Abstract
Whilst the depletion of poly(ADP-ribose) polymerase (PARP) activity associated with PARP-1 and PARP-2 in cells causes radiosensitivity, its inhibition by small molecule inhibitors is showing great potential as a mechanism to potentiate the effects of radiotherapy. Indeed as over 50 % of all cancer patients will receive radiotherapy at some point in their treatment there is considerable interest in the development of radiosensitisers that can replace chemotherapeutic agents without the associated dose-limiting toxicities. Potent and specific inhibitors of PARP activity that compete with NAD+ at the enzyme’s activity site have been developed. Their use in preclinical in vitro and in vivo models is associated with enhanced radiosensitivity through mechanisms that not only involve the trapping of the PARP proteins at sites of strand breaks and the modulation of DNA repair in a proliferation dependent manner but also through the targeting of the endothelium and tumour vasculature and changes in tumour oxygenation and thus hypoxia-related radioresistance. However as both PARP-1 and PARP-2 are also involved in transcription regulation, chromatin modification and cellular homeostasis, the impact of PARP inhibition on these processes and long-term therapeutic responses needs to be investigated, as well as issues relating to scheduling, dose and radiation quality on the efficacy of this combined therapy.
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Acknowledgements
Research in Inserm U612 is supported by Inserm and Institut Curie and is part of the Comprehensive Cancer Centre “SIRIC” program (INCa 2011-189). CF is supported by INCa (PL-BIO 2013-11) and AF by a PhD fellowship from the French Ministry of Research. MTB was supported by Institute Curie’s International Postdoctoral fellow program.
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Fouillade, C., Fouquin, A., Boudra, MT., Favaudon, V., Pennaneach, V., Hall, J. (2015). Radiosensitisation by Poly(ADP-ribose) Polymerase Inhibition. In: Curtin, N., Sharma, R. (eds) PARP Inhibitors for Cancer Therapy. Cancer Drug Discovery and Development, vol 83. Humana Press, Cham. https://doi.org/10.1007/978-3-319-14151-0_11
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