Ardalan B, Luis R, Jaime M, Franceschi D
Department of Medicine, University of Miami, School of Medicine, Sylvester Comprehensive Cancer Center, Florida, USA.
Cancer Invest. 1998;16(4):237-51. doi: 10.3109/07357909809039773.
5-Fluorouracil (5-FU) remains the agent of choice for the treatment of colorectal cancer. Research has focused on the biomodulation of 5-FU in order to attempt to improve the cytotoxity and therapeutic effectiveness of this drug in the treatment of advanced colorectal cancer. Modulation of 5-FU by methotrexate (MTX), trimetrexate (TMTX), interferon-alpha (IFN-alpha), leucovorin (LV), or N-(phosphonacetyl)-L-asparte acid (PALA) has produced higher response rates than those observed with 5-FU alone. Methotrexate may improve the durability of response to or survival with 5-FU, but with inferior results compared with those in trials of 5-FU and leucovorin. Trimetrexate produces a number of responses, and further phase III trials are in progress to confirm the results of promising phase II trials with this drug. IFN-alpha has shown therapeutic efficiency when combined with 5-FU alone or with 5-FU and leucovorin, but latest studies with these combinations have shown increased toxicity. Initial single-institution phase I trials with 5-FU and PALA reported promising responses, but the latter responses with PALA were not substantiated in randomized multicenter trials. Leucovorin enhances the cytotoxic activity of 5-FU in vitro and in vivo, and several clinical trials have shown improved response rates and possible trends in improved survival when such therapy is compared with the use of 5-FU as a single-agent. More recent randomized trials have focused their attention on determining the optimal dose and schedule with this combination for producing a better clinical response with minimal toxicity. Schedules using infusional 5-FU appear to be the most active regimens when 5-FU is used as a single agent, as demonstrated by recent randomized trials. The Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) have performed separate randomized trials and have shown that the optimal regimens employ infusional 5-FU as a single agent, and that these are the least toxic regimens, perhaps more effective, and associated with a better quality of life. Future studies will focus on infusional regimens involving either short-term, high-dose protracted or long-term, low-dose protracted infusion of 5-FU, since these regimens have shown the most favorable toxicity spectrum and produced the longest survival times. Future research will also focus on the evaluation of various methods of delivery of 5-FU, including oral administration of the drug in combination with compounds that can modify its catabolism.
5-氟尿嘧啶（5-FU）仍然是治疗结直肠癌的首选药物。研究主要集中在5-FU的生物调节方面，旨在提高该药物在治疗晚期结直肠癌时的细胞毒性和治疗效果。甲氨蝶呤（MTX）、三甲曲沙（TMTX）、α-干扰素（IFN-α）、亚叶酸钙（LV）或N-（膦酰乙酰）-L-天冬氨酸（PALA）对5-FU的调节所产生的缓解率高于单独使用5-FU时观察到的缓解率。甲氨蝶呤可能会提高对5-FU的反应持续时间或生存率，但与5-FU和亚叶酸钙联合试验的结果相比效果较差。三甲曲沙产生了一些反应，进一步的III期试验正在进行中，以证实该药物有前景的II期试验结果。α-干扰素与单独的5-FU或与5-FU和亚叶酸钙联合使用时已显示出治疗效果，但最近这些联合用药的研究显示毒性增加。最初关于5-FU和PALA的单机构I期试验报告了有前景的反应，但PALA的后续反应在随机多中心试验中未得到证实。亚叶酸钙在体外和体内均可增强5-FU的细胞毒性活性，一些临床试验表明，与单独使用5-FU相比，这种联合治疗的缓解率有所提高，并且可能有生存率改善的趋势。最近的随机试验将注意力集中在确定这种联合用药产生更好临床反应且毒性最小的最佳剂量和给药方案上。如最近的随机试验所示，当5-FU作为单一药物使用时，采用持续输注5-FU的方案似乎是最有效的治疗方案。西南肿瘤协作组（SWOG）和东部肿瘤协作组（ECOG）分别进行了随机试验，结果表明最佳方案是将持续输注5-FU作为单一药物使用，这些方案毒性最小，可能更有效，并且与更好的生活质量相关。未来的研究将集中在涉及短期、高剂量持续或长期、低剂量持续输注5-FU的持续输注方案上，因为这些方案显示出最有利的毒性谱并且产生最长的生存时间。未来的研究还将集中在评估5-FU的各种给药方法上，包括口服该药物并与可改变其分解代谢的化合物联合使用。
