Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers

Approximately two million fractions of radiotherapy are administered in the UK every year, as part of adjuvant, radical or palliative cancer treatment. For many tumour types, radiotherapy is routinely combined with concomitant chemotherapy as part of adjuvant or radical treatment. In addition, new agents have been developed in recent years and tested in phase 1, 2 and 3 trials concomitantly with radiotherapy or chemoradiotherapy. One such class of drugs, the poly(ADP-ribose) polymerase (PARP) inhibitors, has shown activity in conjunction with radiotherapy in several cancer cell lines. Pre-clinical data suggest that PARP inhibitors may potentiate the effects of radiotherapy in several tumour types, namely lung, colorectal, head and neck, glioma, cervix and prostate cancers. In vitro, PARP inhibitors are radiosensitisers in various cell lines with enhancement ratios of up to 1.7. In vivo, non-toxic doses of PARP inhibitors have been shown to increase radiation-induced growth delay of xenograft tumours in mice. Clinical trials to assess the toxicity and potential benefit of combining radiotherapy with PARP inhibition are now needed.