Cytotoxicity and Mode of Action of 5-Azacytidine on LI 210 Leukemia1

This study attempts to determine the primary actions of 5-azacytidine (5-azaCR) on L1210 leukemia. This agent was cytotoxic toward L1210 cells growing in culture with 50 and 90% inhibition dose values of 0.019 and circa 0.15 jug/ml, respectively. 5-AzaCR inhibits the incorporation of tritiated thymidine or deoxyadenosine into DNA to a greater extent than it inhibits the incorporation of tritiated uridine into RNA. Similar results were obtained with ascitic cells isolated from leukemic mice. Equimolar amounts of cytidine reduced the inhibition of DNA synthesis, as well as the inhibition of cell growth in culture caused by 5-azaCR. Uridine, but not deoxycytidine or deoxyuridine, was also effective, but to a lesser extent than was cytidine. With cell-free extracts isolated from LI210 cells in culture, no significant effect was found on enzyme systems directly or indirectly involved in DNA synthesis. With 5-azaCR-4-14C as the precursor, this agent was found