Jamieson S M F, Liu J, Hsu T, Baguley B C, McKeage M J
1Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Br J Cancer. 2003 Jun 16;88(12):1942-7. doi: 10.1038/sj.bjc.6601012.
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.
紫杉醇和奥沙利铂是用于联合试验的有前景的药物，但二者都会诱发周围神经毒性。为了研究这种毒性，给10周龄的雌性Wistar大鼠腹腔注射单剂量的紫杉醇和奥沙利铂，单独给药或联合给药。通过L5背根神经节形态测定和H反射相关的感觉神经传导速度评估神经毒性。采用电感耦合等离子体质谱法测定背根神经节和血浆中的铂浓度。单剂量给予10和20mg/kg（-1）的紫杉醇后24小时和6天时，背根神经节核仁大小显著增加（P<0.02）。相比之下，单剂量给予3至30mg/kg（-1）的奥沙利铂后，在2小时至14天的时间点，背根神经节核仁大小显著减小。单剂量给予奥沙利铂后感觉神经传导速度改变，但给予紫杉醇后未改变。与奥沙利铂联合使用时，紫杉醇不会改变奥沙利铂衍生铂的血浆药代动力学或背根神经节蓄积。然而，预先给予紫杉醇可抑制奥沙利铂诱导的背根神经节核仁直径减小（P<0.02）。单独给予奥沙利铂后感觉神经传导速度降低（P<0.05），但在奥沙利铂之前给予紫杉醇时感觉神经传导速度未改变。总之，在体内给予药理相关剂量的紫杉醇后可诱导背根神经节神经元核仁增大，并减轻奥沙利铂的核仁损伤和神经毒性。
