Escalante Paula I, Quiñones Luis A, Contreras Héctor R
Laboratory of Chemical Carcinogenesis and Pharmacogenetics (CQF), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, 8500000 Santiago, Chile.
Laboratory of Cellular and Molecular Oncology (LOCYM), Department of Basic and Clinical Oncology (DOBC), Faculty of Medicine, University of Chile, 8380453 Santiago, Chile.
Pharmaceutics. 2021 Jan 8;13(1):75. doi: 10.3390/pharmaceutics13010075.
The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (), thymidylate synthase (), methylenetetrahydrofolate reductase (), the DNA repair enzymes , , and , and the phase 2 enzyme impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of , , , and . In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of , , , , , and expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.
基于5-氟尿嘧啶与奥沙利铂联合使用的FOLFOX方案，是诊断为转移性结直肠癌患者最常使用的化疗方案。然而，化疗耐药的发生是与该疾病相关的主要挑战之一。据报道，上皮-间质转化（EMT）与微小RNA驱动的肿瘤细胞对5-氟尿嘧啶和奥沙利铂反应的调节有关。此外，从药物基因组学研究可知，编码二氢嘧啶脱氢酶、胸苷酸合成酶、亚甲基四氢叶酸还原酶、DNA修复酶以及2期酶的基因过表达会损害对FOLFOX的反应。据观察，EMT与、、和的过表达有关。在本综述中，我们研究了微小RNA作为肿瘤细胞中EMT促进因子的作用，及其对、、、、和表达上调的潜在影响，这会导致结直肠癌肿瘤细胞对5-氟尿嘧啶和奥沙利铂产生耐药性。这构成了FOLFOX化疗下转移性结直肠癌患者获得性耐药迟发所涉及的表观遗传调控的潜在机制。这些生物标志物微小RNA的表达可作为个性化医疗的工具，并在未来作为潜在的治疗靶点。
