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Epothilones are a novel class of microtubule-targeting anticancer agents that are neurotoxic. In this study, we investigated the epothilone B toxic effect in vitro and we characterized in vivo the general and neurological side effects of epothilone B administration in Wistar and Fischer rats. The in vitro experiments made it possible to explore a wide concentration range (0.1 nM-1 muM) and evidenced a dose-dependent effect of epothilone B exposure on neuron neurite elongation. This dose-dependent neurotoxic effect was confirmed in both in vivo studies performed on two different rat strains at the neurophysiological, behavioral and pathological levels in the dose range 0.25-1.5 mg/kg iv weekly x 4 weeks and tubulin hyper-polymerization was demonstrated in sciatic nerve specimens. These are the first studies of the neurological effects of epothilone B and they can provide a basis for extending pre-clinical investigation to other members of the epothilone family.

Original publication

DOI

10.1016/j.nbd.2009.05.006

Type

Journal article

Journal

Neurobiol Dis

Publication Date

08/2009

Volume

35

Pages

270 - 277

Keywords

Animals, Body Weight, Dose-Response Relationship, Drug, Epothilones, Female, Ganglia, Spinal, In Vitro Techniques, Myelin Sheath, Neural Conduction, Neurites, Neurons, Neurotoxins, Pain Threshold, RNA, Messenger, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Rats, Wistar, Sciatic Nerve, Skin, Tubulin