Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy.
Poly(ADP-ribose)polymerase (PARP) is a ubiquitously present nuclear enzyme that is not only involved in many important cellular pathways but also contributes to chromosomal structure and genomic stability. The development of highly selective and potent PARP inhibitors has become of increasing clinical interest because of their promising efficacy in patients with breast or ovarian cancer. Furthermore, recent Phase I and Phase II trials have demonstrated that PARP inhibitors have low toxicity rates. In particular patients with either deficiency or dysfunction of BRCA, which is involved in DNA double strand break repair, appear to benefit from PARP inhibition. This article summarizes the present knowledge regarding the physiological function of PARP and ([poly]ADP-ribose) PAR, the functional product of PARP, the development of PARP inhibitors, the recent clinical data of PARP inhibitors in cancer treatment and the selection of patients who may benefit from PARP inhibition.
Heitz
Florian
F
Department of Gynecology & Gynecological Oncology, Dr Horst Schmidt-Kliniken (HSK), Wiesbaden, Ludwig Erhard Str.100, 65199 Wiesbaden, Germany. florian.heitz@gmx.net
Harter
Philipp
P
Ewald-Riegler
Nina
N
Papsdorf
Michael
M
Kommoss
Stefan
S
du Bois
Andreas
A
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000172:deficiency / Q000502:physiology; D024682:BRCA2 Protein / Q000172:deficiency / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000378:metabolism; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human