谷胱甘肽S-转移酶P1基因Ile(105)Val多态性与多西他赛诱导的周围神经病变的关系：氧化应激在紫杉烷毒性中作用的临床证据

Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity.

作者信息

Mir O, Alexandre J, Tran A, Durand J-P, Pons G, Treluyer J-M, Goldwasser F

机构信息

Department of Medical Oncology, Teaching Hospital Cochin, Université Paris Descartes, Assistance Publique Hôpitaux de Paris, Paris, France.

出版信息

Ann Oncol. 2009 Apr;20(4):736-40. doi: 10.1093/annonc/mdn698. Epub 2009 Feb 17.

DOI:10.1093/annonc/mdn698

PMID:19223573

Abstract

BACKGROUND

Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN).

PATIENTS AND METHODS

The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile(105)Val and Ala(114)Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade > or = 2 DIPN as primary end point was studied.

RESULTS

Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 (105)Ile/(105)Ile genotype had a higher risk of developing a grade > or = 2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17-31.94; P = 0.03). In multivariate analysis, grade > or = 2 DIPN was strongly correlated with GSTP1 (105)Ile/(105)Ile genotype (P = 0.01) and the number of cycles (P = 0.03).

CONCLUSION

We found a significant correlation between GSTP1 (105)Ile/(105)Ile genotype and the development of grade > or = 2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

摘要

背景

谷胱甘肽 - S - 转移酶（GST）调节细胞对氧化应激的反应。我们之前强调了氧化应激在紫杉烷毒性中的重要性，因此研究了GST同工型M1、T1和P1基因多态性与多西他赛（泰索帝）诱导的周围神经病变（DIPN）之间的关系。

患者与方法

在一组接受多西他赛治疗并录入临床试验数据库的癌症患者中，测定了GSTM1（缺失型）、GSTT1（缺失型）和GSTP1（Ile(105)Val和Ala(114)Val）基因多态性。研究了GST基因多态性与作为主要终点的≥2级DIPN之间的关系。

结果

58例患者（中位年龄61岁）共接受了261个周期的多西他赛单药治疗。GSTP1（105）Ile/（105）Ile基因型患者发生≥2级DIPN的风险高于其他GSTP1基因型患者（分别为27例中的8例和31例中的2例，比值比6.11；95%置信区间1.17 - 31.94；P = 0.03）。在多变量分析中，≥2级DIPN与GSTP1（105）Ile/（105）Ile基因型（P = 0.01）和周期数（P = 0.03）密切相关。