Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding
Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding
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DOI：
10.1016/j.neuro.2006.04.010
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发表时间：
2006-12-01
期刊：
影响因子：
3.4
通讯作者：
Windebank, Anthony J.
中科院分区：
文献类型：
--
作者：
Ta, Lauren E.;Espeset, Laura;Windebank, Anthony J.
顺铂已使用 40 年，主要用于治疗卵巢癌和睾丸癌。奥沙利铂是治疗转移性结直肠癌的唯一有效方法。高达 30% 的患者会出现神经毒性，并且这两种药物都有剂量限制。神经病的特征是四肢选择性感觉丧失。顺铂治疗与高水平的 Pt-DNA 结合和背根神经节 (DRG) 神经元凋亡有关。在本研究中，我们直接比较了奥沙利铂在体外对 DRG 的影响。与顺铂相比，奥沙利铂在 6、12、24 和 48 小时后形成的 Pt-DNA 加合物较少（0.007 ng Pt/mu g DNA、0.012 ng/mu g、0.011 ng/mu g、0.011 ng/mu g 与 0.014 ng/mu g、0.022 ng/mu g、分别为0.041 ng/μg、0.030 ng/μg)。这些发现与细胞存活数据密切相关，其中等摩尔浓度的奥沙利铂诱导的细胞死亡少于顺铂。奥沙利铂诱导的 DRG 死亡与通过 4'-6-二脒基-2-苯基吲哚和膜联蛋白/碘化丙啶染色定义的细胞凋亡的形态学特征相关。 Caspase 抑制剂 z-VAD-fmk 完全抑制了死亡。我们的结果表明，两种化合物都会引起 DRG 神经元凋亡，但与顺铂相比，奥沙利铂形成的 Pt-DNA 加合物较少，并且在体外对 DRG 神经元的神经毒性较小。 (c) 2006 Elsevier Inc. 保留所有权利。
Cisplatin has been in use for 40 years, primarily for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Neurotoxicity occurs in up to 30% of patients and is dose-limiting for both drugs. The neuropathy is characterized by selective sensory loss in the extremities. Cisplatin treatment is associated with high levels of Pt-DNA binding and apoptosis of dorsal root ganglion (DRG) neurons. In this study, we directly compared the effects of oxaliplatin on DRG in vitro. Compared with cisplatin, oxaliplatin formed fewer Pt-DNA adducts following 6, 12, 24, and 48 h (0.007 ng Pt/mu g DNA, 0.012 ng/mu g, 0.011 ng/mu g, 0.011 ng/mu g versus 0.014 ng/mu g, 0.022 ng/mu g, 0.041 ng/mu g, 0.030 ng/mu g), respectively. These findings closely correlated with data on cell survival where equimolar concentrations of oxaliplatin induced less cell death than cisplatin. Oxaliplatin-induced DRG death was associated with the morphological characteristics of apoptosis defined by 4'-6-diamidino-2-phenylindole and annexin/propidium iodide staining. Death was completely inhibited by the caspase inhibitor z-VAD-fmk. Our results demonstrate that both compounds cause apoptosis of DRG neurons but compared to cisplatin, oxaliplatin forms fewer Pt-DNA adducts and is less neurotoxic to DRG neurons in vitro. (c) 2006 Elsevier Inc. All rights reserved.