Therapeutic potential of drugs to modulate DNA repair in cancer

Abstract

Most established cancer therapy regimes involve DNA-damaging chemotherapy or radiotherapy. The DNA repair capacity of the tumour, therefore, represents a mechanism of therapeutic resistance. Drugs to inhibit DNA repair pathways have been developed and they demonstrate good chemosensitisation and radiosensitisation activity in preclinical models. Two classes of DNA repair inhibitors have entered clinical trial and show promising activity. Genetic instability in tumours may be at least partially due to defects in DNA repair pathways; such defects may underlie the inherent sensitivity of some tumours to certain classes of anticancer agent. DNA repair defects may also make the tumour dependent on complimentary or back-up pathways; laboratory evidence shows that targeting these complimentary pathways results in tumour-selective therapy.

Keywords::

• cancer
• DNA protein kinase
• DNA repair
• O⁶-alkylguanine DNA alkyltransferase
• poly(ADP-ribose) polymerase

Acknowledgements

The author gratefully acknowledges the continued financial support from Cancer Research UK. The author has collaborated with Agouron Pharmaceuticals, now Pfizer GRD, in the development of AG-14361 and AG-014699, including the Phase I trial of AG-014699 (1997 – 2005) and with KuDOS pharmaceuticals in the development of NU-7026 and NU-7441 (2000 – 2006) and is co-inventor on some patents on these compounds.