Experimental epothilone B neurotoxicity: results of in vitro and in vivo studies.
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.
Chiorazzi
Alessia
A
Department of Neuroscience and Biomedical Technologies, University of Milan Bicocca, Monza, Italy. a.chiorazzi@campus.unimib.it
Nicolini
Gabriella
G
Canta
Annalisa
A
Oggioni
Norberto
N
Rigolio
Roberta
R
Cossa
Giacomo
G
Lombardi
Raffaella
R
Roglio
Ilaria
I
Cervellini
Ilaria
I
Lauria
Giuseppe
G
Melcangi
Roberto Cosimo
RC
Bianchi
Roberto
R
Crippa
Donatella
D
Cavaletti
Guido
G
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D009186:Myelin Sheath / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000008:administration & dosage / Q000633:toxicity*; D017288:Pain Threshold / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D012867:Skin / Q000187:drug effects / Q000294:innervation; D014404:Tubulin / Q000378:metabolism
D034261:Epothilones; D009498:Neurotoxins; D012333:RNA, Messenger; D014404:Tubulin; C093788:epothilone B