Pinedo H M, Peters G F
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
J Clin Oncol. 1988 Oct;6(10):1653-64. doi: 10.1200/JCO.1988.6.10.1653.
Fluorouracil (5FU) is still considered the most active antineoplastic agent in the treatment of advanced colorectal cancer. The drug needs to be converted to the nucleotide level in order to exert its effect. It can be incorporated into RNA leading to interference with the maturation of nuclear RNA. However, its conversion to 5-fluoro-2'deoxy-5' monophosphate (FdUMP) leading to inhibition of thymidylate synthase (TS) and subsequently of DNA synthesis, is considered to be its main mechanism of action. In the presence of a folate cofactor a covalent ternary complex is formed, the stability of which is the main determinant of the action of 5FU. Resistance against 5FU can be mainly attributed to aberrations in its metabolism or to alterations of TS, eg, gene amplification, altered kinetics in respect to nucleotides or folates. Biochemical modulation of 5FU metabolism can be applied to overcome resistance against 5FU. A variety of normal purines, pyrimidines, and other antimetabolites have been studied in this respect, but only some of them have been clinically successful. Delayed administration of uridine has recently been shown to "rescue" mice and patients from toxicity, while pretreatment with leucovorin is the most promising combination to enhance the therapeutic efficacy. 5FU is frequently administered in an intravenous (IV) injection, and shows a rapid distribution and a triphasic elimination. The nonlinearity of 5FU pharmacokinetics is related to saturation of its degradation. Continuous infusion of 5FU led to different kinetics. Regional administration, such as hepatic artery infusion, offers a way to achieve higher drug concentrations in liver metastases and is accompanied by lower systemic concentration. The current status of the biochemical and pharmacokinetic data is reviewed.
氟尿嘧啶（5FU）仍然被认为是治疗晚期结直肠癌最有效的抗肿瘤药物。该药物需要转化为核苷酸水平才能发挥作用。它可以掺入RNA，导致干扰核RNA的成熟。然而，其转化为5-氟-2'-脱氧-5'-单磷酸（FdUMP）从而抑制胸苷酸合成酶（TS）并随后抑制DNA合成，被认为是其主要作用机制。在叶酸辅因子存在的情况下，会形成一种共价三元复合物，其稳定性是5FU作用的主要决定因素。对5FU的耐药性主要可归因于其代谢异常或TS的改变，例如基因扩增、核苷酸或叶酸动力学改变。5FU代谢的生化调节可用于克服对5FU的耐药性。在这方面已经研究了多种正常嘌呤、嘧啶和其他抗代谢物，但只有其中一些在临床上取得了成功。最近已证明延迟给予尿苷可使小鼠和患者“免受”毒性影响，而亚叶酸钙预处理是提高治疗效果最有前景的联合用药。5FU通常通过静脉注射给药，表现出快速分布和三相消除。5FU药代动力学的非线性与其降解的饱和有关。持续输注5FU会导致不同的动力学。区域给药，如肝动脉灌注，提供了一种在肝转移灶中实现更高药物浓度的方法，同时全身浓度较低。本文综述了生化和药代动力学数据的现状。
