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

Glutathione S-transferases (GSTs) are metabolic phase II enzymes that promo te reactive metabolite elimination by conjugating them to glutathione (GSH) . Because of their important role in xenobiotic metabolism and detoxificati on, they have been implicated in carcinogenesis processes, especially epith elium transformation. Moreover, their influence on response to chemotherapy in cancer patients has been demonstrated. Genetic polymorphisms for GSTM1, GSTT1' and GSTP1 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 ne ck squamous cell carcinoma (HNSCC), GSTP1, GSTM1 and GSTT1 were studied pro spectively in a large series of HNSCC patients. Correlations between GST al terations, p53 mutation status and clinical response to chemotherapy were i nvestigated. We showed that the risk of developing laryngeal cancer was inc reased by 2.6-fold [9S% Cl 1.6-6.1] in patients with the GSTM1 null genotyp e and by 2.8-fold [95% CI 0.9-8.1] in patients with the homozygous GSTP1 va l105 genotype. Furthermore, individuals with this latter genotype were over represented in the p53 mutation group (p = 0.05). After storage duration an d hemolysis adjustement, a significantly lower plasmatic GSTP1 level was ob served in complete responders compared with partial and non-responders (mea n: 4.4 +/- 0.06 mug/l, 4.7 +/- 0.06 mug/l and 4.7 +/- 0.07 mug/l; p = 0.05) , respectively. The prevalence of p53-mutated tumors was significantly high er in the group of non-responders (81%) compared with partial (60%) and com plete responders (64%) (p = 0.05). Two types of multivariate analysis were performed including parameters that have been shown to influence response t o chemotherapy significantly in univariate analysis. p53 mutations and high tumor stage are independent factors of non-response to chemotherapy, where as plasmatic GSTP1 levels and low tumor stage are independent factors of co mplete response. Our data suggest that GST enzymes are associated with lary nx cancer and that their use as predictive factors and treatment targets sh ould be further explored. (C) 2001 Wiley-Liss, Inc.