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)

UCLA-P3 human lung adenocarcinoma cells were grown in nude mice and given repetitive treatments of a monoclonal antibody-Vinca alkaloid immunoconjugate. Although this therapy resulted in a greater than 4-fold reduction in mean tumor mass of the established tumors, some animals experienced a reinitiation of tumor growth after cessation of conjugate treatment. Two such animals were treated again with high doses of monoclonal antibody-Vinca but one of the tumors was no longer regressed by the drug conjugate. The tumor was excised, enzymatically dissociated, and grown in tissue culture. Cultured cells were reimplanted in nude mice and subjected to further therapy with a monoclonal antibody-Vinca conjugate. The resulting tumors were also refractory to the immunoconjugate therapy. This cycle was repeated for a total of three times and resulted in the serial in vivo selection of three conjugate resistant variants. The mechanism responsible for the in vivo resistance of human tumor cells to the monoclonal antibody-Vinca immunoconjugate is unknown but does not appear to involve antigen modulation, altered tumor cell growth rate, or an apparent decrease in tumor targeting in vivo. The resistance was also not accompanied by any detectable elevation in multidrug resistance 1 mRNA or P-glycoprotein expression. Significantly, the resistance pattern was observed only in vivo and was not maintained by cells grown in vitro.
Cancer Res 1990 Dec 01
PMID:In vivo selection of human tumor cells resistant to monoclonal antibody-Vinca alkaloid immunoconjugates. 197 47

First-step Adriamycin (doxorubicin)-resistant mutants of the murine erythroleukemia cell line PC4 were cloned from Adriamycin-containing (10 ng/ml) methylcellulose at a frequency of 3 x 10(-4). They demonstrated 1.6- to 2.4-fold stable resistance to Adriamycin. Most were cross-resistant to etoposide, but not to vincristine, and were without enhanced expression of mdr genes, which code for P-glycoproteins. Two different murine erythroleukemia cell lines, PC4 and C7D, were passaged in suspension culture into stepwise increasing amounts of Adriamycin. No high-level resistant mutants were isolated de novo; cells initially displayed low-level resistance to Adriamycin and etoposide. Two stepwise doublings of the drug concentration were needed before PC4 cells acquired vincristine resistance, but there was no detectable overexpression of mdr or a change in anthracycline uptake. In a subsequent doubling of Adriamycin concentration, the cells showed a further increase in resistance to all three drugs and now a decreased anthracycline accumulation. However, there was still no detectable increase in mdr expression as judged by Northern analysis of poly(A)+ enriched RNA and Western blot analysis of membrane proteins. Only after a fourth doubling of Adriamycin concentration did the cells demonstrate enhanced expression of mdr and P-glycoprotein. Equivalent mutants of C7D were selected, but generally at lower Adriamycin concentrations. Verapamil partially lowered resistance, but failed to restore parental susceptibility in any mutant; it caused an increased uptake in those mutants showing decreased anthracycline accumulation, including those that did not overexpress mdr. This study demonstrated different resistance phenotypes among mutants appearing spontaneously under stepwise drug selection; mutants with vincristine resistance and decreased anthracycline uptake preceded those associated with over-expression of P-glycoprotein.
Cancer Res 1990 Dec 15
PMID:Sequential emergence of distinct resistance phenotypes in murine erythroleukemia cells under adriamycin selection: decreased anthracycline uptake precedes increased P-glycoprotein expression. 197 51

Seeking to optimize the immunocytochemical assay of P-glycoprotein, a 170-kilodalton (P-170) molecule associated with multidrug resistance, we experimented with a variety of antibodies (JSB-1, C219, and MRK-16), fixation conditions, and titers using both human myeloma cell lines and clinical myeloma specimens. Under optimized conditions, using all three antibodies and the cell lines as standards and controls, the ICC method proved sensitive, specific, reliable, rapid, and within the realm of everyday hospital laboratory expertise. The 3 anti-P-glycoprotein antibodies revealed different reactivities with P-170. Both C219 and JSB1 were optimized by fixation in cold acetone. With MRK-16 optimal results were obtained on unfixed or formalin fixed specimens. Under optimal fixation and titering conditions, low level (DOX 4) detection was possible. Given that the three antibodies differ in reactivity and recognize different P-170 epitopes, it follows that using the antibodies in a small panel is a useful strategy in increasing the likelihood of detecting true P-glycoprotein expression by the immunocytochemical method. In dilution experiments, the immunocytochemical method was as sensitive as RNase protection assay and more sensitive than Western blot detection. Immunocytochemistry coupled to computer-assisted single-cell densitometry, showed a strong correlation (R = 0.98) between cellular P-170 density and in vitro resistance to doxorubicin. Multidrug-resistant specific probes for RNA expression and Western blot assays confirmed the specificity of P-170 expression in both cell lines and clinical samples. Thus, a small panel of antibodies, under optimized immunocytochemical conditions, appears to have potential as a rapid, sensitive, clinically useful assay for multidrug resistance in myeloma.
Lab Invest 1990 Dec
PMID:Optimization of immunocytochemical P-glycoprotein assessment in multidrug-resistant plasma cell myeloma using three antibodies. 197 62

Staurosporine, a potent inhibitor of C-kinase, enhances accumulation of vincristine (VCR) in multidrug-resistant cells. We investigated this enhancement by two methods: (I) ATP-dependent VCR binding system; (II) azidopine photolabeling system. The ATP-dependent VCR binding to the resistant cell membrane was inhibited more efficiently by staurosporine than by verapamil. Staurosporine also inhibited the azidopine photolabeling of P-glycoprotein. These results indicate that staurosporine, an inhibitor of C-kinase, might directly bind to P-glycoprotein as well as antitumor agents and Ca2+ channel blockers. These findings also indicate that C-kinase might be involved in the function of P-glycoprotein.
Biochem Biophys Res Commun 1990 Dec 31
PMID:Staurosporine, a potent inhibitor of C-kinase, enhances drug accumulation in multidrug-resistant cells. 198 66

We examined the effect of hemin, sodium butyrate and mitomycin C on levels of P-glycoprotein mRNA in human myelogenous K562 cells by northern blot analysis. After treatment with sodium butyrate a dose-dependent increase of P-glycoprotein mRNA expression was observed in the adriamycin-resistant K562 and vincristine-resistant K562 lines. With 10 mM sodium butyrate, the level of P-glycoprotein mRNA reached 20 times that of control adriamycin-resistant K562 and with 30 mM sodium butyrate, it exceeded 5 times that of control vincristine-resistant K562. In contrast, hemin and mitomycin C had almost no effect on P-glycoprotein mRNA. In this experiment, since expression of P-glycoprotein mRNA was not necessarily accompanied with induction of erythroid differentiation, the increased amount of P-glycoprotein mRNA is unlikely to be a result of differentiation.
Jpn J Cancer Res 1990 Dec
PMID:Increase in the level of P-glycoprotein mRNA expression in multidrug-resistant K562 cell lines treated with sodium butyrate is not accompanied with erythroid differentiation. 198 Apr 93

Multidrug resistance (MDR) associated with overexpression of P-glycoprotein (Pgp) is a well-described experimental phenomenon that appears to have clinical correlates. However, recent descriptions of non-P-glycoprotein forms of MDR have complicated efforts to detect and circumvent MDR in the tumors of patients. One major form of natural product MDR appears to be due to alterations in the amount of activity of DNA topoisomerase II. Compared to Pgp-MDR cells, cells expressing this form of MDR (at-MDR) do not overexpress the mdr1 gene or its product, Pgp, are unaltered in drug accumulation and retention, are unaffected by such 'modulators' of Pgp-MDR as verapamil, and express this phenotype recessively. Recently, other MDR cell lines have been described with some characteristics of Pgp-MDR (decreased drug accumulation and retention, increased drug cytotoxicity by modulators of MDR), but not others (no expression of the mdr1 gene or Pgp). Whether any non-Pgp forms of MDR occur in patients' tumors remains to be determined.
Cancer Treat Rev 1990 Dec
PMID:Mechanisms of multidrug resistance in human tumor cells. The roles of P-glycoprotein, DNA topoisomerase II, and other factors. 198 39

Recent progress in the understanding of drug resistance has led to the discovery of new targets for chemotherapy. By attacking the molecules that make cancer cells insensitive to chemotherapy, it is hoped that drug-resistant disease will respond to treatment. This review describes some of the latest advances in understanding of the biochemistry of drug resistance. Following a general introduction four areas of topical interest are discussed: (1) multidrug resistance and P-glycoprotein, (2) glutathione and its related enzymes, (3) topoisomerase II and (4) DNA repair.
Radiother Oncol 1990 Dec
PMID:Biochemical basis of resistance to chemotherapy. 228 41

Multidrug-resistant (MDR) cells demonstrate the increased activity of the membrane transport system performing efflux of diverse lipophylic drugs and fluorescent dyes from the cells. In order to detect MDR cells we have developed a simple test consisting of three steps: staining of the cells with fluorescent dye rhodamine 123, incubation in the dye-free medium and, finally, detection by fluorescence microscopy of the cells that have lost accumulated dye. The experiments with B-lymphoma cell lines with different degrees of MDR have shown that the cell fluorescence after the poststaining incubation is indeed inversely proportional to the degree of resistance. Application of this testing procedure to normal human or mouse leukocytes revealed the presence of the cells rapidly losing the dye in these populations. Cell fractionation experiments have shown that there are T-lymphocytes (most T-killers/suppressors and a part of T-helpers) that demonstrate rapid efflux of rhodamine 123. This characteristic was detected also in T-killer clones and cell line and in some T-lymphomas. The inhibitors of the MDR transport system, reserpine and verapamil, blocked the efflux of the dye from these cells. Rhodamine-losing T-lymphoma contained large amounts of the mRNA coding P-glycoprotein, the MDR efflux pump, and demonstrated increased resistance to rhodamine 123, gramicidin D, colchicine, and vincristine, the drugs belonging to the cross-resistance group for the MDR cells. The role of the increased activity of the MDR membrane transport system in T-lymphocytes is discussed.
Exp Cell Res 1989 Dec
PMID:Multidrug-resistance phenotype of a subpopulation of T-lymphocytes without drug selection. 248 Sep 10

Trimetrexate (TMQ) is a lipophilic antifolate shown to have antitumor activity in humans. TMQ-resistant sublines of the MOLT-3 human acute lymphoblastic leukemia cell line were developed and were designated as MOLT-3/TMQ200, MOLT-3/TMQ800, and MOLT-3/TMQ2500 based on degrees of resistance to TMQ. The TMQ resistance was accompanied by 5- to 7-fold increases in dihydrofolate reductase activity and markedly reduced cellular TMQ accumulation. Methotrexate accumulation was not impaired in TMQ-resistant cells. TMQ retention (efflux) was unchanged in these TMQ-resistant cells. Verapamil enhanced the TMQ accumulation in the resistant cells to the level seen in the parent cells but had no effects on the TMQ retention. These sublines were cross-resistant not only to methotrexate but also to vincristine, doxorubicin, daunorubicin, and mitoxantrone. There was no cross-resistance to bleomycin or cisplatin. Resistance to vincristine, doxorubicin, daunorubicin, and mitoxantrone was reversed by verapamil. TMQ resistance was only minimally reversed by verapamil and methotrexate resistance not affected at all. Both cellular accumulation and retention of vincristine and daunorubicin in the TMQ-resistant cells were markedly decreased. Verapamil enhanced both accumulation and retention of the drug. Plasma membrane fractions of the TMQ-resistant cells analyzed by urea-sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by staining with Coomassie Blue revealed the presence of a distinct band with a molecular weight of 170,000. Immunoblot analysis with 125I-labeled monoclonal antibody raised against P-glycoprotein of multidrug-resistant Chinese hamster ovary cells (C219) cross-reacted with the Mr 170,000 protein of the TMQ-resistant cells. These results show that the TMQ-resistant cells displayed not only decreased TMQ uptake and increased dihydrofolate reductase but also characteristics associated with a classical multidrug-resistant phenotype. Multidrug resistance includes lipophilic antifolate.
Cancer Res 1989 Dec 01
PMID:Multidrug resistance in a human leukemic cell line selected for resistance to trimetrexate. 257 16

The study of multidrug resistance (MDR) in tumor cell lines has led to the discovery of the plasma membrane P-glycoprotein (Pgp) molecule. This protein functions as an energy-dependent pump for the efflux of diverse anticancer drugs from MDR cells. It now appears that Pgp-mediated MDR tumor cells do occur in human cancers, and that they are likely to play a role in the ultimate response of patients to chemotherapy. Chemosensitizers, compounds able to reverse the MDR phenotype, have been identified and offer the exciting possibility of improving efficacy for some nonresponsive malignancies. Surprisingly, Pgp-like molecules can be found in evolutionarily distant species among both eukaryotes and prokaryotes. As a group, these proteins form a superfamily of ATP-dependent transport proteins. This finding has broad implications and provides new insights into how living organisms use this fundamental transport system to regulate the trafficking of diverse molecules across biological membranes.
FASEB J 1989 Dec
PMID:P-glycoprotein: multidrug-resistance and a superfamily of membrane-associated transport proteins. 257 19


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