ORAL PRESENTATIONS

The spectrum of DNA lesions induced by ionising radiation varies according to the dose delivered; hence the relative importance of different DNA repair proteins is also likely to vary with dose. Depletion or inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) is associated with radiosensitisation to doses of 2 Gy and above; that it is activated by single strand breaks and interacts with the base excision repair pathway also indicates a potential role in the response to lower doses. Inhibition of PARP-1 may thus enhance the response of tumours to low dose per fraction and low dose rate radiotherapy protocols. We tested the effect of chemical inhibitors of PARP-1 on low dose clonogenic survival in a range of hamster fibroblast and human tumour cell lines and compared these survival curves with those derived from PARP-1 knockout mouse embryo fibroblasts (MEF). Methods: Clonogenic survival of T98G and U373 human glioma cells, V79 and CHO hamster fibroblasts, and 3T3 MEF PARP-1 knockout and control cells following low-dose irradiation in the presence and absence of chemical PARP inhibitors was measured using a fluorescenceactivated cell sorting assay. Results: Whilst PARP inhibition induced radiosensitisation of V79, CHO and T98G cells in the 0.05 -0.5 Gy dose range, there was no such effect in the PARP-1 knockout cells compared with controls.Radiosensitisation to doses greater than 1.5 Gy occurred in all cell lines. Discussion: The discrepancy between the effect of chemical inhibition of PARP-1 and deletion of the PARP-1 gene may be explained by upregulation of compensatory low dose repair mechanisms in PARP-1 knockout cells. Another possibility is that inhibition of both PARP-1 and PARP-2 is required for low dose radiosensitisation.