Chemical basis for the detoxification of cisplatin-derived hydrolysis products by sodium thiosulfate
Chemical basis for the detoxification of cisplatin-derived hydrolysis products by sodium thiosulfate
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DOI：
10.1016/j.jinorgbio.2016.06.012
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发表时间：
2016-09-01
影响因子：
3.9
通讯作者：
George, Graham N.
中科院分区：
文献类型：
--
作者：
Sooriyaarachchi, Melani;Gailer, Jurgen;George, Graham N.
顺铂仍然是使用最广泛的铂类抗癌药物，并被列入世界卫生组织的基本药物清单。顺铂也表现出严重的毒副作用，特别是对肾脏和内耳的损害，这被认为主要来自比顺铂本身毒性更大的水解产物。选择性失活这些水解产物已成为减轻副作用和将顺铂转化为更好的药物的可行策略。硫代硫酸钠是目前考虑的最有希望的缓减剂之一，大量与顺铂共同施用已被证明可以大大减少动物的毒副作用，而不会取消有用的抗癌细胞毒性。然而，这种对抗的结构基础仍然不确定。本文报道了顺铂与硫代硫酸盐在水溶液中水解反应产物的x射线吸收光谱结构表征。这揭示了Pt- s键长为230埃的四坐标Pt（II）物质[Pt(S2O3)(4)]（6-）的形成。我们的结构结论得到了密度泛函理论计算的支持。更一般地说，这种pt -硫代硫酸盐复合物的结构特征重新激活了通过共同施用适当的改进剂来降低顺铂（以及可能的其他铂基抗癌药物）毒性的主要策略，从而使患者直接受益。(C) 2016年由Elsevier Inc.出版。
Cisplatin remains the most widely used platinum-based anti-cancer drug and is included on the World Health Organization's list of essential medicines. Cisplatin also exhibits severe toxic side-effects, in particular damage to both the kidney and the inner ear, which are thought to derive primarily from hydrolysis products that are more toxic than cisplatin itself. Selective inactivation of these hydrolysis products has emerged as a feasible strategy to mitigate side effects and transform cisplatin into a better medicinal drug. Sodium thiosulfate is one of the most promising of currently considered mitigation agents, and co-administration of large quantities with cisplatin has been shown to considerably reduce toxic side effects in animals without abolishing useful anti-cancer cytotoxicity. The structural basis of this antagonism has, however, remained uncertain. We report herein the structural characterization of the reaction product of hydrolyzed cisplatin and thiosulfate in aqueous solution using X-ray absorption spectroscopy. This reveals the formation of the four-coordinate Pt(II) species [Pt(S2O3)(4)](6-) with Pt-S bond lengths of 230 angstrom. Our structural conclusions are supported by density functional theory calculations. More generally speaking, the structural characterization of this Pt-thiosulfate complex reinvigorates the principle strategy to reduce the toxicity of cisplatin (and possibly other platinum-based anti-cancer drugs) by co-administering appropriate ameliorating agents for direct benefits to patients. (C) 2016 Published by Elsevier Inc.