Pharmacogenetics of fluoropyrimidine and cisplatin. A future application to gastric cancer treatment

Abstract

Chemotherapy plays an important role in the treatment of gastric cancer both in adjuvant or advanced settings. Recent randomized trials in Japan have proved that S-1, a novel fluoropyrimidine derivative, and cisplatin are the most promising agents. However, both the efficacy and toxicity of a given regimen vary widely among patients due to the inherited variability of genes that involve drug anabolism and catabolism. A narrow therapeutic index of antitumor agents, i.e. a given regimen being too toxic and/or less effective to some segment of patients, prevents the overall improvement of treatment outcomes. Pharmacogenetics, a research field elucidating genetic polymorphism in drug metabolizing enzymes, may contribute to identifying patients who benefit from chemotherapy or who will experience life-threatening toxicity. There are several crucial enzymes identified involving anabolism and the catabolism of fluoropyrimidine and cisplatin, including dihydropyrimidine dehydrogenase, thymidylate synthase, orotate phosphoribosyl transferase, glutathione S transferase, and excision repair cross complementary group. Various polymorphisms and ethnic variabilities of these genes have been elucidated. This review highlights variations within biological functions, detection systems, and possible clinical applications of these enzymatic polymorphisms. This knowledge provides a tool to determine an optimum regimen according to the patient's drug metabolizing characteristics. This stance will contribute to establishing individualized therapies for gastric cancer, which offers superior efficacy with a minimal chance of severe toxicity.