Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future
Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future
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DOI：
10.1634/theoncologist.2014-0044
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发表时间：
2015-04-01
期刊：
影响因子：
5.8
通讯作者：
Peters, Godefridus J.
中科院分区：
文献类型：
--
作者：
Avan, Abolfazl;Postma, Tjeerd J.;Peters, Godefridus J.
神经毒性是铂类化疗的一个严重副作用，它使患者无法充分发挥有效剂量，并常常导致停药。周围感觉神经毒性从手指感觉异常到步态共济失调不等，可能是短暂的或不可逆的。由于接受这些神经毒性药物治疗的患者数量仍在增加，因此了解这种严重副作用的发病机制是至关重要的。铂衍生物，如顺铂和卡铂，主要损害周围神经和背根神经节神经元，可能是因为DNA加合物的进进式积累和DNA修复途径（如细胞外信号调节激酶1/2、c-Jun n末端激酶/应激激活蛋白激酶和p38丝裂原激活蛋白激酶）的抑制，最终介导细胞凋亡。奥沙利铂具有完全不同的药代动力学特征，也可能通过草酸渣作为钙螯合剂固定钙离子而改变钙敏感的电压门控钠通道动力学，并引起急性神经毒性。一些基因的多态性，如电压门控钠通道基因或影响关键金属转运体活性的基因（如有机阳离子转运体、有机阳离子/肉碱转运体和一些金属转运体，如铜转运体和多药耐药相关蛋白），也可以影响药物神经毒性和治疗反应。然而，大多数药物遗传学研究需要强有力的证据来阐明。关于几种神经保护剂（如维生素E、谷胱甘肽、氨磷汀、沙利proden和文拉法辛）的有效性有支持的报道，但剂量调整和/或停药似乎是铂诱导的周围神经毒性管理中最常用的方法。为了开发治疗铂诱导神经病变的替代方案，在未来的神经保护策略设计中应结合体外模型研究和适当的试验计划，以找到最佳的以患者为导向的解决方案。
Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stressactivated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.