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Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies

Paul Lesueur _, François Chevalier, Jean-Baptiste Austry, Waisse Waissi, Hélène Burckel, Georges Noël, Jean-Louis Habrand, Yannick Saintigny and Florence Joly

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Oncotarget. 2017; 8:69105-69124. https://doi.org/10.18632/oncotarget.19079

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Abstract

Paul Lesueur1,2, François Chevalier1, Jean-Baptiste Austry1, Waisse Waissi3, Hélène Burckel3, Georges Noël3, Jean-Louis Habrand2, Yannick Saintigny1,* and Florence Joly4,*

1Laboratoire d’Accueil et de Recherche avec les Ions Accélérés, CEA, CIMAP-GANIL, 14000 Caen, France

2Centre Francois Baclesse Centre de Lutte Contre le Cancer, Radiotherapy Unit, 14000 Caen, France

3EA 3430, Laboratoire de Radiobiologie, Centre Paul Strauss, 67000 Strasbourg, France

4Centre Francois Baclesse Centre de Lutte Contre le Cancer, Clinical Research Unit, 14000 Caen, France

*These authors contributed equally to this work and are co last authors

Correspondence to:

Paul Lesueur, email: Paul.Lesueur89@gmail.com

Keywords: radiosensitization, poly(ADP-ribose)-polymerase inhibitors, radiotherapy, radiobiology

Received: May 27, 2017     Accepted: June 19, 2017     Published: July 07, 2017

ABSTRACT

Background: Poly-(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 Methods: Here, 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.

Results: Sixty 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.

Conclusion: PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.


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PII: 19079