van Laar J A, Rustum Y M, Ackland S P, van Groeningen C J, Peters G J
Department of Medical Oncology, University Hospital VU, Amsterdam, The Netherlands.
Eur J Cancer. 1998 Feb;34(3):296-306. doi: 10.1016/s0959-8049(97)00366-3.
Despite more than 30 years of intensive studies on new drugs against advanced colorectal cancer, the fluoropyrimidines remain the drugs of choice for systemic treatment and for hepatic artery infusion (HAI). This overview describes new developments in advanced colorectal cancer chemotherapy, providing a rationale for more effective use of the fluoropyrimidines, with biochemical modulation, scheduling or by revealing biochemical mechanisms of action that correlate with antitumour activity. In human colorectal cancer cell lines and various animal tumour model systems 5-fluoro-2'-deoxyuridine (FdUrd) is more effective than 5-fluorouracil (5-FU). Comparably, FdUrd's modulation by leucovorin (LV) is more potent than 5-FU. In animal studies it is shown that intermittent high-bolus administration of FdUrd generates better antitumour activity, compared with equal toxic doses or any other schedule of 5-FU. These effects are related to prolonged-thymidylate synthase (TS) inhibition and the prevention of TS induction, rather than RNA incorporation. Preclinical studies with modulators such as N-phosphonacetyl-L-aspartate (PALA), WR-2721, mitomycin C and platinum derivatives provide a rationale for clinical use in the future. The first choice systemic chemotherapy of patients with advanced colorectal cancer remains 5-FU combined with LV. Some improvement in therapeutic efficacy has been achieved with locoregional HAI. In randomised studies HAI FdUrd improves the quality of life and survival as compared with optimal systemic therapy. Chronomodulation decreases toxicity, allowing dose intensification, while modulators such as LV or dexamethasone increase survival of patients treated with HAI FdUrd to 86% after 1 year. In conclusion, the clinical use of FdUrd has not been fully explored. Intermittent high-dose FdUrd, chronomodulation together with the use of modulators or drugs focused on prolonged TS inhibition, should be studied in large randomised studies.
尽管针对晚期结直肠癌的新药进行了30多年的深入研究，但氟嘧啶仍然是全身治疗和肝动脉灌注（HAI）的首选药物。本综述描述了晚期结直肠癌化疗的新进展，为更有效地使用氟嘧啶提供了理论依据，包括生化调节、给药方案，或揭示与抗肿瘤活性相关的生化作用机制。在人结直肠癌细胞系和各种动物肿瘤模型系统中，5-氟-2'-脱氧尿苷（FdUrd）比5-氟尿嘧啶（5-FU）更有效。同样，亚叶酸（LV）对FdUrd的调节作用比5-FU更强。动物研究表明，与同等毒性剂量或5-FU的任何其他给药方案相比，间歇性高剂量推注FdUrd可产生更好的抗肿瘤活性。这些作用与胸苷酸合成酶（TS）的长期抑制和TS诱导的预防有关，而不是与RNA掺入有关。使用N-膦酰乙酰-L-天冬氨酸（PALA）、WR-2721、丝裂霉素C和铂衍生物等调节剂的临床前研究为未来的临床应用提供了理论依据。晚期结直肠癌患者的首选全身化疗仍然是5-FU联合LV。局部HAI在治疗效果上有了一些改善。在随机研究中，与最佳全身治疗相比，HAI FdUrd可提高生活质量和生存率。时辰调节可降低毒性，允许剂量强化，而LV或地塞米松等调节剂可使接受HAI FdUrd治疗的患者1年后的生存率提高到86%。总之，FdUrd的临床应用尚未得到充分探索。间歇性高剂量FdUrd、时辰调节以及使用专注于长期抑制TS的调节剂或药物，应在大型随机研究中进行研究。
