RETINAL DEGENERATION IN RATS INDUCED BY CI-1010, A 2-NITROIMIDAZOLE RADIOSENSITIZER

The anti-cancer compound CI-1010, designated as ethyl)amino]methyl)-2- nitro-1H-imidazole-1-ethanol monohydrobromide, has a proposed dual mec hanism of action due to alkylating and radiosensitizing activities. To assess potential toxicity, adult Wistar rats were treated with a sing le intravenous injection (0, 50, 100, 150, 225, or 350 mg/kg) and necr opsied at 4 or 29 days following treatment. In a repeated dose experim ent, 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 retina l degeneration by 4 days after a single injection of greater than or e qual to 225 mg/kg or by 3 wk of repeated injections of greater than or equal to 40 mg/kg. The locally extensive to diffuse retinal degenerat ion involved the photoreceptor and outer nuclear layer. The photorecep tor layer was vacuolated and compressed corresponding to ultrastructur al evidence of inner segment swelling and outer segment fragmentation. The outer nuclear layer was thinned due to loss of nuclei and contain ed numerous pyknotic or karyorrhectic nuclei. These nuclear changes we re morphologically consistent with apoptosis and many outer nuclear la yer nuclei labeled with in situ TdT-mediated dUTP-digoxigenin nick end labeling (Apoptag(R)). The retinal degeneration was nonreversible, ev idenced by increased lesion severity and incidence after CI-1010 was w ithdrawn for either 25 or 28 days.