Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets
Cet article passe en revue les mécanismes cellulaires associés à l'irinotecan, un inhibiteur de la topoisomérase 1, et évalue les données précliniques suggérant l'intérêt de diverses petites molécules inhibant les protéines clés de ces mécanismes
The topoisomerase I (Top 1) poison irinotecan is an important component of the modern treatment of colorectal cancer. By stabilising Top 1-DNA complexes, irinotecan generates Top 1-linked DNA single-strand breaks that can evolve into double-strand breaks and ultimately cause cell death. However, cancer cells may overcome cell killing by releasing the stalled topoisomerase from DNA termini, thereby reducing the efficacy of Top 1 poisons in clinics. Thus, understanding the DNA repair mechanisms involved in the repair of Top 1-mediated DNA damage provides a useful tool to identify potential biomarkers that predict response to this class of chemotherapy. Furthermore, targeting these pathways could enhance the therapeutic benefits of Top 1 poisons. In this review, we describe the cellular mechanisms and consequences of targeting Top 1 activity in cells. We summarise preclinical data and discuss the potential clinical utility of small-molecule inhibitors of the key proteins.