Preclinical evaluation of hematopoietic toxicity of antileukemic agent, 5-aza-2'-deoxycytidine.

The hematopoietic toxicity of 5-aza-2'-deoxycytidine (5-AZA-CdR), an experimental antileukemic agent, was investigated in mice and dogs. Mice were administered a 12 h intravenous infusion of 5-AZA-CdR at a total dose of 20 mg/kg and at different times after treatment samples of bone marrow were analyzed for cell count, DNA synthesis and colony-forming activity (CFUc). The 5-AZA-CdR treatment produced a marked decrease in femur cell count and CFUc activity with recovery occurring on days 8-14. DNA synthesis activity increased significantly during the recovery period. Dogs were also administered a 12 h intravenous infusion at doses 3-7 mg/kg and the blood hemogram evaluated. This treatment produced a pronounced leukopenia, granulocytopenia and thrombocytopenia with a nadir between days 7-16 with recovery occurring on days 19-21. These results indicate that 5-AZA-CdR produces marked hematopoietic toxicity in mice and dogs and this toxicity appears to be reversible under these experimental conditions.