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.
|Titolo:||Experimental epothilone B neurotoxicity: results of in vitro and in vivo studies|
|Parole Chiave:||animals; skin; dose-response relationship, drug; epothilones; pain threshold; ganglia, spinal; myelin sheath; neurites; rats; body weight; RNA, messenger; rats, sprague-dawley; rats, inbred F344; neurons; rats, wistar; neural conduction; tubulin; neurotoxins; sciatic nerve; female|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
Settore MED/26 - Neurologia
|Data di pubblicazione:||ago-2009|
|Digital Object Identifier (DOI):||10.1016/j.nbd.2009.05.006|
|Appare nelle tipologie:||01 - Articolo su periodico|