title: Topoisomerase I inhibition in colorectal cancer: biomarkers and therapeutic targets.
abstract: 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.
authors: Sussex Cancer Centre, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE, UK. Duncan.Gilbert@bsuh.nhs.uk
authors: D C
authors: DC
authors: Gilbert
authors: A J
authors: AJ
authors: Chalmers
authors: S F
authors: SF
authors: El-Khamisy
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D059004:Topoisomerase I Inhibitors / Q000627:therapeutic use*
chemical_list: D014408:Biomarkers, Tumor; D059004:Topoisomerase I Inhibitors