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 resistance of tumor cells to chemotherapeutic drugs is a major obstacle to successful cancer chemotherapy. In human cells, expression of the MDR1 gene, encoding a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of lipophilic drugs (multidrug resistance; MDR). The levels of MDR in cell lines selected in vitro have been shown to correlate with the steady-state levels of MDR1 mRNA and P-glycoprotein. In cells with a severalfold increase in cellular drug resistance, MDR1 expression levels are close to the limits of detection by conventional assays. MDR1 expression has been frequently observed in human tumors after chemotherapy and in some but not all types of clinically refractory tumors untreated with chemotherapeutic drugs. We have devised a highly sensitive, specific, and quantitative protocol for measuring the levels of MDR1 mRNA in clinical samples, based on the polymerase chain reaction. We have used this assay to measure MDR1 gene expression in MDR cell lines and greater than 300 normal tissues, tumor-derived cell lines, and clinical specimens of untreated tumors of the types in which MDR1 expression was rarely observed by standard assays. Low levels of MDR1 expression were found by polymerase chain reaction in most solid tumors and leukemias tested. The frequency of samples without detectable MDR1 expression varied among different types of tumors; MDR1-negative samples were most common among tumor types known to be relatively responsive to chemotherapy.
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PMID:Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. 197 52

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.
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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

Multidrug resistance in animal cells is defined as the simultaneous resistance to a variety of compounds which appear to be structurally and mechanistically unrelated. One type of multidrug resistance is characterized by the decreased accumulation of hydrophobic natural product drugs, a phenotype which is mediated by an ATP-dependent integral membrane multidrug transporter termed P-glycoprotein or P170. The gene coding for P170 is called MDR. The nucleotide-binding domain of P-glycoprotein shares sequence homology with a family of bacterial permease ATP-binding components. In addition, P170 as a whole is structurally very similar to a number of prokaryotic and eukaryotic proteins believed to be involved in transport activities. This review summarizes our current knowledge of the molecular biology and clinical significance of MDR expression and P-glycoprotein transport activity, as well as some theories about the function of this protein in normal cells.
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PMID:Genetic basis of multidrug resistance of tumor cells. 197 44

The MDR P-glycoprotein has been described as a major factor of multidrug resistance. This transmembrane glycoprotein acts like an energy dependent efflux pump which possesses a broad specificity. It seems to be acting as a pump requiring drug fixation prior to extrusion. With the aim of investigating which parameters influence the recognition of drugs by the MDR system, we have determined the toxicities of different drugs on human and murine sensitive and resistant cell lines. For this purpose we have isolated and characterized a human adriamycin-resistant cell line, CEM/Adr, which presents an MDR phenotype. The tested drugs were ellipticine and olivacine derivatives which differ through discrete lateral chain substitutions. The influence of lateral chain lipophilicity and nitrogen quaternarization on drug recognition was studied. Small modifications in the chemical structure of the drugs have induced large changes in their toxicities and in the cross-resistance levels of the MDR cells to the tested compounds. The cross-resistances of the murine and human cells to the various compounds were strikingly different. The validity of murine screening models in the selection of anti-tumor drugs for human therapy must therefore be questioned.
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PMID:Comparative cytotoxicities of a series of ellipticine and olivacine derivatives on multidrug resistant cells of human and murine origins. 198 10

Two genes, MDR1 and MDR3, constitute the human P-glycoprotein gene family. To examine the evolutionary relationship between the three known classes of mammalian P-glycoprotein genes, we have cloned the MDR3 gene and compared its structure with that of the human MDR1 and the mouse mdr1 (mdr1b) genes analyzed by other groups. The MDR3 gene contains 28 exons and 27 of these contain coding sequences for the two homologous halves of the protein that correlate with functional domains. This structure is virtually identical to that of the human MDR1 gene and the mouse mdr1 (mdr1b) gene, indicating that the exon/intron structure was fixed before the duplication events that generated different classes of P-glycoproteins, but after the P-glycoproteins diverged from related genes, like the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which has an entirely different exon/intron structure. The four alternatively spliced transcripts of the MDR3 gene arise from alternative splicing of exons 23 and 26. Our analysis of DNA clones covering about 120 kilobases (kb) of the human MDR locus, including the entire MDR3 gene (74 kb) and the intergenic region between both genes (34 kb), combined with pulsed-field gel electrophoresis data shows that the human MDR locus covers about 230 kb. In contrast to the mouse mdr genes, both human genes are transcribed in the same direction (MDR3 located downstream of MDR1). The CpG-rich sequences marking the 5' ends of both genes are hypomethylated to different extents in different cell lines. Hypomethylation roughly correlates with transcriptional activity.
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PMID:Structure of the human MDR3 gene and physical mapping of the human MDR locus. 200 63

We examined the effectiveness of a previously characterized plasma cell-reactive monoclonal antibody (MoAb), MM4, in eliminating multi-drug resistant (MDR1) multiple myeloma (MM) clonogenic colony-forming cells (CCCs). MDR1 sublines with 6-fold (RPMI8226/DOX6) and 40-fold (RPMI 8226/DOX40) resistance to doxorubicin (DOX) were selected from the chemosensitive MM parent line RPMI 8226/S. Both sublines remained reactive with plasma cell MoAbs MM4 and PCA-1, as measured by flow cytometric immunophenotype analysis. MM4 and rabbit complement (C') were cytotoxic to MDR DOX6 (74 +/- 8.5%) and DOX40 (75 +/- 11.3%) cells as well as to chemosensitive 8226/S (80 +/- 5.6%) cells. Treatment with MM4 + C' depleted up to 3 logs of chemosensitive and MDR myeloma CCCs (8226/S: 99.26 +/- 0.52%; DOX6 99.91 +/- 0.08%' DOX40 99.15 +/- 0.55%). In addition, this approach abrogated the selfrenewing capacity of chemoresistant and MDR1 myeloma cell lines, according to doubling time analyses. By comparison, the P-glycoprotein-reactive MoAb MRK-16 and C' was effective in deleting MDR1 CCCs (DOX10: 95.71 +/- 2.51%; DOX40: 99.61 +/- 0.43%) but affected chemosensitive myeloma CCCs only slightly (5.93 +/- 14.52%). When DOX40 cells were mixed with normal bone marrow (BM) in a ratio of 10:90 (MM:BM), treatment with MM4 plus C' deleted MM CCCs (98.80 +/- 0.71%) without affecting the majority of normal BM progenitors. The combination of MM4 and MRK-16 did not enhance MDR myeloma CCC depletion. These observations suggest that MM4 + C' may be useful for depleting MDR as well as chemosensitive myeloma clonogenic cells from human bone marrow.
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PMID:Elimination of chemoresistant myeloma clonogenic cells from human bone marrow by monoclonal antibody and complement. 230 79

Typical multidrug resistance in human and animal cell lines is caused by overactivity of an unidirectional transmembrane drug efflux pump, encoded by the MDR genes, called mdr genes in mice and humans and pgp genes in hamsters. In humans, two mdr genes, mdr1 and mdr3, with approximately 80% nucleotide homology, have been identified. There is increasing evidence that overexpression of the mdr1 gene plays a role in resistance to anticancer agents in specific tumor types. However, currently no data are available on a possible role for mdr3 in drug resistance. Here we report high levels of expression of mdr3 gene sequences in leukemic cells from 6 out of 6 patients with prolymphocytic leukemia (PLL). No mdr1 expression was detected in 5 out of 6 of these samples, whereas a low level of mdr1 expression was found in a sample from one PLL patient in the course of transformation to non-Hodgkin's lymphoma. Except for this patient, all other PLL cases studied had not received prior chemotherapy. In vitro drug uptake studies showed that daunorubicin accumulation in PLL cells was increased by cyclosporin A. Since cyclosporin A is an inhibitor of the mdr1-encoded P-glycoprotein drug pump, these data suggest that in PLL cells mdr3 also codes for a drug efflux pump. Our findings could partly explain the primary refractoriness of PLL to chemotherapy.
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PMID:Expression of the mdr3 gene in prolymphocytic leukemia: association with cyclosporin-A-induced increase in drug accumulation. 232 39

Multidrug-resistance is frequently characterized by enhanced drug efflux resulting from a membrane glycoprotein of 170,000 daltons (P-glycoprotein). Analysis of cloned cDNAs for the human MDR 1 gene, whose product is the P-glycoprotein, indicates that P-glycoprotein is an energy-dependent drug-efflux system for cytotoxic hydrophobic anticancer drugs. We have demonstrated that a photoanalog of a reversing agent, SDB-ethylenediamine, specifically binds to P-glycoprotein. The binding site on P-glycoprotein seems to be identical with that of anticancer agents and other reversing agents. On the other hand, the radioactive photoactive dihydropyridine calcium channel blocker, [3H] azidopine, photolabels P-glycoprotein in membrane vesicles from multidrug-resistant cells. This photolabeling is almost completely inhibited by excess dihydropyridine analogs that reverse or lower drug-resistance. In contrast, the labeling is not significantly inhibited by analogs that do not reverse resistance. These results suggest that it may be possible to quickly screen for dihydropyridine analogs that reverse multidrug resistance by measuring the inhibition of [3H] azidopine labeling of P-glycoprotein.
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PMID:[A molecular basis for multidrug resistance and reversal of the resistance]. 256 48

Mammalian tumours displaying multidrug resistance overexpress a plasma membrane protein (P-glycoprotein), which is encoded by the MDR1 gene and apparently functions as an energy-dependent drug efflux pump. Tissue-specific expression of MDR1 and other members of the MDR gene family has been observed in normal cells, suggesting a role for P-glycoproteins in secretion. We have isolated a gene from the yeast Saccharomyces cerevisiae that encodes a protein very similar to mammalian P-glycoproteins. Deletion of this gene resulted in sterility of MATa, but not of MAT alpha cells. Subsequent analysis revealed that the yeast P-glycoprotein is the product of the STE6 gene, a locus previously shown to be required in MATa cells for production of a-factor pheromone. Our findings suggest that the STE6 protein functions to export the hydrophobic a-factor lipopeptide in a manner analogous to the efflux of hydrophobic cytotoxic drugs catalysed by the related mammalian P-glycoprotein. Thus, the evolutionarily conserved family of MDR-like genes, including the hlyB gene of Escherichia coli and the STE6 gene of S. cerevisiae, encodes components of secretory pathways distinct from the classical, signal sequence-dependent protein translocation system.
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PMID:The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. 256 66


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