Retinal and Peripheral Nerve Toxicity Induced by the Administration of a Pan-Cyclin Dependent Kinase (cdk) Inhibitor in Mice:

摘要: Cyclin-dependent kinases (cdks) play a crucial role in cell cycle regulation and are considered promising targets for cancer therapy. Intravenous administration of AG-012986, pan-cyclin-dependent kinase inhibitor (cdki), resulted unexpected retinal peripheral nerve toxicity mice. AG-012986 was administered daily to CD-1 or B6C3F1 mice 5 consecutive days. Mice were euthanized 24 h after the last dose (study day 6) 21-day post-dose period 26). Compound related microscopic findings seen sciatic nerves (axonal degeneration) both strains retina (retinal degeneration/atrophy) only period. Although degeneration/atrophy not detected by routine histology on 6, apoptotic cells evident at this time using TUNEL assay. To our knowledge secondary cdkis has been previously reported. pathogenesis these lesions is unclear, toxicities may reflect unique profile cdk inhibition, off-target inhibition receptor binding, metabolism/distribution properties AG-012986. Multi-targeted-inhibitors interfere with cdks other involved wide range functions than regulation, which could result that hinder their clinical applications.