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

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