Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China.
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China.
Cell Oncol (Dordr). 2020 Dec;43(6):989-1001. doi: 10.1007/s13402-020-00529-1. Epub 2020 May 30.
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.
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.
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，它对其他多种实体瘤也有很好的疗效。然而，不幸的是，由于耐药性的出现，治疗效果可能会大大降低。在过去的十年中，在 5-FU 耐药性的分子机制、临床前（动物）模型和临床试验方面取得了重大进展。
本文系统地综述和更新了结直肠癌中与药物摄取和激活、靶酶（DPD、TS 和 MTHFR）表达和活性以及关键信号通路相关的 5-FU 药物基因组学的最新知识。此外，还总结了旨在针对特定基因和/或通路以逆转 5-FU 耐药性的药物联合策略。基于此，我们建议应从多维角度系统考虑基因、通路和药物敏感性之间的因果关系。在研究方法的设计中，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，以提高与临床相关结果的准确性。
