1-β-d-Arabinofuranosylcytosine (cytarabine; ara-C) and 5-azacytidine (5-azaCR), cytosine nucleoside antimetabolites with different mechanisms of action, are both effective in the treatment of human leukemia, and the clinical use of these two agents in combination has been suggested. We have studied the therapeutic effect in L1210 leukemic mice of single i.p. doses of ara-C and 5-azaCR in combination. Therapeutic effects observed depended markedly on the sequence and time interval between the doses of each agent. Antagonism was observed when both agents were administered simultaneously. The optimal therapeutic effect was observed when 5-azaCR was administered after ara-C at a time when tumor DNA synthesis had maximally recovered after the ara-C dose. The dose-interval effect and correlation with recovery of DNA synthesis capacity were also observed in studies in vitro in which the survival of L1210 cells in culture was examined. ara-C was shown to inhibit the incorporation of [4-14C]-5-azaCR-derived radioactivity into DNA of L1210 cells in culture, and the therapeutic effects observed are interpreted in terms of these latter results and the mechanisms of action of the two agents.
This study was supported in part by Contracts NO1-CM-33707 and NO1-CM-43753 from the Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education, and Welfare. A preliminary report of this work was presented at the Fall Meeting, American Society for Pharmacology and Experimental Therapeutics, Montreal, Quebec, Canada, August 19, 1974 (40).