Abstract

Background:The spectrum of DNA lesions induced by ionising radiation varies according to dose delivered; hence the relative importance of DNA repair proteins is also likely to vary with dose. Depletion or inhibition of PARP-1 is associated with radiosensitisation to doses of 2 Gy and above [1]; its activation by single strand breaks and interactions with the base excision repair pathway [2] suggest a potential role in the response to lower doses. Inhibition of PARP-1 may thus enhance the response of tumours to ultrafractionated and low dose rate radiotherapy protocols. We tested the effect of chemical inhibitors of PARP on low dose clonogenic survival in a range of hamster fibroblast and human tumour cell lines in PARP-1 knockout mouse embryo fibroblasts (MEF) [3]. Material/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 of chemical PARP inhibitors was measured using a fluorescence-activated cell sorting assay [4].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 enzymes and deletion of the PARP-1 gene suggests that compensatory low dose repair mechanisms are upregulated in PARP-1 knockout cells, or that inhibition of both PARP-1 and PARP-2 is required for low dose radiosensitisation.References: 1.Shall S, de Murcia G: Mutation Research, 2000; 460: 1-15 2.Dantzer F, de la Rubia et al: Biochemistry, 2000; 39: 7559-69 3.de Murcia JM, Niedergang C et al: Proc Nat Acad Sci, 1997; 95: 7303-7 4.Skwarchuk MW, Wouters BG, Skarsgard LD: Int J Radiat Biol, 1993; 64: 601-12

Keywords: poly(ADP-ribose) polymerase-1, chemical inhibitors, low dose radiation