Lecomte Thierry, Landi Bruno, Beaune Philippe, Laurent-Puig Pierre, Loriot Marie-Anne
Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris, European Georges Pompidou Hospital, France.
Clin Cancer Res. 2006 May 15;12(10):3050-6. doi: 10.1158/1078-0432.CCR-05-2076.
Glutathione S-transferases (GST) are xenobiotic metabolizing enzymes involved in the detoxification of a variety of chemotherapeutic drugs, including platinum derivatives. Genetic polymorphisms of GSTs have been associated with enzyme activity variations. Thus, a study was done to investigate the relationship between GST polymorphisms and oxaliplatin-related cumulative neuropathy in gastrointestinal cancer patients treated with oxaliplatin-based chemotherapy.
Ninety patients were included. Clinical neurologic evaluation was done at baseline and before each cycle of treatment. We determined genetic variants for GSTP1 exon 5 (Ile105Val), GSTP1 exon 6 (Ala114Val), GSTM1 (homozygous deletion), and GSTT1 (homozygous deletion). We conducted analyses in a subgroup of 64 patients receiving a minimal cumulative dose of 500 mg/m2 of oxaliplatin to examine whether the GST polymorphisms are associated with oxaliplatin-related cumulative neuropathy.
Among patients receiving a minimal cumulative dose of 500 mg/m2 of oxaliplatin, 15 patients showed clinically evident oxaliplatin-related cumulative neuropathy scored grade 3 according to an oxaliplatin-specific scale. The oxaliplatin-related cumulative neuropathy scored grade 3 was significantly more frequent in patients homozygous for the GSTP1 105Ile allele than in patients homozygous or heterozygous for the GSTP1 105Val allele (odds ratio, 5.75; 95% confidence interval, 1.08-30.74; P = 0.02). No association was found with respect to any of the GSTM1, GSTT1, or GSTP1 exon 6 genotypes.
The results of the current study suggest that the 105Val allele variant of the GSTP1 gene at exon 5 confers a significantly decreased risk of developing severe oxaliplatin-related cumulative neuropathy.
谷胱甘肽S-转移酶（GST）是参与多种化疗药物（包括铂类衍生物）解毒的外源性物质代谢酶。GST的基因多态性与酶活性变化有关。因此，开展了一项研究以调查GST多态性与接受基于奥沙利铂化疗的胃肠道癌患者中奥沙利铂相关累积性神经病变之间的关系。
纳入90例患者。在基线时以及每个治疗周期前进行临床神经学评估。我们确定了GSTP1第5外显子（Ile105Val）、GSTP1第6外显子（Ala114Val）、GSTM1（纯合缺失）和GSTT1（纯合缺失）的基因变异。我们在接受最低累积剂量500mg/m²奥沙利铂的64例患者亚组中进行分析，以检查GST多态性是否与奥沙利铂相关累积性神经病变有关。
在接受最低累积剂量500mg/m²奥沙利铂的患者中，15例患者出现了根据奥沙利铂特异性量表评分为3级的临床明显的奥沙利铂相关累积性神经病变。GSTP1 105Ile等位基因纯合子患者中奥沙利铂相关累积性神经病变评分为3级的情况显著多于GSTP1 105Val等位基因纯合子或杂合子患者（比值比，5.75；95%置信区间，1.08 - 30.74；P = 0.02）。未发现与GSTM1、GSTT1或GSTP1第6外显子的任何基因型有关联。
当前研究结果表明，GSTP1基因第5外显子的105Val等位基因变异显著降低了发生严重奥沙利铂相关累积性神经病变的风险。
