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