Human multidrug-resistant cells, K562/ADM, KB-C-4, AdrRMCF-7 and CEM/VLB100 showed 21-, 7.5-, 105- and 3.4-fold cross-resistance to mitomycin C (MMC). The resistance to MMC in K562/ADM, KB-C-4, AdrRMCF-7, CEM/VLB100 cells was reversed by 6.6 microM verapamil. Accumulation of [3H]MMC in K562/ADM, AdrRMCF-7 and CEM/VLB100 cells also decreased by 37, 26 and 33%, as compared with their drug-sensitive counterparts. In KB-C-4 cells, accumulation of [3H]MMC decreased by 60%, and efflux rate of [3H]MMC was slightly increased as compared to their parental KB-3-1 cells. Verapamil at 6.6 microM increased accumulation of [3H]MMC in these multidrug-resistant sublines. K562/ADM10, K562/ADM50, K562/ADM100 and K562/ADM250 cells, which showed 17- to 230-fold resistance to Adriamycin, also showed 0.8- to 7.3-fold cross-resistance to MMC. In these cell lines, the extent of resistance to Adriamycin (ADM) that was consistent with expression levels of P-glycoprotein shown by immunoblotting was directly proportional to the extent of their resistance to MMC. Regression analysis indicated that relative resistance to Adriamycin was correlated with relative resistance to MMC (r = 0.98). These results indicate that MMC can be transported by P-glycoprotein overexpressed in multidrug-resistant cells.
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