GSTP1 as a potential predictive factor for adverse events associated with platinum‑based antitumor agent‑induced peripheral neuropathy

Abstract

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/m 2 oxaliplatin and 200 mg/m 2 leucovorin followed by a bolus administration of 400 mg/m 2 5-fluorouracil and a continuous 48-h infusion of 2,400 mg/m 2 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.

<p>Genetic Polymorphisms and the Efficacy of Platinum-Based Chemotherapy: Review</p>

“…This polymorphism results in the reduced activity of the GSTP1 enzyme and loss of this gene's alleles causes the complete loss of enzymatic activity. 85,86 Other studies suggest that polymorphisms at these sites are associated more with changes in PBC toxicity, such as granulocytopenia and peripheral neuropathy induced by platinum. 86,87 Several recent studies showed that the GSTP1 polymorphism represents a predictive factor for the outcome of NSCLC patients treated with PBC 88 ( Table 1).…”

“…85,86 Other studies suggest that polymorphisms at these sites are associated more with changes in PBC toxicity, such as granulocytopenia and peripheral neuropathy induced by platinum. 86,87 Several recent studies showed that the GSTP1 polymorphism represents a predictive factor for the outcome of NSCLC patients treated with PBC 88 ( Table 1). Data from a meta-analysis showed that the Asian GSTP1 genotype, IIe105Val IIe/Val and Val/Val, exhibited a better response compared with IIe/IIe 89 (Table 1).…”

Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

“…The GSTP1 Ile105Val (rs1695, A>G) is a missense mutation and affects the activity of the GSTP1 enzyme. Oxaliplatin-related cumulative peripheral neuropathy was reported to be more frequent and severe in patients with heterozygous (AG) genotype when compared to patients with wild-type alleles (AA) [ 9 ]. Wiese et al [ 10 ] conclude that GSTP1 c.313A>G polymorphism was associated with the overall survival of patients treated with oxaliplatin-based therapy.…”

Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms

“…The GSTP1 Ile105Val (rs1695, A>G) is a missense mutation and affects the activity of the GSTP1 enzyme. Oxaliplatin-related cumulative peripheral neuropathy was reported to be more frequent and severe in patients with heterozygous (AG) genotype when compared to patients with wild type alleles (AA) [6]. Wiese et al [7] conclude that GSTP1 c.313A>G polymorphism was associated with the overall survival of patients treated with oxaliplatin-based therapy.…”