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

Abstract

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.

Expression of Serine/Threonine Protein-Kinases and Related Factors in Normal Monkey and Human Retinas: The Mechanistic Understanding of a CDK2 Inhibitor Induced Retinal Toxicity

“…The same type of retinal toxicity with a non-selective 'pan'-CDK inhibitor was recently observed in mice (Illanes et al, 2006). Also in this case after systemic exposure, the injury was localized at the photoreceptors layer and they supposed the inhibition of CDK5 as a possible cause of the observed damage.…”

Knockdown of Cyclin-dependent Kinase 10 (cdk10) Gene Impairs Neural Progenitor Survival via Modulation of raf1a Gene Expression

“…By contrast, cdk5 was found to support neuronal survival by Bcl-2 phosphorylation (40) and significantly influence the extension and maintenance of axons as well as the stability and steering of RGCs (41). Administration of the pan-CDK inhibitor AG-012986 also induced apoptosis in retina cells (42).…”

A current practice for predicting ocular toxicity of systemically delivered drugs

“…During the development of a new medicine, pharmaceutical companies use animal models to identify, characterize, and manage risk of adverse ocular side effects in patients (6). However, the identification of an ocular safety concern during traditional animal toxicity testing can occur after millions of dollars and many years of research and development have been spent on a particular drug development program (7). Moreover, the welfare of animals used in traditional animal toxicity testing is a concern of the public (8).…”