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.

Experimental epothilone B neurotoxicity: results of in vitro and in vivo studies / A. Chiorazzi, G. Nicolini, A. Canta, N. Oggioni, R. Rigolio, G. Cossa, R. Lombardi, I. Roglio, I. Cervellini, G. Lauria, C. Melcangi, R. Bianchi, D. Crippa, G. Cavaletti. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 35:2(2009 Aug), pp. 270-277.

Experimental epothilone B neurotoxicity: results of in vitro and in vivo studies

I. Roglio;G. Lauria;C. Melcangi;
2009-08

Abstract

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.
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 MED/13 - Endocrinologia
Settore MED/26 - Neurologia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/180297
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