Nitro-imidazole radiosensitizer-induced toxicity in cynomolgus monkeys.
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.
Breider
M A
MA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division of Warner-Lambert Co., Ann Arbor, Michigan 48105, USA. Breidem@aa.wl.com
Ulloa
H M
HM
Pegg
D G
DG
Gough
A W
AW
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D008252:Macaca fascicularis; D008297:Male; D009593:Nitroimidazoles / Q000633:toxicity*; D010182:Pancreatic Diseases / Q000139:chemically induced; D011355:Prodrugs / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*; D012164:Retinal Diseases / Q000139:chemically induced; D013733:Testicular Diseases / Q000139:chemically induced
D009593:Nitroimidazoles; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; C067834:RB 6145