Retinal degeneration in rats induced by CI-1010, a 2-nitroimidazole radiosensitizer.
The anti-cancer compound CI-1010, designated as (R)-alpha-([(2-bromoethyl)amino]methyl)-2-nitro-1H-imidazole-1-ethanol monohydrobromide, has a proposed dual mechanism of action due to alkylating and radiosensitizing activities. To assess potential toxicity, adult Wistar rats were treated with a single intravenous injection (0, 50, 100, 150, 225, or 350 mg/kg) and necropsied at 4 or 29 days following treatment. In a repeated dose experiment, rats were injected daily (0, 10, 40, or 80 mg/kg; 5 doses/wk) for 3 wk and necropsied at the end of week 3 or 7. CI-1010 induced retinal degeneration by 4 days after a single injection of > or = 225 mg/kg or by 3 wk of repeated injections of > or = 40 mg/kg. The locally extensive to diffuse retinal degeneration involved the photoreceptor and outer nuclear layer. The photoreceptor layer was vacuolated and compressed corresponding to ultrastructural evidence of inner segment swelling and outer segment fragmentation. The outer nuclear layer was thinned due to loss of nuclei and contained numerous pyknotic or karyorrhectic nuclei. These nuclear changes were morphologically consistent with apoptosis and many outer nuclear layer nuclei labeled with in situ TdT-mediated dUTP-digoxigenin nick end labeling (Apoptag). The retinal degeneration was nonreversible, evidenced by increased lesion severity and incidence after CI-1010 was withdrawn for either 25 or 28 days.
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
Pilcher
G D
GD
Graziano
M J
MJ
Gough
A W
AW
D000287:Administration, Topical; D000818:Animals; D005123:Eye / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D008297:Male; D009593:Nitroimidazoles / Q000633:toxicity*; D011355:Prodrugs / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012162:Retinal Degeneration / Q000139:chemically induced* / Q000473:pathology
D009593:Nitroimidazoles; D011355:Prodrugs; D011838:Radiation-Sensitizing Agents; C067834:RB 6145