Poly(ADP-ribosyl)ation polymerases: mechanism and new target of anticancer therapy

Abstract

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 hase 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.

Keywords::

• BRCA deficiency
• BRCA mutation
• clinical benefit
• clinical trial
• DNA damage
• DNA double strand break
• DNA repair
• DNA replication
• DNA single strand break
• PARP
• PARP inhibition
• PARP inhibition resistance
• PARP-physiological function
• poly(ADP-ribose)polymerase
• toxicity

Financial & competing interests disclosure

The authors recieved grants for scientific enterprises by AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing assistance was provided by Monika Schoell.