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.

Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer

“…This is in agreement with other studies showing a decrease in expression and activity of Topo-1 after treatment with camptothecin or its analogs. 16,35 Our results also showed significantly decreased expression of Topo-1 in patients with longer survival duration as compared to the group with shorter survival duration. These results are not supported by the earlier hypothesis that lower expression of Topo-1 is correlated with a worse response to Topo-1 inhibitors.…”

“…6,11,33,34 It has also been suggested that the cytotoxic effects of these inhibitors are dependent on the stabilization of topoisomerase-DNA complex. 35 Both in vitro and in vivo studies have demonstrated that sensitivity to these agents is modulated by absolute value of Topo-1 levels and Topo-1 protein expression is correlated well with poor patient survival. Our results showed a significant decrease in the expression of Topo-1 in post treatment sections.…”

Preclinical Activity of Nanoliposomal Irinotecan Is Governed by Tumor Deposition and Intratumor Prodrug Conversion

“…Pharmacogenetic and pharmacodynamic markers such as TOP1 have shown limited correlations with free irinotecan response (6,(32)(33)(34). In addition to the intrinsic sensitivity of tumor cells to SN-38, our data indicate that the duration for which tumor cells are exposed to SN-38 (tumor SN-38 duration) also plays a critical role in driving treatment response to irinotecan.…”

Activation of a PGC-1-related Coactivator (PRC)-dependent Inflammatory Stress Program Linked to Apoptosis and Premature Senescence

“…Nevertheless, human U2OS cells are known to undergo premature senescence, demonstrating that this program can be reactivated in these tumor cells (24). SN-38 is the active metabolite of irinotecan, a topoisomerase I inhibitor that is used in the treatment of colorectal cancer (54).…”