The potential of PARP inhibitors in genetic breast and ovarian cancers.
The abundant nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), represents an important novel target in cancer therapy. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer associated (BRCA) 1 and 2 genes. This theory of selectively exploiting cells defective in one DNA repair pathway by inhibiting another is a major breakthrough in the treatment of cancer. BRCA1/2 mutations are responsible for the majority of genetic breast/ovarian cancers, known as the hereditary breast ovarian cancer syndrome. This review summarizes the preclinical and clinical evidence for the potential of PARP inhibitors in genetic breast and ovarian cancers.
Drew
Yvette
Y
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, United Kingdom. Yvette.drew@ncl.ac.uk
Calvert
Hilary
H
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors