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Review
. 2017 Jul 7;8(40):69105-69124.
doi: 10.18632/oncotarget.19079. eCollection 2017 Sep 15.

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

Paul Lesueur  1   2 , François Chevalier  1 , Jean-Baptiste Austry  1 , Waisse Waissi  3 , Hélène Burckel  3 , Georges Noël  3 , Jean-Louis Habrand  2 , Yannick Saintigny  1 , Florence Joly  4
Affiliations
Review

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

Paul Lesueur et al. Oncotarget. .

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.

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

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Conflict of interest statement

CONFLICTS OF INTEREST None.

Figures

Figure 1
Figure 1. Mechanisms and advantages of PARPi radiosensitization
Figure 2
Figure 2. Flow chart of the systematic review following PRISMA guidelines
Figure 3
Figure 3. Clonogenic survival rate of chondrosarcoma cell after protontherapy sensitization with alkylant agents and PARPi
Chondrosarcoma cells were first cultured with Temozolomide and /or PARPi for 2 hours, then irradiated with proton beam at 2 Gy (62 MeV.u−1, SOBP, 1,1 keV u−1 at LNS, Catania, Italy) and then left overnight at 37°C. Cells were then seeded at low density for subsequent clonogenic assay, as previously described [116]. Left: survival fraction of SW1353 chondrosarcoma cells after 2 Gy proton alone, and with olaparib (2 μM), temozolomide (Sigma-Aldrich ref T2577) (20 μM) and olaparib with temozolomide (2 μM + 20 μM respectively). Right: survival fraction as a function of different chondrosarcoma cell lines. CH 2879 and Oums 27 are two other chondrosarcoma cell lines, showing that the variability of the response to the treatment is related to the cell line used. Cells were irradiated alone or with Olaparib (Focus biomolecules Ref 102154) at 2 μM, or AG (AG14361, Tebu-Bio, ref 27602-3) at 0.4 μM. Each treatment is estimated as a percentage of the control sample, repeated 3 times.
See this image and copyright information in PMC

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