5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence.

中文翻译：

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5-氟尿嘧啶和其他氟嘧啶在大肠癌中的作用：过去，现在和将来。

5-氟尿嘧啶（5-FU）是姑息治疗和辅助治疗大肠癌（CRC）全身化疗的重要组成部分。在过去的四十年中，已经开发并测试了几种调节策略，包括基于5-FU的联合方案和5-FU前药的实施，以增加5-FU的抗肿瘤活性并克服临床耐药性。尽管迄今为止CRC治疗取得了令人鼓舞的进展，但是患者对治疗的反应率仍然保持较低水平，化学抗药性的发展常常损害了患者从基于5-FU的治疗中获益。CRC患者治疗反应的个体差异可能源自每个个体的独特遗传和表观遗传组成。当前个性化医学趋势中的关键要素是正确理解引起肿瘤组织对基于5-FU的治疗敏感性低或缺乏的原因和机制。对现有的基于5-FU的新疗法和针对CRC的新靶向疗法的预测性生物标记物的鉴定和验证可能会在将来改善患者的治疗效果。本文中，我们提出了一个全面的综述，总结了CRC治疗的选择以及5-FU在分子水平上的作用机理，包括同化和分解代谢方式。本综述的主要部分包括CRC患者化学耐药性的当前已知分子机制。我们还专注于开发各种5-FU前药，以增加循环中的5-FU量并限制毒性。最后，