title: Intracellular levels of two cyclosporin derivatives valspodar (PSC 833) and cyclosporin a closely associated with multidrug resistance-modulating activity in sublines of human colorectal adenocarcinoma HCT-15.
abstract: P-Glycoprotein, which mediates multidrug resistance (MDR) in cancer chemotherapy, is a principal target of cyclosporin A and [3'-keto-Bmt(1)]-[Val(2)]-cyclosporin (valspodar; PSC 833). To clarify mechanisms contributing to the different MDR-modulating activities of valspodar and cyclosporin A, we investigated the relation of the intracellular levels of the two cyclosporin derivatives to their modulating effect on MDR in different P-glycoprotein-expressing human colorectal carcinoma HCT-15 cells (parental HCT-15 and adriamycin-resistant sublines). In this study, valspodar was found to be much more potent than cyclosporin A in both sensitizing resistant cells to MDR-related anticancer drugs (e.g., adriamycin, vincristine and paclitaxel (taxol)) and increasing 2-[6-amino-3-imino-3H-xanthen-9-yl]benzoic acid methyl ester (rhodamine 123) retention and [G-(3)H]vincristine sulfate ([(3)H]vincristine) accumulation in these cells. Furthermore, a good correlation was detected between P-glycoprotein levels and the MDR-reversing effect of valspodar. In contrast, the effects of cyclosporin A could not be linked to P-glycoprotein levels in the MDR cells. In addition, the intracellular accumulation of valspodar was found to be 3 - 6 fold higher than that of cyclosporin A in four sublines and verapamil, an inhibitor of P-glycoprotein-mediated transport, enhanced the accumulation of cyclosporin A, but not valspodar. These results suggested that valspodar accumulation is not actively regulated by the P-glycoprotein-mediated efflux system.
authors.affiliation: Tsukuba Research Institute, Novartis Pharma K.K., Ohkubo 8, Tsukuba, Ibaraki 300-2611. Noriko.Uchiyama@Pharma.Novartis.com
authors.forename: N
authors.initials: N
authors.lastname: Uchiyama-Kokubu
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: D
authors.initials: D
authors.lastname: Cohen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D003524:Cyclosporins / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016588:Anticarcinogenic Agents; D003524:Cyclosporins; D020112:Rhodamine 123; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; C070272:valspodar