PARP inhibitors – theoretical basis and clinical application

• Main Authors: Sylwia Dębska, Joanna Kubicka, Rafał Czyżykowski, Maja Habib, Piotr Potemski
• Format: Article
• Language: English
• Published: Index Copernicus International S.A. 2012-05-01
• Series: Postępy Higieny i Medycyny Doświadczalnej
• Subjects: synthetic lethality; poly-ADP-ribose polymerase; Base excision repair; homologous recombination repair; Nonhomologous end joining; BRCA1/2 genes; ovarian cancer; Triple negative breast cancer
• Online Access: http://journals.indexcopernicus.com/fulltxt.php?ICID=999033

 Poly-ADP-ribose polymerases (PARP) are involved in a number of processes that are vital for every living cell. Once activated by the presence of DNA damage they trigger poly-ADP-ribosylation of various proteins which are crucial for DNA repair, preserving of genom integrity, regulation of transcription, proliferation and apoptosis. PARP1, which is the best known enzyme of PARP protein family, plays a role in single-strand breaks (SSB) repair. Decrease of its activity results in accumulation of single strand DNA breaks (SSB) which leads as a consequence to double- strand breaks (DSBs). This disorder is particularly harmful to cells with deficiency of BRCA1/2 protein which is involved in repair of DNA double-strand breaks.This phenomenon is an example of “synthetic lethality” concept and contributes to research on application of PARP inhibitors in treatment of cancers associated with BRCA1/2 protein defect (breast or ovarian cancer).Noticed synergism between PARP inhibitors and genotoxic chemotherapy or radiotherapy determined another direction of research on application of these medicaments.After promising results of phase I and II trials with most commonly investigated PARP inhibitors – iniparib and olaparib- which recruited patients with triple negative breast cancer and ovarian cancer, further studies started.This paper presents theoretical basis of PARP inhibitors action as well as critical review of most important clinical trials of these medicaments.