Abstract
BackgroundPoly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect.Materials and MethodsHere, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported.ResultsSixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data.ConclusionPARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.
Highlights
Poly-(adenosine diphosphate-ribose)-polymerase (PARP) is a family of enzymes involved in a wide number of cellular processes, including DNA replication, transcription, repair and cell death
The ten years will be determining for judging their real potential
Further studies have shown that PARP1 and PARP-2 were implicated in DNA breaks repair by Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR)
Summary
Poly-(adenosine diphosphate-ribose)-polymerase (PARP) is a family of enzymes involved in a wide number of cellular processes, including DNA replication, transcription, repair and cell death. PARP proteins have been studied for decades for notably their roles in DNA repair. PARP1 is the most abundant and active enzyme of the PARP family, but roles of other members including PARP2 and PARP3 in DNA damage responses is emerging. They play an important role by detecting the presence of damaged DNA and by activating signalization pathways that promote appropriate cellular responses. PARP is involved in base excision repair (BER) by allowing the recruitment and activation of BER www.impactjournals.com/oncotarget actors and make easier the DNA single strand break (SSB) reparation. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, participate to their radio-sensitization effect
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