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In Vitro Biochemical and Cytotoxicity Studies with 1-β-D-Arabinofuranosylcytosine and 5-Azacytidine in Combination¹

Division of Hematology-Oncology, Childrens Hospital of Los Angeles, Los Angeles, California 90027 [R. L. M., J. G., M. K.], and Departments of Pharmacology [R. L. M., J. G.] and Pediatrics [R. L. M., M. K.], University of Southern California School of Medicine, Los Angeles, California 90033

The effect of 1-β-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine (5-aza-C), alone and in combination, on DNA synthesis and cytotoxicity in hamster fibrosarcoma cells has been studied. After a 2-hr exposure of S-phase cells to ara-C at concentrations of 2 to 200 µM, the cells required about 4 to 6 hr to recover from inhibition of DNA synthesis. When 2 exposures to ara-C were used, maximal cytotoxicity occurred when the 2nd dose of ara-C was administered at the time when the cells recovered from the inhibition of DNA synthesis. When the S-phase cells were exposed to ara-C, the maximal killing effect of 5-aza-C occurred when this agent was administered 6 hr later, at the time when the cells had recovered from the inhibition of DNA synthesis. When S-phase cells were exposed to 5-aza-C, the maximal cell kill produced by ara-C also occurred 5 to 6 hr later. When the S-phase cells were exposed simultaneously to both ara-C and 5-aza-C, significant antagonism with respect to cytotoxicity was observed between these 2 agents. When cells in G₁ were exposed to 5-aza-C, the cytotoxicity produced by ara-C on these cells when they entered S phase was additive with respect to the cytotoxicity produced by 5-aza-C exposure alone.

¹ This work was supported in part by Grant C1-85-D from the American Cancer Society and NIH Grants CA11050 and CA14089.

² Scholar of Leukemia Society of America. Deceased November 16, 1974.

Received 12/18/74. Accepted 7/ 8/75.