Ajani Jaffer A
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Gan To Kagaku Ryoho. 2006 Jun;33 Suppl 1:117-20.
Therapy for patients with advanced gastric cancer is not satisfactory. The median survival of patients with advanced gastric cancer is approximately 6-9 months and less than 10% of patients survive one year. Despite identification of new classes of agents, such as camptothecins, taxanes, and new platinum analogs, the improvement has been limited and therapy intensive resulting in considerable morbidity. More intensive therapies are challenging not only for the patients and their relatives but also for the health care providers. Oral fluropyrimidines like capecitabine and S-1 have generated considerable interest because of convenience and their activity against gastric carcinoma. S-1 is of significant interest because of many studies in Japan in gastric cancer patients demonstrating its substantial activity as a single agent and in combination with other agents. Furthermore, S-1 represents a fourth generation "designer" drug. It has a component that enhances the cytotoxic activity of tegafur by inhibiting dihydropyrimidine dehydrogenase (DPD) and also has a component that reduces phosphorylation of 5-fluorouracil in the gastrointestinal tract to potentially reduce toxicity. This unique combination is rarely found in an oral agent. In addition, considerable ethnic differences in the tolerated doses of S-1 have been considered related to varying efficiency rates of conversion of tegafur to 5-fluorouracil by the CYP450 enzyme system. The varying efficiency is thought to be due to the presence of certain polymorphisms in the CYP2A6 gene responsible for metabolizing tegafur to 5-fluorouracil. S-1 is under rapid development in the West for gastric carcinoma. Phase I/II studies of the combination of S-1 plus cisplatin have been completed and a global phase III study, accruing rapidly, is comparing S-1 plus cisplatin to 5-fluorouracil plus cisplatin (a reference regimen).
晚期胃癌患者的治疗效果并不理想。晚期胃癌患者的中位生存期约为6至9个月，只有不到10%的患者能存活一年。尽管已发现了新的药物类别，如喜树碱、紫杉烷和新型铂类类似物，但治疗效果的改善有限，且强化治疗导致了相当高的发病率。更强化的治疗不仅对患者及其家属具有挑战性，对医疗服务提供者也是如此。像卡培他滨和S-1这样的口服氟嘧啶类药物因其便利性以及对胃癌的活性而引起了广泛关注。S-1备受关注，因为日本对胃癌患者进行的多项研究表明，它作为单一药物以及与其他药物联合使用时都具有显著活性。此外，S-1是一种第四代“设计型”药物。它有一个成分通过抑制二氢嘧啶脱氢酶（DPD）来增强替加氟的细胞毒性活性，还有一个成分可减少胃肠道中5-氟尿嘧啶的磷酸化，从而有可能降低毒性。这种独特的组合在口服药物中很少见。此外，人们认为S-1耐受剂量存在相当大的种族差异与CYP450酶系统将替加氟转化为5-氟尿嘧啶的效率不同有关。这种效率差异被认为是由于负责将替加氟代谢为5-氟尿嘧啶的CYP2A6基因存在某些多态性。S-1在西方正迅速开展针对胃癌的研究。S-1加顺铂联合方案的I/II期研究已经完成，一项正在迅速入组的全球III期研究正在比较S-1加顺铂与5-氟尿嘧啶加顺铂（一种对照方案）。
