PARP inhibitors for anticancer therapy.
PARP-1 [poly(ADP-ribose) polymerase-1], which plays a key role in DNA repair, was discovered 50 years ago. PARPi (PARP inhibitors), originally made to probe the function of the enzyme, inhibit DNA repair and increase the potency of anticancer cytotoxic agents. PARPi of increasing potency were developed as chemo- and radio-sensitizers and first entered clinical trial in cancer patients in 2003. However, it was the revelation in 2005 that they were synthetically lethal in cells with DNA repair defects, found almost exclusively in some tumours, that led to a major interest in this class of drug. Several PARPi have entered clinical trials and show promising activity in breast, ovarian and other cancers associated with BRCA (breast cancer early-onset) mutations or other defects in homologous recombination DNA repair. It is likely that at least one of these will be licensed soon. The present review describes key events from the discovery to clinical application of PARPi.
*Newcastle University, Newcastle Cancer Centre and Northern Institute for Cancer Research, Newcastle upon Tyne NE2 4HH, U.K.
Nicola
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Curtin
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004357:Drug Synergism; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D059767:Recombinational DNA Repair
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases