title: Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma.
abstract: Glutathione S-transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum-based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first-line FOLFOX-4. Combined analysis of GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX-4 (56.1%vs 37.6%, P = 0.04), and a longer progression-free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, had significantly longer progression-free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX-4 treatment.
authors.affiliation: National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Yen-Chung
authors.initials: YC
authors.lastname: Chen
authors.forename: Cheng-Hwai
authors.initials: CH
authors.lastname: Tzeng
authors.forename: Po-Min
authors.initials: PM
authors.lastname: Chen
authors.forename: Jen-Kou
authors.initials: JK
authors.lastname: Lin
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Lin
authors.forename: Wei-Shone
authors.initials: WS
authors.lastname: Chen
authors.forename: Jeng-Kae
authors.initials: JK
authors.lastname: Jiang
authors.forename: Huann-Sheng
authors.initials: HS
authors.lastname: Wang
authors.forename: Wei-Shu
authors.initials: WS
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D009944:Organoplatinum Compounds / Q000009:adverse effects / Q000627:therapeutic use; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D002955:Leucovorin; D005472:Fluorouracil