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.

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.