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Comparative Studies of the Cytostatic Action and Metabolism of 5-Azacytidine and 5,6-Dihydro-5-azacytidine

Laboratory of Medicinal Chemistry and Biology, [P. V., J. A. B., M. M. A.] and Drug Evaluation Branch [M. K. W-D.], Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20014

5,6-Dihydro-5-azacytidine hydrochloride, a chemically stable, soluble analog of 5-azacytidine, has cytostatic activity against mouse leukemic L1210 cells grown in culture, but concentrations on the order of 10 µM, 10-fold higher. than the parent drug, are necessary to inhibit cell growth. The addition of either cytidine or uridine protected against growth inhibition by 5-azacytidine and 5,6-dihydro-5-azacytidine, whereas thymidine potentiated the cytostatic action of both drugs. Deoxycytidine also enhanced the action of 5-azacytidine but had no effect with the reduced analog. Cell suspensions of L1210 cells were able to phosphorylate 5-azacytidine and, to a lesser extent, 5,6-dihydro-5-azacytidine. In cell-free extracts in the presence of ATP and Mg²⁺, both drugs were converted to nucleotides but at less than 5% the rate of cytidine. As a substrate for mouse kidney cytidine deaminase, the apparent K_m value for 5,6-dihydro-5-azacytidine (33 µM) is of the same order of magnitude as that for cytidine (37 µM) but less than that for 5-azacytidine (2.1 x 10³ µM). The V_m for deamination of the reduced analog is one-tenth that for 5-azacytidine. 3,4,5,6-Tetrahydrouridine, a potent inhibitor of cytidine deaminase, is more effective in blocking deamination of 5-azacytidine than 5,6-dihydro-5-azacytidine.

Received 12/16/76. Accepted 3/23/77.