Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The glycoproteins on the surface of HL-60/S wild-type, drug-sensitive human leukemia cells and HL-60/AR anthracycline-resistant cells which do not overexpress the P-glycoprotein, were characterized by labeling with [35S]-methionine, NaB[3H4], phosphorus 32, or sodium iodide I 125. HL-60/S and HL-60/AR cell lysates and membrane fractions tagged with [35S]-methionine or phosphorus 32 showed no significant differences in their protein patterns as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and by autoradiography. HL-60/S cells labeled with NaB[3H4] yielded glycoproteins that were smeared predominantly in the molecular-weight range of 210,000 and 160,000 Da, with pI values ranging between pH 4 and pH 4.4. In contrast, NaB[3H4]-labeled HL-60/AR cells showed 7-8 discrete glycoproteins within a molecular-weight range of 170,000 and 140,000 Da, with pI values also ranging between pH 4 and pH 4.4. In addition, [3H]-glucosamine incorporation into HL-60/S and HL-60/AR cells revealed that the latter showed lower uptake of [3H]-glucosamine than did the former. Following treatment with tunicamycin, [3H]-glucosamine uptake in HL-60/S cells decreased, whereas that in HL-60/AR cells remained unchanged. Surface-membrane radioiodination of HL-60/S and HL-60/AR cells showed two distinct protein electrophoretic patterns, with differences being observed in both the high-(220-95 kDa) and low-molecular-weight ranges (21 kDa). Flow cytometric analysis of HL-60/S and HL-60/AR cells using myeloid and lymphoid antigen-specific antibodies demonstrated no antigenic differences between HL-60/S and HL-60/AR cells. HL-60/S cells incubated in the presence of tunicamycin, an inhibitor of N-linked glycosylation, or the protein kinase C agonist phorbol 12-myristate 13-acetate (PMA) developed a glycoprotein pattern similar to that observed in HL-60/AR cells. In addition, tunicamycin treatment of HL-60/S cells decreased daunorubicin (DNR) retention and altered its intracellular distribution as compared with that in HL-60/AR cells. These data indicate that HL-60/AR cells do not possess either de novo or amplified high-molecular-weight surface-membrane proteins; instead, existing proteins are hypoglycosylated. These results also show that HL-60/AR cells exhibit the multidrug-resistant phenotype in association with altered membrane glycoproteins of both high (220-95 kDa) and low molecular weight (21 kDa), but without overexpression of the P-glycoprotein. Furthermore, in HL-60/S cells, the multidrug-resistant phenotype is partially inducible by inhibition of N-linked glycosylation of cell-surface proteins.
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PMID:Membrane glycoprotein changes associated with anthracycline resistance in HL-60 cells. 171 35

Resistance to multiple chemotherapeutic agents has been related to the production of P-glycoprotein, a trans-membrane drug efflux pump that is encoded by the multidrug resistance (MDR) gene mdr1. To investigate whether mdr1 could be involved in clinical resistance to chemotherapy in acute leukemias, we have analyzed retrospectively the RNA from adult acute leukemia cells by slot-blot hybridization with a human mdr1 probe. Units of mdr1 expression were defined by reference to drug-sensitive human sarcoma and K562 leukemia cell lines (1 U) and the highly resistant doxorubicin selected leukemia cells K562/R7 (50 U). We studied 41 adult patients with acute leukemias: 5 acute lymphoblastic leukemias, 23 acute myeloid leukemias, and 13 secondary leukemias or blast crisis of chronic myelogenous leukemia. Expression of 10 U or more of mdr1 was found in 6 of 31 (19%) leukemias at diagnosis, versus 5 of 10 (50%) after relapse from therapy, P = .06. The complete remission rate and in vitro sensitivity to daunorubicin were both correlated with low expression (1 U, v 2 U or more) of mdr1. Among 36 evaluable attempts to induce remission, the complete remission rate was 67% (8 of 12) for patients with undetectable or minimal mdr1 expression (1 U), versus 29% (7 of 24) in patients with 2 U or more of expression, P = .03. In vitro resistance to daunorubicin or other MDR-related drugs was associated with expression of 2 U or more of mdr1 in 11 of 11 cases, while specimens that were sensitive to these agents were negative for mdr1 expression in 5 of 11 cases, P = .03. These data suggest that mdr1 expression contributes to chemoresistance in acute leukemia. Determination of mdr1 gene expression may be useful in designing therapy for patients with leukemia.
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PMID:Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. 185 77

Newly synthesized 1,4-dihydropyridine derivatives (NK-compounds) were screened to determine whether they could overcome vincristine (VCR) resistance in VCR-resistant (P388/VCR) leukemia-bearing mice. Among the 57 NK-compounds examined, six compounds had strong reversing ability (Grade A), 18 partially overcame the resistance (Grade B), and 33 did not reverse the resistance (Grade C). The ability to overcome resistance varied considerably with the nature of substituents at positions 3.5 of the 1,4-dihydropyridine, and the most suitable substituents were the pyridylalkyl-including esters. Calcium antagonistic activity of NK-compounds having pyridylalkyl-including esters at positions 3.5 and dithiene ring at position 4 of the 1,4-dihydropyridine was greater than in those compounds having the dioxene ring at position 4. NK-242, which was assessed at Grade A and had no calcium antagonistic activity, improved therapeutic effects in both VCR-sensitive (P388/S) leukemia- and P388/VCR leukemia-bearing mice when combined with VCR. Fourteen NK-compounds were screened to determine whether they could inhibit photoaffinity labeling of the P-glycoprotein (Mr 170,000 glycoprotein) in a multidrug-resistant cell line by [3H]azidopine. All six compounds of Grade A and two of the three compounds of Grade B almost completely inhibited the labeling of Mr 170,000 glycoprotein at 1 to 10 microM. Thus there was a good correlation between the ability to reverse VCR resistance in vivo and the inhibition of photoaffinity labeling of Mr 170,000 glycoprotein.
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PMID:Activities of newly synthesized dihydropyridines in overcoming of vincristine resistance, calcium antagonism, and inhibition of photoaffinity labeling of P-glycoprotein in rodents. 196 23

The overexpression of a cell-surface glycoprotein termed P-glycoprotein (P-gp) is frequently associated with multidrug resistance (MDR) in cell lines in vitro. To evaluate the implications of P-gp expression in clinical drug-resistance, we examined the expression of P-gp in fresh leukaemia cells from chronic myelogenous leukaemia (CML) patients in blast crisis. By using immunoblotting with a monoclonal antibody against P-gp, C219, we showed that leukaemia cells from three CML patients in blast crisis were P-gp negative at the stage when these patients were in complete remission, and that the cells showed high levels of P-gp expression at times when the same patients had relapsed and had not responded to chemotherapy. Six out of 11 patients (nine in the refractory state) were P-gp positive and they rarely responded to chemotherapy. These data suggest that the expression of P-gp is closely associated with drug-resistance in CML.
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PMID:Expression of the multidrug transporter, P-glycoprotein, in chronic myelogenous leukaemia cells in blast crisis. 196 62

We determined the expression levels of the mdr1 and mdr3 multidrug-resistance genes (also known as PGY1 and PGY3, respectively) in peripheral blood cells from 69 adult patients with acute and chronic leukemias, using an RNase protection assay. Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven). Expression of mdr3 was only detected in samples from B-cell lymphocytic leukemias: CML, lymphoid blast crisis (one of one), B-cell ALL (two of two), B-CLL (17 of 17), B-PLL (seven of seven), and HCL (two of two). In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3, the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil. Because cyclosporine and verapamil are known as inhibitors of the mdr1-encoded P-glycoprotein drug-efflux pump, and because the mdr1 and mdr3 genes are highly homologous, our data suggest that the mdr3 gene encodes a functional drug pump in B-cell lymphocytic leukemias. The results of this study may have implications for clinical therapy for acute or chronic leukemias expressing the mdr1 or mdr3 gene, in particular, treatment with combinations of cytotoxic drugs plus agents that reverse multidrug resistance. Since mdr1 and mdr3 are frequently expressed in untreated as well as treated leukemia, such combination therapy should be considered for untreated patients as well as treated patients.
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PMID:Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. 197 61

The overexpression of a cell-surface glycoprotein termed P-glycoprotein (P-gp) is frequently associated with multi-drug resistance (MDR) in cell lines in vitro. To evaluate the implications of P-gp expression in clinical drug resistance, the authors examined the expression of P-gp in leukemia cells from patients with acute myelogenous leukemia (AML) and those with acute lymphoblastic leukemia (ALL) at initial presentation and relapse, using immunoblotting with a monoclonal antibody against P-gp, C219. Nine of 17 patients with AML and four of 11 patients with ALL had P-gp-positive results at the initial presentation, and most P-gp-positive patients did not respond to chemotherapy. Four of seven patients at the relapsed stage and all three patients with preceding myelodysplastic syndrome had P-gp-positive results. The expression of P-gp and clinical refractoriness to chemotherapy were highly correlated. These data indicate that the expression of P-gp is closely related to clinical drug resistance in acute leukemia.
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PMID:Expression of the multidrug transporter, P-glycoprotein, in acute leukemia cells and correlation to clinical drug resistance. 197 21

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

We investigated whether two representative 1,4-dihydropyridine derivatives, NK-250 and NK-252, could potentiate the antitumor activity of multiple anticancer agents including vincristine (VCR), vinblastine, vindesine and actinomycin D in drug-resistant tumor cells and their parental drug-sensitive tumor cells. NK-250 and NK-252 at 5-10 microM almost completely reversed VCR resistance in cultured VCR-resistant P388/VCR cells derived from the mouse drug-sensitive P388/S leukemia cell line and also potentiated the cytocidal activity of VCR in drug-sensitive P388/S cells. NK-250 and NK-252 at 1-10 microM inhibited the photoaffinity labeling by [3H]azidopine of the cell-surface 170,000-molecular-weight P-glycoprotein. In chemotherapeutic experiments with leukemia-bearing mice, NK-250 or NK-252 was orally administered in combination with different drugs of the MDR phenotype administered intraperitoneally. The antitumor activity of the various combinations was found to be augmented in mice bearing P388/S- and P388/VCR-leukemia. Among the combinations examined, the combination of NK-250 and VCR was the most effective. These two 1,4-dihydropyridines, NK-250 and NK-252, are unique compounds because they were effective not only in circumventing the drug resistance, but also in potentiating the action of antitumor drugs against drug-sensitive tumors.
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PMID:Reversal by two dihydropyridine compounds of resistance to multiple anticancer agents in mouse P388 leukemia in vivo and in vitro. 197 28

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


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