Gastrointestinal Unit, Settlement Clinic, Towa, Adachi-ku, Tokyo, Japan.
J Gastroenterol Hepatol. 2009 Jun;24(6):970-81. doi: 10.1111/j.1440-1746.2009.05856.x.
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.
化疗在胃癌的辅助和晚期治疗中都起着重要作用。最近日本的随机试验证明，新型氟嘧啶衍生物 S-1 联合顺铂是最有前途的药物。然而，由于涉及药物合成和分解代谢的基因存在遗传变异，同一方案在患者中的疗效和毒性差异很大。抗肿瘤药物的治疗指数较窄，即某些方案对某些患者毒性太大且/或疗效较差，这阻碍了治疗结果的整体改善。药物遗传学是阐明药物代谢酶中遗传多态性的一个研究领域，它可能有助于确定受益于化疗或可能发生危及生命的毒性的患者。已经确定了几个涉及氟嘧啶和顺铂合成和分解代谢的关键酶，包括二氢嘧啶脱氢酶、胸苷酸合成酶、乳清酸磷酸核糖转移酶、谷胱甘肽 S 转移酶和切除修复交叉互补组。这些基因的各种多态性和种族差异已经阐明。这篇综述强调了这些酶多态性在生物学功能、检测系统和可能的临床应用方面的差异。这些知识为根据患者的药物代谢特征确定最佳方案提供了工具。这种方法将有助于为胃癌建立个体化治疗方法，从而以最小的严重毒性风险提供更好的疗效。
