PARP-1 inhibitors: a novel genetically specific agents for cancer therapy.

ABSTRACT

The nuclear poly(ADP-ribose) polymerase-1 (PARP-1) represents an important novel target in cancer therapy. The enzyme is essential for single strand DNA breaks repair via base excision repair pathway. Inhibition of PARP-1 exerts "synthetic lethality" effect towards the tumors with defects in DNA repair by homologous recombination, specifically the tumors with mutations in the breast cancer associated BRCA1 and BRCA2 genes. Recent clinical data confirmed the early in vitro studies and suggest that PARP-1 inhibitors could be used not only as chemosensitizers but as well as single agents to selective kill tumors with defective DNA repair by homologous recombination. Such concept of "synthetic lethality" for tumors which have lost one DNA repair pathway by targeting a second DNA repair pathway, represents groundbreaking therapeutic strategy. The review highlights our current knowledge and ongoing clinical development/trials of PARP-1 inhibitors.