subline displayed a modal number of 50, which included structural rearrangements involving chromosomes 2 and 7 and concomitant replacement of DMs by a homogeneously staining region (HSR). Southern blotting analysis demonstrated a approximately 35-fold amplification of P-glycoprotein homologous sequences in the J7.Cl-30 subline and approximately 70-fold amplification in the J7.Cl-100 subline. Chromosomal in situ hybridization localized the amplified P-glycoprotein sequences to DMs (J7.Cl-30) and the HSR (J7.Cl-100) in these CLCR sublines. Our results suggest that CLCR in J774.2 cells results from overexpression of P-glycoprotein via gene amplification which was accompanied by chromosomal evolution from DMs to an HSR.
Leukemia 1988 Jul
PMID:Molecular/cytogenetic alterations accompanying the development of multidrug resistance in the J774.2 murine cell line. 289 84


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