DNA Repair and Resistance to Topoisomerase I Inhibitors: Mechanisms, Biomarkers and Therapeutic Targets

Abstract

Irinotecan and topotecan are derivatives of the naturally occurring cytotoxic compound camptothecin that are used in the treatment of patients with colorectal cancer, either as single agents or in combination with radiotherapy and/or other chemotherapy drugs. They are inhibitors of DNA topoisomerase I (Top I) and exert their cytotoxic effects in replicating cells by inducing DNA strand breaks. A wide range of DNA repair proteins is involved in the recognition and repair of these breaks, and depletion or inhibition of some of these proteins increases the cytotoxic effects of Top I inhibitors. Building on these laboratory observations, ongoing translational research is aiming to establish whether this mechanistic information can be used to improve the treatment of patients with certain types of cancer. Two potential strategies are under investigation: (1) individualising treatment by evaluating levels and/or patterns of expression of DNA repair proteins that predict clinical response to Top I inhibitors, and (2) developing small molecule inhibitors of these repair enzymes to overcome tumour resistance and improve outcomes. This review summarises the current status of these research endeavours, focusing on the key roles of tyrosyl DNA phosphodiesterase 1 (Tdp1) and poly(ADP-ribose) polymerase (PARP), and examines the pre-clinical and clinical data that support the potential value of these and other DNA repair proteins as predictive markers and therapeutic targets. Since irinotecan is increasingly being combined with radiotherapy, the potential for these proteins to act as predictive biomarkers for both Top I inhibitors and radiation is proposed, and the possibility of synergistic potentiation of chemoradiation regimes by Tdp1 and/or PARP inhibitors is considered.

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.…”

BMI-1 is important in bufalin-induced apoptosis of K562 cells

“…Inhibiting Tdp1 provides an attractive approach to potentiating clinically used Top1 inhibitors (66,67). Bufalin is able to reduce the quantity, activity and mRNA levels of topoisomerase II (11).…”

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

“…Targeting TDP1 for cancer therapy is clinically attractive for many reasons. First, TDP1 is a broad-spectrum 3′ DNA end-processing enzyme: therefore, suppressing its activity is predicted to potentiate a number of cancer therapy protocols that induce PDBs either directly or indirectly, such as TOP1 poisons, alkylating agents, radiotherapy and chain terminators 22,29,53,61,63,[69][70][71] . Second, TDP1 deficiency is well tolerated in vertebrates and thus targeting TDP1 is likely to result in minimal toxicity.…”