Pan Xie1,2, Jun-Luan Mo3, Jin-Hong Liu3, Xi Li1,2, Li-Ming Tan4, Wei Zhang1,2, Hong-Hao Zhou1,2, Zhao-Qian Liu5,6. 1. Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China. 2. Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China. 3. Shenzhen Center for Chronic Disease Control, 518020, Shenzhen, People's Republic of China. 4. Department of Pharmacy, The Second People's Hospital of Huaihua City, 418000, Huaihua, People's Republic of China. 5. Department of Clinical Pharmacology and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, People's Republic of China. zqliu@csu.edu.cn. 6. Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, 410078, Changsha, People's Republic of China. zqliu@csu.edu.cn.
Abstract
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.
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.
Entities:
Keywords:
5-FU; Colorectal cancer; Drug resistance; Pharmacogenomics
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