Modulation of etoposide (VP-16) cytotoxicity by verapamil or cyclosporine in multidrug-resistant human leukemic cell lines and normal bone marrow.

We studied the effects of two modulators of multidrug resistance (MDR), cyclosporine and verapamil, on the cytotoxicity of etoposide (VP-16) in normal human bone marrow; two human leukemia cell lines, K562 and CEM; their MDR variants, K562/DOX and CEM/VLB; and mixtures of normal marrow and leukemic cells. VP-16 was selectivity toxic to the parental leukemic cells, with IC-50 values of 2 microM for CEM cells, 1.5 microM for K562 cells, and 12 microM for normal marrow CFU-GM. This selectivity was lost in the MDR variant leukemia cells, with IC-50s of 20 microM in K562/DOX and 8 microMs in CEM/VLB. Cyclosporine, 6 microMs, and verapamil, 20 microM, alone were nontoxic to bone marrow CFU-GM, and did not significantly increase the toxicity of VP-16 to normal marrow cells or to the two drug-sensitive leukemic cell lines. However, cyclosporine specifically enhanced the cytotoxicity of VP-16 in the MDR leukemia cells, reducing the IC-50 to the same level as the parental sensitive cells. Verapamil was considerably less effective. In a mixing experiment that included K562/DOX cells and normal bone marrow, cyclosporine increased the toxicity of VP-16 to the resistant leukemic cells by nearly 20-fold. Because the cytotoxic effect of cyclosporine is additive for resistant tumor cells, its combination with VP-16 may be useful in the purging of contaminating tumor cells prior to autologous bone marrow transplantation.