TAS-102，一种新型抗肿瘤药物：作用机制综述。,Cancer Treatment Reviews

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TAS-102，一种新型抗肿瘤药物：作用机制综述。
Cancer Treatment Reviews ( IF 9.6 ) Pub Date : 2015-10-03 , DOI: 10.1016/j.ctrv.2015.06.001
Heinz-Josef Lenz ₁ , Sebastian Stintzing ₂ , Fotios Loupakis ₃

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抑制核苷代谢是癌症治疗的重要原则，氟嘧啶类药物（例如 5-氟尿嘧啶 (5-FU)）和抗叶酸剂在许多癌症治疗中的作用就证明了这一点。TAS-102是一种口服联合疗法，由三氟尿苷（FTD）（一种基于胸苷的核苷类似物）和盐酸替匹拉西（TPI）组成，这是一种新型胸苷磷酸化酶抑制剂，可提高FTD的生物利用度。TAS-102基于不同的作用机制在5-FU难治性患者中显示出疗效，并已在日本被批准用于治疗转移性结直肠癌。本综述描述了 TAS-102 的作用机制，强调了 TAS-102 和基于 5-FU 的疗法之间的主要差异。虽然 FTD 和 5-FU 均抑制胸苷酸合酶 (TS)（DNA 合成中的一种中心酶），但 FTD 充分抑制 TS 需要连续输注；因此，它不被认为是口服给药的临床相关机制。相反，每日两次口服给药（TAS-102 临床开发中使用的时间表）的主要细胞毒性机制是 DNA 掺入。FTD 掺入 DNA 会导致 DNA 功能障碍，包括 DNA 链断裂。基于尿嘧啶的类似物（例如 5-FU）也可以掺入 DNA 中；然而，它们会立即被尿嘧啶-DNA 糖基化酶裂解，从而降低了它们损伤 DNA 的能力。此外，TPI成分可以增强对FTD的响应的持久性。凭借其独特的作用和代谢机制，TAS-102 对于对 5-FU 氟嘧啶耐药或不耐受的患者来说是一种有前景的治疗选择。

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TAS-102, a novel antitumor agent: a review of the mechanism of action.

Inhibition of nucleoside metabolism is an important principle in cancer therapy as evidenced by the role of fluoropyrimidines, such as 5-fluorouracil (5-FU), and antifolates in the treatment of many cancers. TAS-102 is an oral combination therapy consisting of trifluridine (FTD), a thymidine-based nucleoside analog, plus tipiracil hydrochloride (TPI), a novel thymidine phosphorylase inhibitor that improves the bioavailability of FTD. TAS-102 has demonstrated efficacy in 5-FU-refractory patients based on a different mechanism of action and has been approved for the treatment of metastatic colorectal cancer in Japan. This review describes the mechanism of action of TAS-102, highlighting key differences between TAS-102 and 5-FU-based therapies. While both FTD and 5-FU inhibit thymidylate synthase (TS), a central enzyme in DNA synthesis, sufficient TS inhibition by FTD requires continuous infusion; therefore, it is not considered a clinically relevant mechanism with oral dosing. Instead, the primary cytotoxic mechanism with twice-daily oral dosing, the schedule used in TAS-102 clinical development, is DNA incorporation. FTD incorporation into DNA induces DNA dysfunction, including DNA strand breaks. Uracil-based analogs such as 5-FU may also be incorporated into DNA; however, they are immediately cleaved off by uracil-DNA glycosylases, reducing their ability to damage DNA. Moreover, the TPI component may enhance the durability of response to FTD. With its distinct mechanism of action and metabolism, TAS-102 is a promising treatment option for patients resistant to or intolerant of 5-FU-based fluoropyrimidines.

更新日期：2015-06-06

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