Gamelin Erick, Gamelin Laurence, Bossi Laura, Quasthoff Stefan
Centre Paul Papin, Cedex, Austria.
Semin Oncol. 2002 Oct;29(5 Suppl 15):21-33. doi: 10.1053/sonc.2002.35525.
Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Acute neurotoxicity is characterized by the rapid onset of cold-induced distal dysesthesia and/or paresthesia. Sensory symptoms may also be accompanied by cold-dependent muscular contractions of the extremities or the jaw. The symptoms, often occurring during or shortly after infusion, are usually transient and mild. A persistent sensory peripheral neuropathy may also develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia, and functional impairment. Studies have shown patients with acute sensory symptoms to display little or no axonal degeneration, suggesting a specific effect of oxaliplatin on sensory neurons and/or motor neurons or muscle cells that is not observed with other platinum agents. The similarity of the acute symptoms induced by oxaliplatin with those caused by several drugs or toxins acting on neuronal or muscular ion channels suggests that these symptoms may result from a specific interaction of oxaliplatin with ion channels located in the cellular membrane. Recent data indicate that oxaliplatin may act on specific isoforms of the voltage gated sodium (Na(+)) channel to increase the excitability of sensory neurons, an action inhibited by the Na(+) channel blocker carbamazepine. This contention is supported by recent clinical findings indicating that pharmacologic blockade of Na(+) channels may prevent and/or repress the acute neurotoxicity of oxaliplatin. Although there is no indication at the moment that a common cellular mechanism induces both the acute and the cumulative neurotoxicity of oxaliplatin, controlled clinical trials are currently underway to establish the value of Na(+) channel blockade against both acute and cumulative oxaliplatin neurotoxicities.
神经毒性是奥沙利铂最常见的剂量限制性毒性。急性神经毒性的特征是迅速出现冷诱导的远端感觉异常和/或感觉异常。感觉症状也可能伴有四肢或下颌的冷依赖性肌肉收缩。这些症状通常在输注期间或输注后不久出现，通常是短暂且轻微的。长期治疗也可能会发展为持续性感觉性周围神经病变，最终导致浅感觉和深感觉丧失、感觉性共济失调及功能障碍。研究表明，有急性感觉症状的患者几乎没有或没有轴突退变，这表明奥沙利铂对感觉神经元和/或运动神经元或肌肉细胞有特定作用，而其他铂类药物未观察到这种作用。奥沙利铂诱发的急性症状与几种作用于神经元或肌肉离子通道的药物或毒素所引起的症状相似，这表明这些症状可能是奥沙利铂与细胞膜上离子通道特异性相互作用的结果。最近的数据表明，奥沙利铂可能作用于电压门控钠（Na(+)）通道的特定亚型，以增加感觉神经元的兴奋性，钠通道阻滞剂卡马西平可抑制这一作用。最近的临床研究结果支持了这一观点，即钠通道的药理阻断可能预防和/或抑制奥沙利铂的急性神经毒性。尽管目前没有迹象表明存在一种共同的细胞机制可诱发奥沙利铂的急性和累积性神经毒性，但目前正在进行对照临床试验，以确定钠通道阻断对奥沙利铂急性和累积性神经毒性的价值。
