Preclinical Toxicologic Evaluation of Aziridinyl Benzoquinone (NSC-182,986) in Dogs, Monkeys and Mice

摘要

Aziridinyl benzoquinone (NSC-182,986) was compatible with canine plasma and serum, but caused hemolysis until it was diluted to a 1:16 concentration. The vehicle alone also caused hemolysis until it was diluted to a 1:8 concentration. The intravenous LD50 study in CDF1 mice revealed no sex related differences in response to AZQ. The LD50 for males was 11.4 mg/kg and for females 11.1 mg/kg. AZQ caused significant toxicity to lymphoid tissue, bone marrow and intestinal tract of dogs and monkeys when administered at the TDH or greater, regardless of dose regimen. Lymphoid toxicity was expressed as lymphoid depletion. Bone marrow toxicity was demonstrated by hematologic changes (leukopenia, reticulocytopenia, thrombocytopenia, decreased hematocrit, hemoglobin and erythrocytes) and by hypocellularity of the bone marrow. Clinical signs (anorexia, emesis, diarrhea, blood and mucous in the feces and weight loss) and histopathologic lesions (degeneration and depletion of the crypt epithelium) characterized AZQ-induced intestinal changes. Other, less consistent, sites of AZQ toxicity included the liver (increased serum enzyme levels and centrilobular congestion) and the kidney (elevated BUN and creatinine levels and tubule dilation). AZQ was less toxic in monkeys than dogs when compared on the per cu m basis. AZQ was equitoxic in dogs whether given as a single i.v. dose or five daily i.v. doses, when the total dose given is compared. AZQ appears to be more toxic, however, when given on an intermittent basis of five daily i.v. doses followed by 9 days, repeated three times or if given as a single i.v. dose on a weekly basis.