Peripheral neuropathy is regularly observed as a side-effect in microtubule-targeted chemotherapies. The length of their axons, together with the absence of protection by a blood brain barrier, renders peripheral neurons particularly vulnerable to disturbances in microtubule dynamics.
The present AOP was developed to summarize mechanistic data that support the link between the interaction of “microtubule stabilizing agents” with microtubules (MIE) and sensory axonal peripheral neuropathy (AO), via disturbances in microtubule dynamic instability (KE1) and an impaired axonal transport (KE2).
The present AOP allowed the identification of the following knowledge gaps in the literature: (i) experimental support for the mechanistic link of microtubule interacting drugs with the onset of sensory axonal peripheral neuropathy is generally limited by laborious and circumstantial access to peripheral neurons in vivo and by limited availability of human in vitro models of peripheral neurons; (ii) it is necessary to distinguish the biological consequences of microtubule-stabilizing drugs on the one side, and microtubule-destabilizing compounds on the other; (iii) the link of clinical symptoms to the action of microtubule stabilizers is complicated by incomplete toxicokinetic data, by the time offset between drug treatment and clinical symptoms, and by partial reversibility of the AO following washout of the microtubule-interacting drugs.
The present AOP was developed to contribute to cross systems testing as well as to experimental studies covering the testing of National Toxicology Program compounds.