Sabeti Aghabozorgi Amirsaeed, Moradi Sarabi Mostafa, Jafarzadeh-Esfehani Reza, Koochakkhani Shabnaz, Hassanzadeh Marziyeh, Kavousipour Soudabeh, Eftekhar Ebrahim
Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad 1394491388, Iran.
Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran.
World J Gastrointest Oncol. 2020 Sep 15;12(9):942-956. doi: 10.4251/wjgo.v12.i9.942.
5-flurouracil (5-FU)-based chemotherapy is the main pharmacological therapy for advanced colorectal cancer (CRC). Despite significant progress in the treatment of CRC during the last decades, 5-FU drug resistance remains the most important cause of failure in CRC therapy. Resistance to 5-FU is a complex and multistep process. Different mechanisms including microsatellite instability, increased expression level of key enzyme thymidylate synthase and its polymorphism, increased level of 5-FU-activating enzymes and mutation of are proposed as the main determinants of resistance to 5-FU in CRC cells. Recently, micro-ribonucleic acids (miRNA) and their alterations were found to have a crucial role in 5-FU resistance. In this regard, the miRNA-mediated mechanisms of 5-FU drug resistance reside among the new fields of pharmacogenetics of CRC drug response that has not been completely discovered. Identification of the biological markers that are related to response to 5-FU-based chemotherapy is an emerging field of precision medicine. This approach will have an important role in defining those patients who are most likely to benefit from 5-FU-based chemotherapy in the future. Thereby, the identification of 5-FU drug resistance mechanisms is an essential step to predict and eventually overcome resistance. In the present comprehensive review, we will summarize the latest knowledge regarding the molecular determinants of response to 5-FU-based chemotherapy in CRC by emphasizing the role of miRNAs.
基于5-氟尿嘧啶（5-FU）的化疗是晚期结直肠癌（CRC）的主要药物治疗方法。尽管在过去几十年中CRC治疗取得了显著进展，但5-FU耐药性仍然是CRC治疗失败的最重要原因。对5-FU的耐药是一个复杂的多步骤过程。包括微卫星不稳定性、关键酶胸苷酸合成酶表达水平增加及其多态性、5-FU激活酶水平增加以及[此处原文缺失相关内容]突变等不同机制被认为是CRC细胞中5-FU耐药的主要决定因素。最近，微小核糖核酸（miRNA）及其改变被发现在5-FU耐药中起关键作用。在这方面，miRNA介导的5-FU耐药机制存在于尚未完全发现的CRC药物反应药物遗传学新领域中。鉴定与基于5-FU的化疗反应相关的生物标志物是精准医学的一个新兴领域。这种方法在确定未来最有可能从基于5-FU的化疗中获益的患者方面将发挥重要作用。因此，鉴定5-FU耐药机制是预测并最终克服耐药性的关键步骤。在本综述中，我们将通过强调miRNA的作用来总结关于CRC中基于5-FU的化疗反应分子决定因素的最新知识。
