NITRO-IMIDAZOLE RADIOSENSITIZER-INDUCED TOXICITY IN CYNOMOLGUS MONKEYS

Intravenously administered nitro-imidazole radiosensitizer and alkylat ing anticancer compound CI-1010, designated as (2-bromoethyl)amino]met hyl]-2-nitro-1H-imidazole-1 -ethanol monohydrobromide, causes multiorg an toxicity in rodents, including retinal degeneration. This study det ermined the potential of CI-1010 to induce similar effects in nonhuman primates. One male and 1 female cynomolgus monkey were given single d aily doses of CI-1010 intravenously for 5 consecutive days each week f or 3 wk. Doses were escalated from 5 mg per kilogram of body weight in week 1 to 40 and 60 mg/kg in week 3. Postdosing emesis occurred in bo th monkeys at 5 mg/kg, and clinical signs at 40 and 60 mg/kg included more pronounced emesis, reduced food consumption, pallor, weakness, an d body weight loss. At study termination, both monkeys had markedly re duced peripheral blood lymphocytes and moderately lowered erythrocyte, hemoglobin, and hematocrit levels, which correlate with a decreased t otal nucleated bone marrow cell count. At necropsy, the monkeys had pa ncytic bone marrow hypocellularity, multiorgan lymphoid depletion, pan creatic acinar cell apoptosis, testicular seminiferous tubular degener ation, and bilateral multifocal retinal degeneration involving the pho toreceptor and outer nuclear layers. Ultrastructurally, selected inner and outer retinal rod segments were swollen and fragmented, a state a ssociated with cytoplasmic condensation and pyknosis of the outer nucl ear cell layer. Thus, CI-1010 induced toxicity of hematopoietic/lympho id organs, retina, testes, and pancreas in monkeys, findings similar t o those of previous studies in rodents.