Schöffski Patrick
Department of Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Anticancer Drugs. 2004 Feb;15(2):85-106. doi: 10.1097/00001813-200402000-00001.
The fluoropyrimidine anticancer agent 5-fluorouracil (5-FU) is active in a wide range of solid tumors, particularly gastric, colorectal, and head and neck cancers. Whilst infusional 5-FU is associated with higher response rates and a favorable safety profile as compared to the classical i.v. bolus administration, prolonged infusions can be inconvenient for the patients and catheter-related problems are common complications. An oral 5-FU formulation would allow for sustained 5-FU plasma concentrations, mimicking the pharmacokinetics (PK) of a continuous infusion with the addition of convenience of administration. The oral administration of 5-FU itself is not feasible due to the high activity of dihydropyrimidine dehydrogenase in the gut wall, which causes rapid metabolism of the drug, and results in decreased and erratic absorption of 5-FU and non-linear PK. To bypass this problem, oral fluoropyrimidine derivatives were developed either in the form of 5-FU prodrugs (i.e. tegafur, doxifluridine or capecitabine), or as enzyme inhibitors (i.e. eniluracil) administered with 5-FU, or as both prodrugs and enzyme inhibitors (i.e. S-1, UFT or BOF-A2). This review will focus on the oral fluoropyrimidine S-1, which consists of the 5-FU prodrug tegafur (ftorafur, FT) and two enzyme inhibitors, i.e. CDHP (5-chloro-2,4-dihydroxypyridine) and OXO (potassium oxonate), in a molar ratio of 1(FT):0.4 (CDHP):1(OXO). Phase II trials have demonstrated that S-1, as a single agent, is active for the treatment of gastric, colorectal, head and neck, breast, non-small cell lung, and pancreatic cancers. Phase III trials are currently underway in gastric cancer and these results are awaited to confirm the phase II findings. Furthermore, the combination of S-1 with cisplatin (CDDP), irinotecan or docetaxel for the treatment of gastric cancer and with CDDP for non-small cell and pancreatic cancer is feasible and active. The activity observed with S-1 in the phase II studies is at least equivalent, if not better, than continuous i.v. and bolus 5-FU and the other oral fluoropyrimidines. Thus, we may finally be seeing the realization of oral treatments for the management of various solid tumors and could be on the brink of a new approach to treatment strategies.
氟嘧啶类抗癌药5-氟尿嘧啶（5-FU）对多种实体瘤有效，尤其是胃癌、结直肠癌和头颈癌。与传统静脉推注给药相比，持续输注5-FU的缓解率更高且安全性良好，但长时间输注对患者不便，且导管相关问题是常见并发症。口服5-FU制剂可使5-FU血浆浓度持续维持，模拟持续输注的药代动力学（PK），且给药方便。由于肠壁中二氢嘧啶脱氢酶活性高，5-FU口服本身不可行，这会导致药物快速代谢，使5-FU吸收减少且不稳定，药代动力学呈非线性。为解决此问题，开发了口服氟嘧啶衍生物，其形式有5-FU前药（如替加氟、去氧氟尿苷或卡培他滨），或与5-FU联用的酶抑制剂（如乙磺酰尿），或兼具前药和酶抑制剂的形式（如S-1、优福定或BOF-A2）。本综述将聚焦于口服氟嘧啶S-1，它由5-FU前药替加氟（呋氟尿嘧啶，FT）和两种酶抑制剂组成，即CDHP（5-氯-2,4-二羟基吡啶）和OXO（氧嗪酸钾），摩尔比为1(FT):0.4(CDHP):1(OXO)。II期试验已证明，S-1作为单药对胃癌、结直肠癌、头颈癌、乳腺癌、非小细胞肺癌和胰腺癌的治疗有效。目前胃癌的III期试验正在进行，有待这些结果来证实II期试验的发现。此外，S-1与顺铂（CDDP）、伊立替康或多西他赛联合用于治疗胃癌，以及与CDDP联合用于治疗非小细胞癌和胰腺癌是可行且有效的。在II期研究中观察到的S-1的活性至少与持续静脉输注和推注5-FU以及其他口服氟嘧啶相当，甚至可能更好。因此，我们最终可能会看到针对各种实体瘤的口服治疗得以实现，并且可能正处于治疗策略新方法的边缘。
