GSTP1 as a potential predictive factor for adverse events associated with platinum-based antitumor agent-induced...

Glutathione S-transferase (GST) exhibits antidotal effects on numerous drugs, including platinum-based antineoplastic drugs. Furthermore, GST Pi 1 (GSTP1) polymorphism is associated with peripheral neuropathy. In the present study, it was determined whether GSTP1 can predict adverse events associated with platinum-based antitumor agent-induced peripheral neuropathy among Japanese patients. The subjects included 122 patients, among whom 105 patients had colorectal, 16 had gastric, and one patient had pancreatic cancer. It was indicated that wild type (AA) GSTP1 was expressed in 99 patients (81.1%), whereas heterozygous (AG) and homozygous (GG) GSTP1 polymorphisms were present in 22 (18.0%) and 1 (0.8%) patients, respectively. Among patients with colorectal cancer, the expression of homozygous GSTP1 was observed in 88 patients (83.8%), whereas that of heterozygous GSTP1 was observed in 17 patients (16.2%). Peripheral neuropathy of grade ≥3 occurred in 10 patients (9.5%) receiving mFOLFOX therapy (a biweekly cycle consisting of a 2-h infusion of 85 mg/m² oxaliplatin and 200 mg/m² leucovorin followed by a bolus administration of 400 mg/m² 5-fluorouracil and a continuous 48-h infusion of 2,400 mg/m² 5-fluorouracil) for colorectal cancer, which included 6 patients with the AA allele (6.8%) and 4 patients with the AG allele (23.5%). The number of peripheral neuropathy cases of grade ≥3 was increased among patients with the AG allele, compared with patients with the AA allele (P=0.032). In patients with gastric cancer, the AA and AG types of GSTP1 were expressed in 11 (68.8%) and 5 (31.2%) patients, respectively. Cisplatin, administered to patients with gastric cancer, did not induce peripheral neuropathy. The aforementioned indicated that GSTP1 genetic polymorphism is associated with peripheral neuropathy induced by oxaliplatin treatment for colorectal cancer, and therefore serves as a predictive marker. Furthermore, early dose reduction or drug withdrawal should be implemented depending on the severity of peripheral neuropathy as a potential method for reducing the number of patients discontinuing the drug, due to adverse events involving peripheral neuropathy.