Title:DNA Repair and Resistance to Topoisomerase I Inhibitors: Mechanisms, Biomarkers and Therapeutic Targets
Volume: 19
Issue: 23
Author(s): M. Alagoz, D. C. Gilbert, S. El-Khamisy and A. J. Chalmers
Affiliation:
Keywords:
Topoisomerase I, tyrosyl DNA phosphodiesterase 1, poly(ADP-ribose) polymerase, colorectal cancer, irinotecan, radiation therapy, chemoradiation, biomarkers, Irinotecan and topotecan
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.
