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)

We have examined the effect of FK506 on the Adriamycin sensitivity of the multidrug resistant human chronic myelocytic leukemia cell line (K562/ADM). In K562/ADM cells, 1.0 microgram/ml FK506 reversed the resistance of Adriamycin, and increased the IC50 value for Adriamycin up to 17 fold. However, IC50 value for the parent cells (K562) increased only 1.5 fold. By cell cycle analysis, the accumulation in late S-G2M phase was confirmed on K562/ADM cells, treated with 1.0 microgram/ml FK506 and low-dose of Adriamycin. Cyclosporin A (CsA) could also restored the Adriamycin sensitivity in the K562/ADM cells, as previously reported. 1.0 microgram/ml FK506 as well as CsA significantly increased radioactive Adriamycin accumulation in K562/ADM cells and blocked [3H]azidopien photoaffinity labeling of P-glycoprotein. These results suggest that 1.0 microgram/ml FK506 could reverse the Adriamycin resistance in a MDR human leukemia cells through the interaction with P-glycoprotein.
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PMID:FK506 reverses adriamycin resistance in a multidrug-resistant human leukemia cell line. 128 34

We developed a multidrug resistant small cell lung cancer line, VPR-2, by exposing H69 parent cells to etoposide (20 microM) for 1 h daily for 3 days every 21-28 days, a schedule similar to that used in the clinic. Resistance (20-fold) to the cytostatic and DNA cleavage activities of etoposide emerged after the third treatment, and this phenotype was stable in the absence of drug exposure for 2.5 years. VPR-2 cells exhibited cross resistance to intercalating agents and vinca alkaloids, but remained sensitive to X-radiation, cisplatin and 5-fluorouracil. The human mdr1 gene was overexpressed in the resistant line, but steady-state concentrations of etoposide were reduced only 1.5-fold. Topoisomerase II catalytic and etoposide stimulated DNA cleavage activity in nuclear extracts from both lines were identical despite retention of a 3-fold level of resistance to etoposide-induced strand breaks in isolated nuclei from VPR-2 cells. Cyclosporin A and verapamil, both of which bind to P-glycoprotein, enhanced accumulation of etoposide in VPR-2 cells, and H69 cells to a lesser extent. Yet only cyclosporin A was effective in differentially enhancing etoposide cytostasis in VPR-2 relative to H69. In VPR-2 whole cells, cyclosporin A enhanced etoposide-induced DNA single-strand break frequency 9-fold but had no effect in isolated nuclei. Rapid selection of this line with a clinically relevant drug exposure schema and stability of the resistant phenotype suggest these cells may have been a steady subpopulation of the parent line through years of serial passage in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multidrug resistance in a small cell lung cancer line: rapid selection with etoposide and differential chemosensitization with cyclosporin A. 133 82

Cyclosporin A (CsA), a cyclic peptide of 11 amino acids isolated from the fungus Tolypoclodium inflatum Gams, is the principle drug used for immunosuppression in organ transplant patients. It is known to have a very specific effect on T-cell proliferation although the precise mechanism remains unclear. Following internalization, CsA binds to a cytosolic protein, cyclophilin, which has been shown to possess peptidyl-prolyl cis-trans isomerase activity. CsA is an effective modifier of multidrug resistance in human and rodent cells at doses in the range of 1 to 5 micrograms/mL. Although it reverses the drug accumulation deficit associated with multidrug resistance in some cell types, this is not always the case. CsA has P-glycoprotein binding activity but less specific membrane effects and inhibition of protein kinase C may also be involved in its resistance modifier action. A number of non-immunosuppressive analogues of CsA have been shown to have resistance modifier activity and some are more potent than the parent compound. One analogue from Sandoz, PSC-833, has been shown to be approximately 10-fold more potent than CsA and is expected to enter clinical trial in the near future. The use of such agents may allow a full test of the hypothesis that reversal of multidrug resistance will prove a useful clinical strategy.
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PMID:Cyclosporins as drug resistance modifiers. 134 94

Cyclosporin A (CsA, Sandimmune) is known to reverse P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use. PSC-833, a new cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the L1210 leukemia cell line transfected with a full-length cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro, PSC-833 was at least as potent as CsA or verapamil in reversing multidrug resistance. In vivo, the drug-resistant L1210 leukemia was completely unresponsive to i.v. monotherapy with adriamycin at its maximum tolerated dose (MTD). PSC-833 enhanced the activity and toxicity of adriamycin. The MTD of adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v. adriamycin in combination with oral PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.
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PMID:SDZ PSC 833, a non-immunosuppressive cyclosporine: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia. 134 37

Cyclosporine A (CyA), a potent reversant of multidrug resistance (mdr), was studied for its effects on the sensitivity of leukemic progenitors (leukemia colony-forming units, CFU-L) to daunorubicin (DNR) and mitoxantrone. CyA was first compared to verapamil and cefoperazone for reversion of mdr in the mdr1+ cell line K562/DOX. A dramatic increase of sensitivity to 10(-6) M DNR was noted with CyA (0.5 and 1 microgram/ml) and verapamil (1 and 5 micrograms/ml), but not for cefoperazone (0.3 and 0.6 mg/ml). The sensitivity of K562/DOX to 10(-6) M mitoxantrone was also slightly enhanced by CyA. The change in CFU-L drug sensitivity in the presence of CyA was then tested in 12 relapsing/resisting patients and in 3 untreated patients with acute myelogenous leukemia (AML). No change in CFU-L sensitivity to DNR was noted, despite the presence of a subset of P-glycoprotein positive (P-gp+) cells in three out of the ten evaluable cases. Among the six evaluable cases tested with mitoxantrone and CyA, an increase of 50% in CFU-L sensitivity to mitoxantrone was noted in one (of three) P-gp+ patient. These data suggest that the CFU-L in AML rarely expressed the P-gp and that other mechanisms of drug resistance could be involved in AML.
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PMID:In vitro effect of P-glycoprotein (P-gp) modulators on drug sensitivity of leukemic progenitors (CFU-L) in acute myelogenous leukemia (AML). 135 Feb 49

[3H]Vinblastine bound with high affinity to surface membranes prepared from H69/LX4 cells which express P-glycoprotein (P-gp) and as a consequence are multidrug resistant (MDR). The KD was 9.8 +/- 1.5 nM and density of sites 31.2 +/- 8.6 pmol/mg of protein. [3H]Vinblastine binding was inhibited by cytotoxics and agents known to reverse MDR. 1,4-Dihydropyridine MDR reversing agents including nicardipine and nifedipine accelerated the dissociation of [3H]vinblastine from P-gp indicating a negative heterotropic allosteric effect. Cyclosporin A, vincristine and actinomycin D did not alter [3H]vinblastine dissociation kinetics. It is concluded that P-gp possesses at least two allosterically coupled drug acceptor sites, receptor site-1 that is selective for vinca alkaloids and cyclosporin A, and receptor site-2 that is selective for 1,4-dihydropyridines.
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PMID:P-glycoprotein possesses a 1,4-dihydropyridine-selective drug acceptor site which is alloserically coupled to a vinca-alkaloid-selective binding site. 135 68

Analysis of a panel of endothelial cells passaged between 5 and 25 times and derived from various organs and species demonstrated that murine and porcine cerebral capillary endothelial cells actively excluded the fluorescent dye rhodamine 123, a substrate of P-glycoprotein. In addition, rhodamine 123 accumulation could be enhanced by the multidrug resistance chemosensitizer verapamil, known to reduce P-glycoprotein-mediated drug efflux. Cloned murine and porcine cerebral capillary endothelial cells were immunoreactive with the C219 monoclonal antibody to P-glycoprotein, and a C219 epitope-specific blocking peptide could abolish staining. The antiproliferative and cytotoxic effects of vincristine, but not cis-platinum(II) diamminedichloride, were increased by the addition of either verapamil or cyclosporin A to brain endothelial cell cultures in a 72-h assay, as determined by [3H]thymidine incorporation and total protein measurement. Cyclosporin A was a more effective reversal agent than verapamil. Thus, a P-glycoprotein isoform may be constitutively expressed in brain endothelial cells in vitro and supports the available data on in situ immunohistochemical staining of P-glycoprotein at the blood-brain barrier. In addition, these findings may indicate that one function of P-glycoprotein in vivo at the blood-brain barrier is the exclusion of xenobiotics from central nervous system tissues.
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PMID:Expression and functional activity of P-glycoprotein in cultured cerebral capillary endothelial cells. 136 Aug 73

Cyclosporin A and verapamil are substrates for P-glycoprotein. Both agents are known to reverse multidrug resistance in cells overexpressing P-glycoprotein. In this investigation, we have examined the effects of cyclosporin A and verapamil on multidrug resistance in HL60/AR cells that lack P-glycoprotein. In addition, a correlation was sought between an alteration in plasma membrane potential as measured with cationic dye DIOC5 and overexpression of P-glycoprotein. HL60/AR cells accumulated 3 fold less daunorubicin than HL60 cells. The drug accumulation defect and drug resistance in HL60/AR cells were partially corrected by verapamil and buthionine sulfoximine. However, cyclosporin A had no detectable effect on daunorubicin accumulation or drug resistance in HL60/AR cells. The multidrug resistant P338/ADR cell line overexpressed P-glycoprotein and exhibited depolarization of plasma membrane when compared to its corresponding drug sensitive parental cell line. In contrast, HL60/AR cells lacked P-glycoprotein and plasma membrane potentials were similar to those of drug sensitive HL60 cells. These results suggest that [1] verapamil modulates daunorubicin transport by a mechanism independent of P-glycoprotein, [2] the mechanisms of reversal of multidrug resistance by verapamil and cyclosporin A are distinct, and [3] the plasma membrane depolarization in multidrug resistant cell lines that overexpress P-glycoprotein, as determined by DIOC5, may be due to an increased efflux of cationic dye by P-glycoprotein, rather than a true measurement of plasma membrane potential in multidrug resistant cells.
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PMID:Lack of reversal of daunorubicin resistance in HL60/AR cells by cyclosporin A. 136 15

Resistance is often defined as a lack of therapeutic response. Cellular resistance involves a decrease in intracellular levels of the antitumor agent due to a variety of mechanisms. These mechanisms are active in tumors with initial resistance as well as in those which respond initially but fail to be completely destroyed by chemotherapy. Although acquired forms of resistance seem to be the result of selection, some studies suggest that antitumor agents may induce resistance. Four main mechanisms of resistance are currently being investigated: 1) multidrug resistance, involving expression of a membrane P-glycoprotein, responsible for resistance to hydrophobic cationic agents; 2) detoxification of hydrophilic agents by the enzyme glutathione-S-transferase; 3) increased production of enzymes targeted by antimetabolites; 4) mutation or decreased synthesis of topoisomerases I and II which are the targets of very recent antitumor agents. New data were presented at the 1992 symposium of the American Association for Cancer Research; expression of P-glycoprotein is controlled by the mutant protein P53, the oncogene ras and differentiation agents. Physiological effects of this molecule are related to the chloride pump. Bone marrow stem cells from transgenic mice obtained by transfection of the gene MDR1 in germ cells exhibit resistance. Many agents can reverse P-glycoprotein-related resistance. Results from three phase I trials with Cyclosporin A as reversion agent were reported. It is essential to conduct clinical trials in order to assess the true value of these new data which hold promise for improving the performance of antitumor agents.
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PMID:[How do cancers resist to chemotherapy?]. 136 90

The major limitation to curative therapy for ovarian cancer is the development of drug resistance. Cyclosporin A (CsA), an immunosuppressive agent that has been used extensively in organ transplantation, also has been shown to decrease the resistance of cancer cells to some chemotherapeutic agents. Since cisplatin (CDDP) is the most common drug used for the treatment of ovarian cancer, we evaluated the potential of CsA to decrease resistance to CDDP in ovarian cancer cells selected for resistance to CDDP (A2780-CDDP). Although CsA significantly increased the sensitivity of A2780-CDDP cells to cytolysis by CDDP it did not increase CDDP sensitivity in the CDDP-sensitive parent cells (A2780), that is, CsA did not decrease basal resistance to CDDP. Both A2780-CDDP and A2780 are sensitive to cytolysis by Adriamycin (ADR). CsA significantly decreased the basal resistance of both cell lines to ADR. Interestingly, the effect of the protein synthesis inhibitors, emetine and cycloheximide, was similar to that of CsA, suggesting that CsA decreased selected resistance to CDDP and decreased basal resistance to ADR by affecting a protein synthesis-dependent resistance mechanism(s). In contrast to CsA and protein synthesis inhibitors, buthionine sulfoximine, an inhibitor of glutathione synthesis, decreased basal resistance of both cell lines to cytolysis by CDDP but not ADR, while verapamil, an inhibitor of P-glycoprotein, had no effect on cytolysis in either cell line. These results suggest that CsA may not decrease resistance to CDDP or ADR-mediated cytolysis by reducing glutathione or by inhibiting P-glycoprotein.
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PMID:The effects of cyclosporin A on the lysis of ovarian cancer cells by cisplatin or adriamycin. 142 96


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