A review of PARP inhibitors: from bench to bedside — Ann Oncol

Ann Oncol (2011) 22 (2): 268-279.
doi: 10.1093/annonc/mdq322
First published online: July 19, 2010

A review of PARP inhibitors: from bench to bedside
C. Underhill1,2, M. Toulmonde1 and H. Bonnefoi1,*

+ Author Affiliations
1Department of Medical Oncology, Insitut Bergonié Cancer Center and University of Bordeaux, Bordeaux, France
2University of New South Wales, Rural Clinical School, Albury, Australia


*Corresponding author: Prof. H. Bonnefoi, Department of Medical Oncology, Institut Bergonié Cancer Center, 229 Cours de l'Argonne, Université de Bordeaux 2, 33076 Bordeaux cedex, France. Tel: +33-556-33-78-17; Fax: +33-556-33-33-30; E-mail: bonnefoi@bergonie.org


Received February 2, 2010.
Revision received April 28, 2010.
Accepted April 28, 2010.


Abstract
Background: Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, with novel and selective mechanisms of action, have moved from the laboratory to the clinic in just the last few years.

Design: We conducted an extensive review of PARP inhibitors using a Medline search. We also searched abstracts in databases of major international oncology meetings from the last 4 years.

Results: To understand the mechanisms of action of PARP inhibitors requires a basic understanding of DNA repair mechanisms and the critical role of the PARP enzyme. We briefly review these DNA repair mechanisms, the concept of ‘synthetic lethality’, and how PARP inhibitors play a role to selectively disrupt DNA repair in cells with absent or dysfunctional BRCA genes. We review the preclinical data highlighting this unique and selective mechanism of action and we discuss early but highly promising clinical data and ongoing studies.

Conclusion: PARP inhibitors show promise as a powerful therapeutic tool, especially in the management of BRCA-associated breast and ovarian cancers but also in tumours where BRCA genes may be dysfunctional. Clinical studies are ongoing and many translational questions remain unanswered that will help clarify how to determine the best way to use PARP inhibitors.


full-text:
A review of PARP inhibitors: from bench to bedside — Ann Oncol