title: Paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons in vivo reducing oxaliplatin toxicity.
abstract: Paclitaxel and oxaliplatin are promising drugs for combination trials but both induce peripheral neurotoxicity. To investigate this toxicity, 10-week-old female Wistar rats were given single intraperitoneal doses of paclitaxel and oxaliplatin, alone or in combination. Neurotoxicity was assessed by L5 dorsal root ganglion morphometry and H-reflex-related sensory nerve conduction velocity. Platinum concentrations in dorsal root ganglia and plasma were measured by inductively coupled plasma mass spectrometry. Dorsal root ganglion nucleolus size was significantly increased following single doses of paclitaxel of 10 and 20 mg kg(-1) at 24 h and 6 days (P<0.02). In contrast, dorsal root ganglion nucleolus size was significantly decreased following single doses of oxaliplatin ranging from 3 to 30 mg kg(-1) at time points ranging from 2 h to 14 days. Sensory nerve conduction velocity was altered after a single dose of oxaliplatin but not after paclitaxel. In combination with oxaliplatin, paclitaxel did not alter the plasma pharmacokinetics or dorsal root ganglion accumulation of oxaliplatin-derived platinum. However, prior paclitaxel inhibited oxaliplatin-induced reductions of dorsal root ganglion nucleolar diameter (P<0.02). Sensory nerve conduction velocity was reduced after oxaliplatin alone (P&<0.05) but unchanged when paclitaxel was given before oxaliplatin. In conclusion, paclitaxel induces nucleolar enlargement in dorsal root ganglion neurons after pharmacologically relevant doses in vivo and reduces oxaliplatin nucleolar damage and neurotoxicity.
authors.affiliation: 1Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: S M F
authors.initials: SM
authors.lastname: Jamieson
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Hsu
authors.forename: B C
authors.initials: BC
authors.lastname: Baguley
authors.forename: M J
authors.initials: MJ
authors.lastname: McKeage
mesh_terms: D000367:Age Factors; D000818:Animals; D004359:Drug Therapy, Combination; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D017239:Paclitaxel