Predictive factors of oxaliplatin neurotoxicity: The involvement of the oxalate outcome pathway
Predictive factors of oxaliplatin neurotoxicity: The involvement of the oxalate outcome pathway
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DOI：
10.1158/1078-0432.ccr-07-0660
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发表时间：
2007-11-01
影响因子：
11.5
通讯作者：
Gamelin, Erick
中科院分区：
文献类型：
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作者：
Gamelin, Laurence;Capitain, Olivier;Gamelin, Erick
目的：奥沙利铂表现出频繁的剂量限制性神经毒性，因为它通过其代谢物之一草酸盐（一种钙螯合剂）干扰神经元电压门控钠通道。除钙镁输注外，不同的临床方法在预防神经毒性方面均失败。我们表征了奥沙利铂给药后的草酸盐结果及其对阳离子和氨基酸的干扰。然后我们寻找奥沙利铂引起的神经毒性的遗传预测因素。实验设计：我们首先测试患者的阳离子和草酸盐水平，并在奥沙利铂输注后进行尿液中的氨基酸色谱图。在第二阶段，在使用 FOLFOX 方案治疗之前，我们前瞻性地寻找编码以下酶的基因变异：(a) 草酸代谢，特别是乙醛酸转氨酶 (AGXT)，(b) 烯氧化谷胱甘肽循环、谷胱甘肽 S-转移酶 pi，以及编码膜流出蛋白 (ABCC2) 的基因。 结果：在前 10 名患者中，尿液中草酸和草酸的排泄量输注奥沙利铂后数小时内，阳离子显着增加，并伴有与草酸代谢相关的四种氨基酸（甘氨酸、丙氨酸、丝氨酸和牛磺酸）的排泄增加。在另外 135 名患者中，发现 AGXT 的次要单倍型可以显着预测急性和慢性神经毒性。我们寻找的谷胱甘肽 S-转移酶 pi 和 ABCC2 单核苷酸多态性均与神经毒性无关。结论：这些数据证实了草酸盐与奥沙利铂神经毒性有关，并支持未来使用 AGXT 基因分型作为治疗前筛选试验来预测个体对神经毒性的易感性。
Purpose: Oxaliplatin displays a frequent dose-limiting neurotoxicity due to its interference with neuron voltage-gated sodium channels through one of its metabolites, oxalate, a calcium chelator. Different clinical approaches failed in neurotoxicity prevention, except calcium-magnesium infusions. We characterized oxalate outcome following oxaliplatin administration and its interference with cations and amino acids. We then looked for genetic predictive factors of oxaliplatin-induced neurotoxicity.Experimental Design: We first tested patients for cations and oxalate levels and did amino acid chromatograms in urine following oxaliplatin infusion. In the second stage, before treatment with FOLFOX regimen, we prospectively looked for variants in genes coding for the enzymes involved (a) in the oxalate metabolism, especially glyoxylate aminotransferase (AGXT), and (b) in the cletoxification glutathione cycle, glutathione S-transferase pi, and for genes coding for membrane efflux proteins (ABCC2).Results: In the first 10 patients, urinary excretions of oxalate and cations increased significantly within hours following oxaliplatin infusion, accompanied by increased excretions of four amino acids (glycine, alanine, serine, and taurine) linked to oxalate metabolism. In a further 135 patients, a minor haplotype of AGXT was found significantly predictive of both acute and chronic neurotoxicity. Neither glutathione S-transferase pi nor ABCC2 single nucleotide polymorphisms we looked for were linked to neurotoxicity.Conclusion: These data confirm the involvement of oxalate in oxaliplatin neurotoxicity and support the future use of AGXTgenotyping as a pretherapeutic screening test to predict individual susceptibility to neurotoxicity.