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)

Multidrug resistance represents a major obstacle in the successful therapy of neoplastic diseases. Studies have demonstrated that this form of drug resistance occurs in cultured tumor cell lines as well as in human cancers. P-glycoprotein appears to play an important role in such cells by acting as an energy-dependent efflux pump to remove various natural-product drugs from the cell before they have a chance to exert their cytotoxic effects. Using the tools of molecular biology, studies are beginning to reveal the true incidence of multidrug resistance, as mediated by the MDR1 gene, in the clinical setting. It has been demonstrated, at least in the laboratory, that resistance mediated by P-glycoprotein may be modulated by a wide variety of compounds, including verapamil and cyclosporine A. These are compounds which, by themselves, generally have little or no effect on the tumor cells, but when used in conjunction with antineoplastic agents act to decrease, and in some instances eliminate, drug resistance. The mechanism(s) by which these agents act to reverse resistance is not fully understood. Clinical trials to modulate P-glycoprotein activity are now under way to determine whether such strategies will be feasible. The detection of the P-glycoprotein in patient samples is very important in the design of these studies, as it appears that drug-resistant cells lacking P-glycoprotein will be unaffected by agents such as verapamil. Clinical studies are needed in which patients are stratified into chemotherapy protocols based on levels of MDR1 mRNA or P-glycoprotein expression in the primary tumors. Several research areas have been identified that are important to the transfer of the discovery of the MDR1 gene and its protein product from the research laboratory to the clinical environment. There is an immediate need for comprehensive information on the prevalence and levels of expression of the human MDR genes and their protein products in human organs and tissues. Data are needed on P-glycoprotein levels in specific subpopulations (e.g., according to age, sex, race, and diet), and the study of the heterogeneity and variability of expression of P-glycoprotein in normal human tissues should be given high priority. Since early studies have indicated some successes in identifying patients with classic multidrug resistance who might be responsive to chemosensitization, it can be anticipated that clinical research will accelerate in this area. The next wave of clinical studies will provide clinical investigators with opportunities to develop and evaluate P-glycoprotein tests and correlate test results with clinical outcomes.
 ...
PMID:Multidrug resistance in the laboratory and clinic. 787 70

The multidrug resistant cell lines HL60/AR and GLC4/ADR show high overexpression of the gene encoding the multidrug resistance associated protein MRP compared to their drug sensitive parental counterparts. This and the virtual absence of mdr1/P-glycoprotein gene expression was proven by a complementary DNA polymerase chain reaction (cDNA-PCR) approach. Applying a 72-hour tetrazolium based colorimetric MTT-assay we demonstrate on both MDR sublines a dose-dependent modulation of drug resistances by the leukotriene LTD4 receptor antagonist MK571. A complete reversal of vincristine resistances was achieved at final MK571 concentrations of 30 microM (HL60/AR) or 50 microM (GLC4/ADR) which by itself did not disturb cellular proliferation. The drug resistance of a mdr1/P-gp overexpressing multidrug-resistant HL60 subline, in contrast, was not significantly affected by MK571. Similar effects were seen using the glutathione (GSH) synthesis inhibitor buthionine sulfoximine (BSO). Our results point to a relationship between MRP and a conjugate transporter and identify MK571 as a new tool structure for developing modulators specific for a MRP associated multidrug resistance.
 ...
PMID:The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. 788 49

It has previously been shown that dexniguldipine-HCl (B8509-035) is a potent chemosensitizer in multidrug resistant cells [Hofmann et al., J Cancer Res Clin Oncol 118: 361-366, 1992]. It is shown here that dexniguldipine-HCl causes a dose-dependent reduction of the labeling of the P-glycoprotein by azidopine, indicating a competition of dexniguldipine-HCl with the photoaffinity label for the multidrug resistance gene 1 (MDR-1) product. Exposure to dexniguldipine-HCl results in a dose-dependent accumulation of rhodamine 123 in MDR-1 overexpressing cells. In the presence of 1 microM dexniguldipine-HCl, rhodamine 123 accumulated in multidrug resistant cells to similar levels as in the sensitive parental cell lines. At this concentration, dexniguldipine-HCl enhances the cytotoxicities of Adriamycin and vincristine. The resistance modulating factors (RMF), i.e. IC50 drug/IC50 drug + modulator, were found to be proportional to the expression of MDR-1, ranging from 8 to 42 for Adriamycin and from 16 to 63 for vincristine. Transfection with the MDR-1 gene was found to be sufficient to sensitize cells to the modulation by dexniguldipine-HCl. The compound does not affect the expression of the MDR-1 gene. Dexniguldipine-HCl has no effect on a multidrug resistant phenotype caused by a mutation of topoisomerase II. It is concluded that dexniguldipine-HCl modulates multidrug resistance by direct interaction with the P-glycoprotein.
 ...
PMID:Mechanism of action of dexniguldipine-HCl (B8509-035), a new potent modulator of multidrug resistance. 788 74

Bone marrow specimens from 100 cases of acute leukemia (AL) diagnosed by MIC were detected with fluorescence microscopy for their mdr-1 expression using monoclonal antibody JSB-1 against P-glycoprotein (P-170). The results showed that almost all subtypes of AL had P-170 expression and M5 of ANLL had a significantly higher expression rate in the newly diagnosed group. The MDR expression highly correlated with the clinical drug resistance and prognosis. The Positive rate of P-170 (20.8% +/- 14.9%) and MDR expression (78.9%) of refractory group were significantly higher than newly diagnosed group (7.5% +/- 9.8% and 18.2% respectively). Cases with MDR expression had poor response to chemotherapy and bad prognosis.
 ...
PMID:[Detection and analysis of multidrug resistance in 100 cases of acute leukemia]. 789 88

P-glycoprotein (Pgp) is a polytopic plasma membrane protein thought to function as a drug efflux pump. Two functional groups of Pgp have been identified in mammalian cells. One group (classes I and II) is associated with MDR and the other (class III) is not. Transmembrane (TM) sequences in Pgp have been postulated to be important for determining drug specificity. TM11 and TM12 have been predicted to bind drugs and play an important role in determining drug specificity of MDR-associated Pgps. Whether or not the membrane insertion and orientation of these TM segments differ amongst the different classes of Pgp has not been examined directly. In this study, we showed that membrane insertion and orientation of TM11 and TM12 of the MDR-associated Pgp may differ from the non-MDR-associated Pgp using an in vitro transcription and translation system. Charged amino acids surrounding TM domains are thought to be important in determining the topology of membrane proteins. The positively charged amino acids surrounding TM11 and TM12 of these two forms of Pgp are different. By site-directed mutagenesis we showed that these amino acids may affect the membrane orientation but not membrane insertion of these TMs. These results raise the possibility that a difference in membrane anchorage may be a underlying cause for the functional difference between the two groups of Pgp.
 ...
PMID:Membrane orientation of transmembrane segments 11 and 12 of MDR- and non-MDR-associated P-glycoproteins. 790 65

It has been shown recently that heterologous expression of human MDR-1 gene, which is responsible for multidrug resistance during cancer therapy, causes appearance of volume-sensitive Cl- currents, thus suggesting that the product of the MDR-1 gene (the P-glycoprotein) has a Cl- channel activity (Valverde, M. A., Diaz, M., Sepulveda, M. A., Gill, D. R., Hyde, S. C., and Higgins, C. F. (1992) Nature 355, 830-833). In the present work, we have tested four epithelial cell lines both for the expression of MDR-1 gene and for the presence of volume-sensitive Cl- currents. LoVo/H and LoVo/Dx cells derive from a human colon adenocarcinoma, the latter cell line being resistant to high concentrations of the antitumoral drug doxorubicin. 9HTEo- cells were obtained by transformation of human tracheal epithelium. The 9HTEo-/Dx cell line was established from these cells by selection in doxorubicin. As expected, higher levels of P-glycoprotein expression were detected in LoVo/Dx and 9HTEo-/Dx by means of reverse transcriptase polymerase chain reaction technique, indirect immunofluorescence, and Western immunoblot assays. In contrast with these data, the size of swelling-induced Cl- current was the same in the sensitive cell line and in its drug-resistant counterpart. Actually, the Cl- conductance of 9HTEo- and 9HTEo-/Dx was 4-fold higher than that of either LoVo/H or LoVo/Dx cells. This indicates that the amplitude of this conductance is not directly related to the expression of the MDR-1 gene.
 ...
PMID:Volume-sensitive chloride currents in four epithelial cell lines are not directly correlated to the expression of the MDR-1 gene. 790

Resistance to cytotoxic agents may be encountered during the treatment of acute myeloblastic leukaemia (AML). P-glycoprotein encoded by the MDR-1 gene has been implicated as a potential drug resistance mechanism in leukaemic cells. In recent years, many data have been accrued concerning the expression of P-glycoprotein in leukaemia, and several studies have been published which have related MDR status to outcome in AML. Conclusions as to the effect of P-glycoprotein expression on prognosis in AML have varied widely. The studies are not immediately comparable, since they differ in methodology, treatment regimens, demographic profile and, perhaps most importantly, criteria for positivity of MDR status. The technique of statistical overview (meta-analysis) can be used to pool observational studies. Application of this statistical method to existing studies suggests an estimated relative risk of 0.68 for P-glycoprotein expression with respect to complete remission in AML. Further large studies are required to determine fully the role of P-glycoprotein in AML.
 ...
PMID:The effect of MDR-1 gene expression on outcome in acute myeloblastic leukaemia. 790 80

Cross-resistance to chemotherapeutic drugs is a significant problem in the treatment of patients with cancer. The discovery that this phenomenon is associated with the overexpression of a membrane glycoprotein, P-glycoprotein, which acts as a drug efflux pump, has provided a new target for drug development. To develop a model for identifying new compounds which can block the function of P-glycoprotein, we infected P388 mouse leukemic cells with a retrovirus containing a cloned human MDR1 complementary DNA. The new cell line, P388/VMDRC.04, incorporated and overexpressed the human gene as evidenced by Southern blots, increased mRNA and protein synthesis, and recognition by the MRK16 monoclonal antibody. P388/VMDRC.04 was cross-resistant to colchicine, vincristine, and doxorubicin, and the degree of resistance correlated with a reduction in cellular drug accumulation. Unlike many cell lines selected for resistance by growth in increasing concentrations of drug for prolonged periods of time, these cells did not show alternative mechanisms of resistance such as increased synthesis of glutathione or alterations in topoisomerase II. In addition, the sensitivity of P388/VMDRC.04 cells was completely restored by cyclosporin A and trans-flupenthixol. P388/VMDRC.04 cells were subcloned and 10 clones were picked for in vivo evaluation. One subclone grew similarly to parental cells in female BALB/c x DBA/2 F1 mice and showed no responsiveness to therapeutic doses of vincristine or etoposide. The combination of vincristine with cyclosporin A significantly increased the survival of mice inoculated with P388/VMDRC.04 cells. The availability of a cell line that displays the MDR phenotype, overexpresses human P-glycoprotein, but does not contain alterations in at least two well-defined alternative mechanisms of resistance, and that can be grown in simple animal models should facilitate the development of new agents active against this form of chemotherapeutic drug resistance.
 ...
PMID:Characteristics of P388/VMDRC.04, a simple, sensitive model for studying P-glycoprotein antagonists. 790 86

N-Benzyladriamycin-14-valerate (AD 198)-resistant murine J774.2 macrophage-like cells (A300) exhibited a novel mechanism of resistance in which P-glycoprotein was overexpressed without decreased AD 198 accumulation. Cross-resistance to Adriamycin (ADR), N-benzyladriamycin, and Adriamycin-14-valerate was due, at least in part, to reduced accumulation, suggesting that circumvention of P-glycoprotein-mediated transport was associated with extreme lipophilicity conferred by both substitutions. Thus, unlike multidrug resistance mediated by either P-glycoprotein, the multidrug resistance-associated protein (MRP), or decreased topoisomerase II activity, cross-resistance in A300 cells was highly structure-specific. In order to further characterize the specificity of AD 198 resistance, the cytotoxicity, accumulation, and intracellular localization of a series of 3'-morpholinyl, 3'-deamino and halogenated ADR congeners that have been reported to circumvent MDR was determined in AD 198-resistant J774.2 and P388 AD 198-resistant cells. Cross-resistance correlating with increased AD 198 resistance was observed for 2'-bromo-4'-epi-hydroxy-daunomycin (13-fold), morpholinyl doxorubicin (24-fold), and 4'-iodo-4'-deoxydoxorubicin (2.8-fold), but was attributable to decreased accumulation. Cross-resistance to 3'-hydroxy-14-O-palmitoyl-doxorubicin (6-fold) was not due to reduced accumulation. No cross-resistance was observed for the highly cytotoxic metabolite of WP474, 3'-hydroxyldoxorubicin (hydroxyrubicin; WP159), nor for the much less cytotoxic 3'-O-benzylated congeners, including 3'-O-benzyl-doxorubicin-14-valerate. These findings indicate that AD 198 resistance confers cross-resistance to compounds that, like AD 198, localize in the cytoplasm but are metabolized to highly cytotoxic, nuclear-localizing compounds.
 ...
PMID:N-benzyladriamycin-14-valerate (AD 198)-resistant cells exhibit highly selective cross-resistance to other anthracyclines that circumvent multidrug resistance. 790 37

Taxol-resistant sublines of HL-60 myeloid leukemia cells (HL-60/TAX100 and HL-60/TAX1000) have been isolated in vitro by subculturing in progressively higher concentrations of taxol. HL-60/TAX100 and HL-60/TAX1000 cells are capable of continuous growth in the presence of 0.1 microM and 1.0 microM taxol, respectively, and the IC50 (50% growth inhibitory dose) values for taxol for the two sublines are 0.34 and 2.44 microM as compared to 3.1 nM for the parent HL-60 cells. HL-60/TAX100 and HL-60/TAX1000 cells display a variable degree of cross-resistance to taxotere, vincristine and doxorubicin, but are sensitive to the antimetabolite Ara-C. Both HL-60/TAX100 and HL-60/TAX1000 cells over-express MDR-1 m-RNA and the membrane efflux multidrug transporter P-glycoprotein (PGP), as determined by Western blot and immunofluorescence labeling with anti-PGP antibodies. Consequently, exposure of the taxol-resistant cells to [3H]taxol or daunomycin results in the accumulation of significantly lower levels of the two drugs. Co-treatment with cyclosporine (0.5 microgram/ml) or verapamil (10 microM) partially overcomes taxol resistance in HL-60/TAX1000 cells. Following treatment with clinically relevant concentration of taxol (1.0 microM for 24 h), HL-60 but not HL-60/TAX1000 cells display intracellular microtubular bundling, markedly enhanced accumulation of the cells in G2/M phase of cell-cycle and internucleosomal DNA fragmentation associated with apoptosis which is independent of bcl-2 gene expression. These taxol-resistant myeloid leukemia cells may serve as in vitro experimental models for examinating strategies which may have potential applicability for overcoming taxol resistance.
 ...
PMID:Characterization of a human myeloid leukemia cell line highly resistant to taxol. 790 95


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>