Therapeutic Intervention by the Simultaneous Inhibition of DNA Repair and Type I or Type II DNA Topoisomerases: One Strategy, Many Outcomes

Abstract

Many anticancer drugs reduce the integrity of DNA, forming strand breaks. This can cause mutations and cancer or cell death if the lesions are not repaired. Interestingly, DNA repair-deficient cancer cells (e.g., those with BRCA1/2 mutations) have been shown to exhibit increased sensitivity to chemotherapy. Based on this observation, a new therapeutic approach termed 'synthetic lethality' has been developed, in which radiation therapy or cytotoxic anticancer agents are employed in conjunction with selective inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1). Such combinations can cause severe genomic instability in transformed cells resulting in cell death. The synergistic effects of combining PARP-1 inhibition with anticancer drugs have been demonstrated. However, the outcome of this therapeutic strategy varies significantly between cancer types, suggesting that synthetic lethality may be influenced by additional cellular factors. This review focuses on the outcomes of the combined action of PARP-1 inhibitors and agents that affect the activity of DNA topoisomerases.