Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy

Purpose: 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. Experimental Design: 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 (Ile(105)Val), GSTP1 exon 6 (Ala(114)Val), GSTM1 (homozygous deletion), and GSTT1 (homozygous deletion). We conducted analyses in a subgroup of 64 patients receiving a minimal cumulative dose of 500 mg/m(2) of oxaliplatin to examine whether the GST polymorphisms are associated with oxaliplatin-related cumulative neuropathy. Results: Among patients receiving a minimal cumulative dose of 500 mg/m(2) 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 (105)Ile allele than in patients homozygous or heterozygous for the GSTP1 (105)Val 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. Conclusions: The results of the current study suggest that the (105)Val allele variant of the GSTP1 gene at exon 5 confers a significantly decreased risk of developing severe oxaliplatin-related cumulative neuropathy.