A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels
A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels
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DOI：
10.1152/jn.2001.85.5.2293
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发表时间：
2001-05-01
影响因子：
2.5
通讯作者：
Gamelin, E
中科院分区：
文献类型：
--
作者：
Grolleau, F;Gamelin, L;Gamelin, E
奥沙利铂是一种新的广泛使用的抗癌药物，它表现出频繁的、有时是严重的急性感觉神经毒性，并伴有神经肌肉症状，看起来像手足抽搐和肌强直的症状。采用全细胞膜片钳技术，研究了草酸铂对短期培养的美洲大蠊中枢神经系统背不配对正中神经元电生理特性的影响。在临床浓度范围内，细胞内应用奥沙利铂(40-500微米)可降低电压门控钠电流的幅度，使动作电位的幅度降低一半。作为比较，另外两个铂的衍生物，顺铂和卡铂，被发现在降低钠电流幅度方面无效。此外，我们还比较了奥沙利铂与其代谢物二氯二氨基环己烷铂(DACH-Cl-2-Platin)和草酸盐的作用。与草酸铂一样，草酸盐(500um)能有效地降低内向钠电流的幅度，而dach-Cl-2-Platin(500um)不能改变电流幅度。有趣的是，用10 mM的双(邻氨基苯氧基)-N，N，N‘，N’-四乙酸(BAPTA)作为钙离子的螯合剂，可以模拟草酸或奥沙利铂的作用。我们得出结论，奥沙利铂能够通过钙离子途径改变电压门控钠通道，钙离子可能被其代谢物草酸固定。讨论了通过输注Ca~(2+)和Mg~(2+)预防奥沙利铂急性神经毒性副作用的医学意义。
Oxaliplatin, a new widely used anticancer drug, displays frequent, sometimes severe, acute sensory neurotoxicity accompanied by neuromuscular signs that look like the symptoms observed in tetany and myotonia. The whole cell patch-clamp technique was employed to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons isolated from the CNS of the cockroach Periplaneta americana. Within the clinical concentration range, oxaliplatin (40-500 muM), applied intracellularly, decreased the amplitude of the voltage-gated sodium current resulting in a reduction of half the amplitude of the action potential. For comparison, two other platinum derivatives, cisplatin and carboplatin, were found to be ineffective at reducing the sodium current amplitude. In addition, we compared the oxaliplatin action to those of its metabolites dichlorodiaminocyclohexane platinum (dach-Cl-2-platin) and oxalate. Oxalate (500 muM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl-2-platin (500 muM) failed to change the current amplitude. Interestingly, the effect of oxalate or oxaliplatin could be mimicked by using intracellularly applied 10 mM bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA), known as chelator of calcium ions. We concluded that oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving calcium ions probably immobilized by its metabolite oxalate. The medical interest of preventing acute neurotoxic side effects of oxaliplatin by infusing Ca2+ and Mg2+ is discussed.