title: Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine.
abstract: OBJECTIVE
  Antineoplastic drugs belonging to platinum or taxane families are severely neurotoxic, inducing the onset of disabling peripheral neuropathies with different clinical signs. Acetyl-L-carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. In this study we have tested the hypothesis that ALC may have a protective role on cisplatin and paclitaxel-induced neuropathy.
  
  
  METHODS
  Sensory nerve conduction velocity (SNCV) was measured in rats before, at end, and after an additional follow-up period from treatments with cisplatin, paclitaxel, or with the respective combination with ALC. In addition, serum from treated animals was collected to measure the levels of circulating NGF, and left sciatic nerves were processed for light and electron microscope observations. ALC interference on cisplatin and paclitaxel antitumor activity and protective mechanisms were investigated using several in vitro and in vivo models.
  
  
  RESULTS
  ALC cotreatment was able to significantly reduce the neurotoxicity of both cisplatin and paclitaxel in rat models, and this effect was correlated with a modulation of the plasma levels of NGF in the cisplatin-treated animals. Moreover, experiments in different tumor systems indicated the lack of interference of ALC in the antitumor effects of cisplatin and paclitaxel. The transcriptional profile of gene expression in PC12 cells indicated that ALC, in the presence of NGF, was able to positively modulate NGFI-A expression, a gene relevant in the rescue from tissue-specific toxicity. Finally, the transcriptionally ALC-mediated effects were correlated to increase histone acetylation.
  
  
  CONCLUSIONS
  In conclusion, our results indicate that ALC is a specific protective agent for chemotherapy-induced neuropathy after cisplatin or paclitaxel treatment without showing any interference with the antitumor activity of the drugs.
authors.affiliation: Research and Development, Sigma-Tau S.p.A. Industrie Farmaceutiche Riunite, Rome, Italy. claudio.pisano@sigmatau.it
authors.forename: Claudio
authors.initials: C
authors.lastname: Pisano
authors.forename: Graziella
authors.initials: G
authors.lastname: Pratesi
authors.forename: Diletta
authors.initials: D
authors.lastname: Laccabue
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.forename: Pietro
authors.initials: P
authors.lastname: Lo Giudice
authors.forename: Augusta
authors.initials: A
authors.lastname: Bellucci
authors.forename: Licia
authors.initials: L
authors.lastname: Pacifici
authors.forename: Barbara
authors.initials: B
authors.lastname: Camerini
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.forename: Massimo
authors.initials: M
authors.lastname: Castorina
authors.forename: Sandra
authors.initials: S
authors.lastname: Cicuzza
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tredici
authors.forename: Paola
authors.initials: P
authors.lastname: Marmiroli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Nicolini
authors.forename: Stefania
authors.initials: S
authors.lastname: Galbiati
authors.forename: Menotti
authors.initials: M
authors.lastname: Calvani
authors.forename: Paolo
authors.initials: P
authors.lastname: Carminati
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
mesh_terms: D000108:Acetylcarnitine / Q000502:physiology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D023421:Models, Animal; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D009498:Neurotoxins; D000108:Acetylcarnitine; D017239:Paclitaxel; D002945:Cisplatin