Background

Colorectal cancer (CRC) is a disease with high morbidity and mortality rates. 5-fluorouracil (5-FU) is the first-line recommended drug for chemotherapy in patients with CRC, and it has a good effect on a variety of other solid tumors as well. Unfortunately, however, due to the emergence of drug resistance the effectiveness of treatment may be greatly reduced. In the past decade, major progress has been made in the field of 5-FU drug resistance in terms of molecular mechanisms, pre-clinical (animal) models and clinical trials.

Conclusions

In this article we systematically review and update current knowledge on 5-FU pharmacogenomics related to drug uptake and activation, the expression and activity of target enzymes (DPD, TS and MTHFR) and key signaling pathways in CRC. Furthermore, a summary of drug combination strategies aimed at targeting specific genes and/or pathways to reverse 5-FU resistance is provided. Based on this, we suggest that causal relationships between genes, pathways and drug sensitivity should be systematically considered from a multidimensional perspective. In the design of research methods, emerging technologies such as CRISPR-Cas, TALENS and patient-derived xenograft models should be applied as far as possible to improve the accuracy of clinically relevant results.

中文翻译：

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5-氟尿嘧啶在结直肠癌中的药物基因组学：回顾和更新。

背景

结直肠癌 (CRC) 是一种发病率和死亡率都很高的疾病。5-氟尿嘧啶（5-FU）是CRC患者化疗的一线推荐药物，对其他多种实体瘤也有良好疗效。然而不幸的是，由于耐药性的出现，治疗的有效性可能会大大降低。近十年来，5-FU耐药领域在分子机制、临床前（动物）模型和临床试验等方面取得了重大进展。

结论

在本文中，我们系统地回顾和更新了与药物摄取和激活、靶酶（DPD、TS 和 MTHFR）的表达和活性以及 CRC 中的关键信号通路相关的 5-FU 药物基因组学的当前知识。此外，还提供了旨在针对特定基因和/或途径来逆转 5-FU 耐药性的药物组合策略的总结。基于此，我们建议从多维度的角度系统地考虑基因、通路和药物敏感性之间的因果关系。在研究方法的设计上，应尽可能应用CRISPR-Cas、TALENS和患者来源的异种移植模型等新兴技术，以提高临床相关结果的准确性。