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The antiproliferative effects of 5-azacytidine (acaCyd) and 5-aza-2'-deoxycytidine (azadCyd) were studied in murine B16 melanoma and a series of B16 melanoma derived mutant strains with selective resistances to the respective drugs. The in vitro cytotoxicities of azaCyd and azadCyd on B16 wild type, expressed in terms of IC50 values, were found to be 5 microM and 0.2 microM, respectively. The in vitro cytotoxicity of both drugs was dependent on the duration of exposure. Uridine and cytidine were able to reverse the in vitro cytotoxicity of azaCyd, but not of azadCyd. Conversely, 2'-deoxycytidine was able to reverse the cytotoxic effect of azadCyd but not of azaCyd. Thymidine and 2'-deoxyuridine had no detectable effects on the in vitro cytotoxicity of either azaCyd or azadCyd. B16 melanoma mutant strains that were selected for resistance to azaCyd showed no cross-resistance to azadCyd, cytosine arabinoside or the fluorinated pyrimidine analogues FUrd, FCyd, FdUrd and FdCyd. Mutant strains that were selected for resistance to azadCyd showed no cross-resistance to azaCyd or fluorinated pyrimidine analogs, but only to cytosine arabinoside. The combined data suggest that azaCyd and azadCyd follow different routes of intracellular metabolic activation and exert their cytotoxic activity via different intracellular targets.
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