Toxicology in Mice of the Antileukemic Agent 5-AZA-2'-Deoxycytidine

Abstract

The toxic effects of 5-AZA-2'-deoxycytidine (5-AZA-CdR) administered as a 12 hr. i.v. continuous infusion to CD2F₁ (Balb/c × DBA/2) mice were investigated. This i.v. route of administration of 5-AZA-CdR was chosen because it produced a potent anti-neoplastic effect in leukemic mice and would probably be the route used for clinical trials of this agent. The LD50 of 5-AZA-CdR for male and female CD2F₁ mice was estimated to be 29.5 and 22.2 mg/ kg, respectively. A toxic dose of 5-AZA-CdR produced a leuko-penia, thrombocytopenia, and weight loss in the mice. Most of these toxic effects were reversible with the exception of leuko-penia with was still present 43 days after the infusion. Histo-pathological analysis of the mice during the acute toxic phase (day 7) and the recovery period (day 28) showed that 5-AZA-CdR at a dose close to the LD₅₀ produced bone marrow hypoplasia, necrosis of the small intestinal mucosa and atrophy of thymus and testes. All these pathological lesions were reversible. The toxic effects produced by 5-AZA-CdR are consistent with its biological action, an agent that is cytotoxic to only proliferating cells.