We studied the effects of two modulators of multidrug resistance (MDR), cyclosporine and verapamil, on the cytotoxicity of etoposide (VP-16) in normal bone marrow cells. VP-16 was toxic to normal bone marrow at concentrations greater than 50 microM, resulting in no granulocyte-macrophage colony-forming units (CFU-GM) in short-term methylcellulose cultures. However, in long-term marrow cultures (LTMC) treatment with VP-16 without the addition of MDR modulators resulted in only a twofold decrease in total cell number at a VP-16 concentration of 50 microM, compared to media alone in the adherent cell layer, and approximately 20% recovery of CFU-GM. The addition of MDR modulators did not result in excessive cytotoxicity, reducing the total CFU-GM by two- to threefold even at the higher VP-16 concentration. Therefore, these modulators in conjunction with VP-16 can be safely used on normal bone marrow cells and may provide an effective method to purge MDR-tumor cells.