Affiliation:
1. Department of Molecular Biology, Ariel University, Ariel 40700, Israel
Abstract
Irinotecan (SN-38) is a potent and broad-spectrum anticancer drug that targets DNA topoisomerase I (Top1). It exerts its cytotoxic effects by binding to the Top1-DNA complex and preventing the re-ligation of the DNA strand, leading to the formation of lethal DNA breaks. Following the initial response to irinotecan, secondary resistance is acquired relatively rapidly, compromising its efficacy. There are several mechanisms contributing to the resistance, which affect the irinotecan metabolism or the target protein. In addition, we have demonstrated a major resistance mechanism associated with the elimination of hundreds of thousands of Top1 binding sites on DNA that can arise from the repair of prior Top1-dependent DNA cleavages. Here, we outline the major mechanisms of irinotecan resistance and highlight recent advancements in the field. We discuss the impact of resistance mechanisms on clinical outcomes and the potential strategies to overcome resistance to irinotecan. The elucidation of the underlying mechanisms of irinotecan resistance can provide valuable insights for the development of effective therapeutic strategies.
Funder
Israel Science Foundation
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
Reference131 articles.
1. Preclinical Evaluation of CPT-11 and Its Active Metabolite SN-38;Lavelle;Semin. Oncol.,1996
2. Irinotecan: Mechanisms of Tumor Resistance and Novel Strategies for Modulating Its Activity;Xu;Ann. Oncol.,2002
3. Irinotecan: 25 Years of Cancer Treatment;Bailly;Pharmacol. Res.,2019
4. Strategies for Monitoring and Combating Resistance to Combination Kinase Inhibitors for Cancer Therapy;Ahronian;Genome Med.,2017
5. Drug Resistance and Combating Drug Resistance in Cancer;Wang;Cancer Drug Resist.,2019
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献