Effects of verapamil on etoposide, vincristine, and adriamycin activity in normal human bone marrow granulocyte-macrophage progenitors and in human K562 leukemia cells in vitro.

We have examined the effects of verapamil on the cytotoxicity of etoposide, vincristine, and Adriamycin in human leukemia K562 cells as well as in normal human bone marrow granulocyte-macrophage progenitors (CFU-GM). Etoposide was 10-fold more potent against K562 cells than against normal human bone marrow CFU-GM. Similarly, vincristine cytotoxicity was about 10-fold greater against K562 cells than against human bone marrow CFU-GM. In contrast, Adriamycin exhibited little selectivity for K562 cells versus normal bone marrow CFU-GM during the 1-h incubation period of the experiments. In the presence of verapamil (2.5-10 microM), etoposide cytotoxicity was enhanced in both malignant and normal cells. Verapamil enhanced vincristine (0.1 microM) cytotoxicity in K562 cells but did not potentiate Vinca alkaloid toxicity in normal bone marrow CFU-GM. Adriamycin, on the other hand, did not display any calcium antagonist-mediated potentiation of cytotoxicity in either malignant or normal tissue. These results indicate that short-term (1 h) incubations with etoposide, vincristine, and Adriamycin yield different profiles of toxicities whether used alone or with chemosensitizing agents such as the calcium antagonists. These differences in activities are consistent with different mechanisms for intracellular disposition of these three classes of anticancer agents and are worthy of further investigation, especially with regard to combinations with calcium antagonists.