Single Dose Acute Toxicity in Mice and Dose Range-Finding in Dogs ofMorpholinodoxorubicin (NSC-354646)

摘要

The antineoplastic Morpholinodoxorubicin (NSC-354646) was given intravenously asa single dose to male CD2F1 mice at the dose levels of 30-100 microgram/kg and to male and female beagle dogs at the dose levels of 3-90 microgram/kg. The maximally tolerated dose was a single intravenous injection of 60 microgram/kg in both species. In mice, dose-related delayed toxicity of general health deterioration, gastrointestinal distress, dehydration, and emaciation were observed on days 2-15, and mortality was observed on days 7-13. In dogs, readily reversible ataxia, decreased activity and head shaking were observed immediately after dosing with 30-90 microgram/kg, which was followed, within a few hours, by emesis or diarrhea. No further clinical signs were observed in dogs until days 11 and 12, when the male dog treated with 90 microgram/kg exhibited decreased activity and limping. This dog was sacrificed moribund on day 12 due to severe leukopenia and thrombocytopenia. Clinical pathologic and histopathologic data indicated target organ toxicity to the bone marrow and lymphoid tissues in both species and to the small and large intestines in mice. Reversibility was evident in surviving mice, but the recovery was incomplete by day 15 in the bone marrow, thymus, and small intestine.