Nitro-imidazole radiosensitizer-induced toxicity in cynomolgus monkeys. 1998

M A Breider, and H M Ulloa, and D G Pegg, and A W Gough
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105, USA. Breidem@aa.wl.com

Intravenously administered nitro-imidazole radiosensitizer and alkylating anticancer compound CI-1010, designated as (R)-alpha-[[(2-bromoethyl)amino]methyl]-2-nitro-1H-imidazole-1-ethanol monohydrobromide, causes multiorgan toxicity in rodents, including retinal degeneration. This study determined the potential of CI-1010 to induce similar effects in nonhuman primates. One male and 1 female cynomolgus monkey were given single daily doses of CI-1010 intravenously for 5 consecutive days each week for 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 both monkeys at 5 mg/kg, and clinical signs at 40 and 60 mg/kg included more pronounced emesis, reduced food consumption, pallor, weakness, and body weight loss. At study termination, both monkeys had markedly reduced peripheral blood lymphocytes and moderately lowered erythrocyte, hemoglobin, and hematocrit levels, which correlate with a decreased total nucleated bone marrow cell count. At necropsy, the monkeys had pancytic bone marrow hypocellularity, multiorgan lymphoid depletion, pancreatic acinar cell apoptosis, testicular seminiferous tubular degeneration, and bilateral multifocal retinal degeneration involving the photoreceptor and outer nuclear layers. Ultrastructurally, selected inner and outer retinal rod segments were swollen and fragmented, a state associated with cytoplasmic condensation and pyknosis of the outer nuclear cell layer. Thus, CI-1010 induced toxicity of hematopoietic/lymphoid organs, retina, testes, and pancreas in monkeys, findings similar to those of previous studies in rodents.

UI MeSH Term Description Entries
D008252 Macaca fascicularis A species of the genus MACACA which typically lives near the coast in tidal creeks and mangrove swamps primarily on the islands of the Malay peninsula. Burmese Long-Tailed Macaque,Crab-Eating Monkey,Cynomolgus Monkey,M. f. aurea,M. fascicularis,Macaca fascicularis aurea,Monkey, Crab-Eating,Monkey, Cynomolgus,Crab-Eating Macaque,Burmese Long Tailed Macaque,Crab Eating Macaque,Crab Eating Monkey,Crab-Eating Macaques,Crab-Eating Monkeys,Cynomolgus Monkeys,Long-Tailed Macaque, Burmese,Macaque, Burmese Long-Tailed,Macaque, Crab-Eating,Monkey, Crab Eating
D008297 Male Males
D009593 Nitroimidazoles IMIDAZOLES having a nitro moiety. Nitroimidazole
D010182 Pancreatic Diseases Pathological processes of the PANCREAS. Disease, Pancreatic,Diseases, Pancreatic,Pancreatic Disease
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D011838 Radiation-Sensitizing Agents Drugs used to potentiate the effectiveness of radiation therapy in destroying unwanted cells. Radiation Sensitizer,Radiosensitizing Agent,Radiosensitizing Agents,Agents, Radiation-Sensitizing,Radiation Sensitizers,Radiation Sensitizing Agents,Radiation-Sensitizing Drugs,Radiation-Sensitizing Effect,Radiation-Sensitizing Effects,Radiosensitizing Drugs,Radiosensitizing Effect,Radiosensitizing Effects,Agent, Radiosensitizing,Agents, Radiation Sensitizing,Agents, Radiosensitizing,Drugs, Radiation-Sensitizing,Drugs, Radiosensitizing,Effect, Radiation-Sensitizing,Effect, Radiosensitizing,Effects, Radiation-Sensitizing,Effects, Radiosensitizing,Radiation Sensitizing Drugs,Radiation Sensitizing Effect,Radiation Sensitizing Effects,Sensitizer, Radiation,Sensitizers, Radiation,Sensitizing Agents, Radiation
D012164 Retinal Diseases Diseases involving the RETINA. Disease, Retinal,Diseases, Retinal,Retinal Disease
D001835 Body Weight The mass or quantity of heaviness of an individual. It is expressed by units of pounds or kilograms. Body Weights,Weight, Body,Weights, Body
D001855 Bone Marrow Diseases Diseases involving the BONE MARROW. Bone Marrow Disease,Disease, Bone Marrow,Diseases, Bone Marrow,Marrow Disease, Bone,Marrow Diseases, Bone
D005260 Female Females

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