Glutathione-associated enzymes in head and neck squamous cell carcinoma and response to cisplatin-based neoadjuvant chemotherapy

Abstract

Glutathione S-transferases (GSTs) are metabolic phase II enzymes that promote reactive metabolite elimination by conjugating them to glutathione (GSH). Because of their important role in xenobiotic metabolism and detoxification, they have been implicated in carcinogenesis processes, especially epithelium transformation. Moreover, their influence on response to chemotherapy in cancer patients has been demonstrated. Genetic polymorphisms for GSTMI, GSTTI and GSTPI have been found in human populations and have been shown to have phenotypic consequences. To investigate the role of GST enzymes in carcinogenesis and in response to chemotherapy in patients with head and neck squamous cell carcinoma (HNSCC), GSTPI, GSTMI and GSTTI were studied prospectively in a large series of HNSCC patients. Correlations between GST alterations, p53 mutation status and clinical response to chemotherapy were investigated. We showed that the risk of developing laryngeal cancer was increased by 2.6-fold [95% CI 1.6-6.1] in patients with the GSTMI null genotype and by 2.8-fold [95% CI 0.9-8.1] in patients with the homozygous GSTPI va1105 genotype. Furthermore, individuals with this latter genotype were over-represented in the p53 mutation group (p = 0.05). After storage duration and hemolysis adjustement, a significantly lower plasmatic GSTPI level was observed in complete responders compared with partial and non-responders (mean: 4.4 ± 0.06 μg/I, 4.7 ± 0.06 μg/I and 4.7 ± 0.07 μg/I; p = 0.05), respectively. The prevalence ofp53-mutated tumors was significantly higher in the group of non-responders (81%) compared with partial (60%) and complete responders (64%) (p = 0.05). Two types of multivariate analysms were performed including parameters that have been shown to influence response to chemotherapy significantly in univariate analysis. p53 mutations and high tumor stage are independent factors of non-response to chemotherapy, whereas plasmatic GSTP I levels and Iow tumor stage are independent factors of complete response. Our data suggest that GST enzymes are associated with larynx cancer and that their use as predictive factors and treatment targets should be further explored. © 2001 Wiley-Liss, Inc.