Sister chromatid exchanges induced by cancer chemotherapeutic agents in vitro and in vivo: consideration of the hazard of drugs as possible mutagens and carcinogens causing second malignancies.

Sister chromatid exchanges (SCEs) induced by chemotherapeutic agents currently used for treating various malignancies were studied in vitro and in vivo. Whether the agents are potentially mutagenic/carcinogenic is discussed on the basis of recent clinicopathological observations on secondary malignancy. In the in vitro studies, the induction of SCEs by various anticancer agents, including three anticancer antibiotics, six alkylating agents, and three antimetabolites, was examined and compared with induction by two known carcinogens, 4-nitroquinoline 1-oxide and N-ethyl-N'-nitronitrosoguanidine. In the in vivo studies, SCE frequencies were examined in the lymphocytes from 74 blood samples drawn from 40 patients with cancer or leukemia at various times after the agents had been administered alone or in combination. The SCE frequencies induced by the anticancer antibiotics were variable because the drugs had different modes of action: generally, the drugs have strong cytotoxicity that must affect the viability of cells. On the other hand, alkylating agents induced significantly high levels of SCE frequencies in vitro; the modes of SCE inducibility were similar to those of the two carcinogens. The fact that cells were viable up to relatively high molar concentrations of the agents and that high SCE levels persisted for a long period suggests that the lesions induced by alkylating agents are long-lived and may therefore be more frequently involved in mutagenesis. This finding may be compatible with the clinical observation that the vast majority of patients with second malignancy are found in the group treated with alkylating agents. Antimetabolites generally showed only a weak SCE induction or none in vivo and in vitro.