Poly(ADP-ribose) polymerase inhibitors as cancer therapy

Poly(ADP-ribose) polymerase (PARP) inhibitors are pharmacologic agents which primarily inhibit the PARP-1 and PARP-2 enzymes within the cell. Inhibition of PARP results in failure of base-excision repair (BER) to correct single-stranded breaks in DNA. This failure results in double-stranded breaks that are subsequently repaired either by homologous recombination (HR) repair, which is error-free, or by non-homologous end joining (NHEJ), which is an error-prone process. Clinically, PARP inhibitors demonstrate activity in tumors which lack a functional HR system (i.e. BRCA1 and BRCA2 mutations) by forcing NHEJ repair. Known as synthetic lethality, the use of NHEJ in these tumors generates genomic instability and eventual cell death due to rapid development of non-viable genetic errors. In addition due their BER effects, PARP inhibitors are being developed as chemotherapy and radiation sensitizers in a number of tumor types. This review will examine the role of the PARP enzymes in DNA repair, PARP inhibitors in HR-deficient tumors, current results of clinical studies of PARP inhibitors and research efforts to expand the clinical activity of PARP inhibitors beyond HR-deficient tumors.