Malet-Martino M, Martino R
Groupe de RMN Biomédicale, Laboratoire des IMRCP, Université Paul Sabatier, Toulouse, France.
Oncologist. 2002;7(4):288-323. doi: 10.1634/theoncologist.7-4-288.
Although 5-fluorouracil (5-FU) was first introduced in 1957, it remains an essential part of the treatment of a wide range of solid tumors. 5-FU has antitumor activity against epithelial malignancies arising in the gastrointestinal tract and breast as well as the head and neck, with single-agent response rates of only 10%-30%. Although 5-FU is still the most widely prescribed agent for the treatment of colorectal cancer, less than one-third of patients achieve objective responses. Recent research has focused on the biomodulation of 5-FU to improve the cytotoxicity and therapeutic effectiveness of this drug in the treatment of advanced disease. As all the anticancer agents, 5-FU leads to several toxicities. The toxicity profile of 5-FU is schedule dependent. Myelotoxicity is the major toxic effect in patients receiving bolus doses. Hand-foot syndrome (palmar-plantar erythrodysesthesia), stomatitis, and neuro- and cardiotoxicities are associated with continuous infusions. Other adverse effects associated with both bolus-dose and continuous-infusion regimens include nausea and vomiting, diarrhea, alopecia, and dermatitis. All these reasons explain the need for more effective and less toxic fluoropyrimidines. In the first part of this review, we briefly present the metabolic pathways of 5-FU responsible for the efficacy and toxicity of this drug. This knowledge is also necessary to understand the target(s) of biomodulation. The second part is devoted to a review of the literature on three recent prodrugs of 5-FU, i.e., capecitabine, UFT (ftorafur [FTO] plus uracil), and S-1 (FTO plus 5-chloro-2,4-dihydroxypyridine plus potassium oxonate). The pharmacological principles that have influenced the development of these new drugs and our current knowledge of the clinical pharmacology of these new agents, focusing on antitumor activity and toxicity, are presented. The literature was analyzed until March 2002. This review is intended to be as exhaustive as possible since it was conceived as a work tool for readers wanting to go further.
尽管5-氟尿嘧啶（5-FU）于1957年首次被引入，但它仍然是多种实体瘤治疗的重要组成部分。5-FU对胃肠道、乳腺以及头颈部发生的上皮恶性肿瘤具有抗肿瘤活性，单药有效率仅为10%-30%。尽管5-FU仍是治疗结直肠癌最广泛使用的药物，但不到三分之一的患者能达到客观缓解。最近的研究集中在5-FU的生物调节上，以提高该药物在治疗晚期疾病中的细胞毒性和治疗效果。与所有抗癌药物一样，5-FU会导致多种毒性。5-FU的毒性特征取决于给药方案。骨髓毒性是接受大剂量推注的患者的主要毒性作用。手足综合征（掌跖红细胞感觉异常）、口腔炎以及神经和心脏毒性与持续输注有关。与大剂量推注和持续输注方案相关的其他不良反应包括恶心、呕吐、腹泻、脱发和皮炎。所有这些原因都说明了需要更有效且毒性更小的氟嘧啶。在本综述的第一部分，我们简要介绍了负责该药物疗效和毒性的5-FU代谢途径。这些知识对于理解生物调节的靶点也是必要的。第二部分致力于综述关于5-FU的三种近期前体药物的文献，即卡培他滨、UFT（替加氟[FTO]加尿嘧啶）和S-1（FTO加5-氯-2,4-二羟基吡啶加草酸钾）。介绍了影响这些新药开发的药理学原理以及我们目前对这些新药物临床药理学的认识，重点是抗肿瘤活性和毒性。对截至2002年3月的文献进行了分析。本综述旨在尽可能详尽，因为它被设想为希望深入了解的读者的工作工具。
