The clinical development of inhibitors of poly(ADP-ribose) polymerase

A number of inhibitors of DNA repair have been evaluated or are undergoing development as potential cancer treatments. Inhibitors of poly(ADP-ribose) polymerase (PARP) are of particular interest in treating hereditary breast cancers occurring in patients who are carriers of BRCA1 or BRCA2 mutations. In vitro PARP inhibitors are highly cytotoxic to cell lines carrying BRCA mutations while only minimally toxic to cell lines without these mutations. This is thought to be due to a phenomenon known as synthetic lethality where the accumulation of single-strand breaks consequent on PARP inhibition are converted to double-strand breaks on cell division. Cancer cells in BRCA carriers are uniquely unable to repair the consequent double-strand breaks that result during cell division. PARP inhibitors were initially developed as possible chemo-potentiating agents but have now been evaluated clinically in BRCA-related tumors, showing remarkable single-agent activity. The potential future development and use is reviewed.