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)

Resistance to multiple chemotherapeutic agents is related to the production of P-glycoprotein, a transmembrane drug efflux pump that is encoded by the multidrug resistance gene (MDR1). To detect low-level or heterogenous expression of the MDR1 gene in acute leukemia, we have developed sensitive, specific and semi-quantitative protocols for measuring levels of MDR1 mRNA, based on the polymerase chain reaction. Using this assay, we screened blasts from 20 patients with untreated adult acute leukemia for evidence of MDR1 gene expression. The level of MDR1 mRNA was normalized to beta 2-microglobulin mRNA and was defined by reference to the highly resistant trimetrexate-selected leukemia cells MOLT-3/TMQ200 (1.80). MDR1 mRNA was observed in 14 out of 20 patients. Higher MDR1 mRNAs were observed in three patients with phenotypes of undifferentiated or minimally differentiated nonlymphocytic acute leukemia, as compared with other types of acute leukemia (0.98 vs. 0.25). In contrast, lower MDR1 mRNAs were found in five patients with acute promyelocytic leukemia, as compared with other types of acute leukemia (0.08 vs. 0.45). These findings suggest that MDR1 gene expression is correlated with the leucocyte differentiation stage of leukemia. MDR1 gene expression may, in part, explain the responsiveness to chemotherapy in these distinct subtypes of acute leukemia.
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PMID:MDR1 (multidrug resistance) gene expression in adult acute leukemia: correlations with blast phenotype. 847 61

Retinoic acid (RA) regulates the differentiation and proliferation of a wide variety of different cell types and all-trans RA induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, clinical resistance to retinoids may develop and poses a serious problem for differentiation-inducing therapy. We studied the effects of RA in combination with a cytochrome P450 inhibitor (clotrimazole) and a P-glycoprotein antagonist (verapamil) on cell growth and differentiation of RA-resistant HL-60 cells and fresh RA-resistant leukemic cells from two APL patients. RA-resistant HL-60 cells and APL cells differentiated to mature granulocytes when cultured with all-trans RA and either clotrimazole and verapamil but not with either of the agents alone. These findings were confirmed in these cells by their increased expression of CD11b antigen and migration-inhibitory factor-related protein-8/14 mRNAs and decreased levels of c-myc mRNA. These combinations also markedly decreased the number of viable cells and inhibited cellular proliferation. After isolation of microsomes, measurements showed that levels of cytochrome P450 activities in both wild-type and RA-resistant HL-60 cells were almost comparable. Moreover, expression of the CYP1A1-type cytochrome P450 gene could not be detected in either cell type. However, RA-resistant HL-60 cells and APL cells, but not RA-sensitive HL-60 cells and APL cells, expressed multidrug-resistance-1 gene transcripts. Taken together, acquired resistance to RA may be explained in part by drug metabolism in leukemic cells. Possible mechanisms for accelerated clearance of RA include the induction of non-CYP1A1 cytochrome P450 enzymes and P-glycoprotein.
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PMID:Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein. 855 97

We examined the multidrug resistant P-glycoprotein (P-gp) on normal bone marrow (BM) cells and acute myeloid leukaemia (AMI) cells, using newly devised flow cytometric multi-parameter analysis with CD33, CD34 and MRK16 monoclonal antibodies. In both normal BM cells and AML cells, CD34+CD33- cells expressed P-gp strongly, CD34+CD33- cells moderately, and CD34-CD33+ cells weakly. Acute promyelocytic leukaemia, mainly expressing CD34-CD33+ but not CD34+CD33- at diagnosis, expressed less P-gp. P-gp expression of AML cells at diagnosis was increased as compared with normal cells of the same phenotype. P-gp expression was more increased in relapsed cases, especially in immature subpopulations.
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PMID:Expression of multidrug resistance P-glycoprotein in myeloid progenitor cells of different phenotype: comparison between normal bone marrow cells and leukaemia cells. 861 58

We examined the multidrug resistance (MDR) P-glycoprotein (P-gp) on normal bone marrow (BM) cells and acute myeloid leukaemia (AML) cells, using newly devised flow cytometric multi-parameter analysis with CD33, CD34 and MRK16 monoclonal antibodies. With biotinylated MRK16 and a Streptavidin-RED670 (SA-RED670) conjugate, we succeeded in the detection of a small amount of P-gp on these cells. In normal bone marrow cells, the percentage of P-gp positive CD34+CD33-, CD34+CD33+ and CD34-CD33+ cells were 12.2 (2.2% (mean +/- standard deviation), 6.3 +/- 3.1% and 1.4 +/- 0.9%, respectively. By the more precise list-mode analysis, myeloid lineage cells showed continuously regressing P-gp expression as they maturated from CD34+CD33- to CD34-CD33+ cells. In AML cells at diagnosis, CD34+ CD33- cells expressed P-gp strongly, CD34+CD33+ cells moderately, and CD34-CD33+ cells weakly, showing the same tendency as observed in normal BM cells. Blast cells from acute promyelocytic leukemia (APL), which mainly expressed CD34-CD33+ but no detectable CD34+CD33- at diagnosis, expressed less amount of P-gp than the other subtypes of AML. P-gp expression on these three phenotypes increased in relapsed cases, especially on the CD34+CD33- subpopulation.
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PMID:[Multidrug resistance in acute leukemia]. 882 70

Overexpression of the multidrug resistance MDR1 gene product P-glycoprotein and/or the multidrug resistance-associated protein MRP confers multidrug resistance to cancer cells. The pipecolinate derivative VX-710 has previously been demonstrated to reverse MDR1-mediated multidrug resistance at concentrations of 0.5-2.5 microM by direct interaction with P-glycoprotein and inhibition of its drug efflux activity. In this study we investigated whether VX-710 as well as four other known MDR1 modulators could also reverse multidrug resistance mediated by MRP. VX-710 at 0.5-5 microM restored senstivity of MRP-expressing HL60/ADR promyelocytic leukemia cells to the cytotoxic action of doxorubicin, etoposide and vincristine. VX-710 was approximately 2-fold more effective than verapamil, MS-209 and CsA in modulating MRP-mediated multidrug resistance, whereas GF120918 had no significant effect. VX-710 was also more effective than verapamil, MS-209 and CsA in restoring the daunorubicin accumulation deficit in HL60/ADR cells and in increasing calcein uptake. A photoaffinity analog of VX-710, [3H]VF-13,159, specifically photo labeled the MRP protein and unlabeled VX-710 inhibited this binding in a concentration-dependent manner. These data suggest that VX-710 is not only a potent modulator of P-glycoprotein-mediated multidrug resistance, but also affects multidrug resistance in MRP-expressing cells and may exert its action, at least in part, by binding directly to MRP.
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PMID:Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP. 907 10

Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients who received continuous treatment with all-trans RA relapsed and develop RA-resistant disease. The detailed mechanisms for this development of RA resistance by APL cells are still unclear. Several possible mechanisms have been considered to explain in vitro resistance to RA. One obvious explanation is the generation of new mutations in the retinoid receptors. However, UF-1 cells (the first permanent APL cell line with RA-resistant features) had no point mutations in the ligand-binding domain of the RAR-alpha gene. Another potential mechanism for clinical RA resistance is the pharmacologic alteration in the metabolism of all-trans RA. Continuous treatment with all-trans RA in APL is associated with a progressive reduction of the plasma concentrations of RA. Induction of cytochrome P-450, cellular RA-binding protein (CRABP) and P-glycoprotein resulted in lower plasma and cellular levels of active retinoids. Thus, acquired resistance to RA may be explained at least in part by drug metabolism in leukemic cells.
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PMID:Retinoid resistance in leukemic cells. 925 Aug 12

We selected an apoptosis-resistant subline (VC-33) in a human promyelocytic leukemia cell line, HL-60, by alternating exposure to camptothecin (CPT) and etoposide (VP-16). When wild-type (WT) and VC-33 cells were incubated with various concentrations of either CPT or VP-16 for 4 h, VC-33 showed several-fold resistance to apoptosis induced by these agents in comparison with WT cells. VC-33 cells also exhibited cross-resistance to apoptosis induced by 1-beta-d-arabinofuranosylcytosine, hydroxyurea, a calcium ionophore (A23187), cycloheximide, or UV irradiation. The levels of protein-DNA cross-linking induced by CPT or VP-16, and the amounts of ara-CTP generation, tended to be smaller in VC-33 cells, but the difference was not sufficient to explain the difference in the sensitivity to apoptosis. The initial rise of intracellular calcium ions with A23187 and the expression of P-glycoprotein, Bcl-2, and Bcl-Xl were comparable between WT and VC-33 cells. This mutant may represent a new phenotype of resistance to apoptosis induced by a variety of agents, and may thus be useful in the study of the mechanisms of apoptosis.
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PMID:Apoptosis-resistant phenotype selected by alternating exposure to camptothecin and etoposide. 928 62

Detection of the multidrug resistance P-glycoprotein (PGP) phenotype was performed at the time of diagnosis in 223 patients with acute myeloid leukemia (AML) by flow cytometry using C219 Monoclonal Antibody (MoAb). On the other hand, JSB1 MoAb was tested in 173 of these samples. At onset, PGP was detected in 57.4% of cases with C219 and 75.9% of cases with JSB1. There was no correlation between PGP expression and sex, age, marrow blast percentage or extramedullary disease. On the contrary, strict correlations were noted either between C219 negativity and FAB M3 subtype or between C219 positivity and FAB M5 group (P = 0.003). Significant correlation was found between PGP phenotype and CD7, as 143 of 223 samples had similar patterns of staining with C219 (P < 0.0001). Finally, there was a close relationship between C219 and JSB1 positivity: all the C219+ cases were positive for JSB1 (P < 0.0001). Concerning the karyotype, most patients with monosomy or del (7) were MDR positive; on the other hand, most patients with t(8;21) or t(15;17) were MDR negative. Rh123 accumulation studies showed a significant decrease of mean fluorescence intensities both in C219 and in JSB1 positive cases in comparison with PGP negative ones (P < 0.001). A significant decrease of remission induction rates (CR) was highlighted both between C219+ and C219- and between JSB1+ and JSB1- cases (32.1% v 62.1% and 32.6% v 73.8%, respectively, with P < 0.0001). The overall survival and the remission duration (CCR) were significantly shorter both in C219+ and in JSB1+ patients with no relationship to age. Furthermore, a higher rate of early relapses was noted among MDR+ when compared with MDR- patients both for C219+ and JSB1+ cases. The combination (C219- JSB1+) identified a subset of patients with an intermediate prognosis. On multivariate analysis, C219 and JSB1 were confirmed to be independent prognostic factors for achievement of CR, overall survival and CCR. In conclusion, the assessment of MDR phenotype by flow cytometry is a crucial prognostic factor of treatment outcome in AML.
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PMID:P-glycoprotein expression in de novo acute myeloid leukemia. 940 25

Complete remission is achieved in a high proportion of patients with acute promyelocytic leukemia (APL) after all-trans retinoic acid (RA) treatment, but most patients relapse and develop RA-resistant APL. We have previously reported that both RA-resistant HL-60 (HL-60R) and APL cells express P-glycoprotein and MDR1 transcripts; and these cells differentiate to mature granulocytes after culture with RA and P-glycoprotein antagonist. Ribozymes have been shown to be able to intercept a target RNA by catalytic activity. To address the role of MDR1 in overcoming RA-resistance in APL cells, we investigated the biologic effects of ribozymes against the MDR1 transcript in HL-60R cells. These ribozymes efficiently cleaved MDR1 mRNA at a specific site in vitro. The 196 MDR1 ribozyme was cloned into an expression vector, and stably transfected (HL-60R/196Rz) cells were obtained. Expression of MDR1 transcripts was decreased in HL-60R/196Rz cells compared with parental HL-60R and empty vector-transfected (HL-60R/neo) cells. Interestingly, RA inhibited cellular proliferation and induced differentiation of HL-60R/196Rz cells in a dose-dependent manner, suggesting reversal of drug resistance in HL-60R cells by the MDR1 ribozyme. These data are direct evidence that P-glycoprotein/MDR1 is responsible in part for acquired resistance to RA in myeloid leukemic cells. The MDR1 ribozyme may be a useful tool for investigating the biology of retinoid resistance and may have therapeutic potential for patients with RA-resistant APL.
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PMID:Restoration of retinoid sensitivity by MDR1 ribozymes in retinoic acid-resistant myeloid leukemic cells. 951 45

Mevalonate pathway inhibitor lovastatin inhibited proliferation of human multidrug-resistant promyelocytic leukemia HL-60/ADR cells in vitro, with MRP-gene coded p190 mediated drug resistance, to a markedly lesser extent than that of the parental drug sensitive HL-60 cells and also that of the other human multidrug resistant (MDR-1, P-glycoprotein) myeloid leukemia cell line HL-60/VCR. The sensitivity of the examined human leukemia cell lines to the cytostatic activity of lovastatin correlated approximately with the potential of lovastatin to induce the characteristic cell cycle alteration (i.e. the accumulation of lovastatin-treated cells in the G0/G1 phase of the cell cycle). The P-glycoprotein positive HL-60/VCR cells and the parental drug sensitive HL-60 cells were more sensitive to this cell cycle alteration than the HL-60/ADR multidrug resistant leukemia cells with MRP drug resistance. Lovastatin (72 hours, 20 micromol) induced apoptosis and cell necrosis in HL-60 cells, apoptosis but not cell necrosis in HL-60/VCR cells and neither apoptosis nor necrosis in HL-60/ADR cells.
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PMID:Human multidrug-resistant (MRP,p190) myeloid leukemia HL-60/ADR cells in vitro: resistance to the mevalonate pathway inhibitor lovastatin. 960 9


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