Abstract
BackgroundThe radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. However, its effect on normal tissues in combination with radiation has not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation in a urethane-induced mouse lung cancer model.MethodsTo assess tolerability, A/J mice were treated with olaparib plus whole thorax radiation (13 Gy), body weight changes were monitored and normal tissue effects were assessed by histology. In anti-tumour (intervention) studies, A/J mice were injected with urethane to induce lung tumours, and were then treated with olaparib alone, left thorax radiation alone or the combination of olaparib plus left thorax radiation at 8 weeks (early intervention) or 18 weeks (late intervention) after urethane injection. Anti-tumour efficacy and normal tissue effects were assessed by visual inspection, magnetic resonance imaging and histology.ResultsEnhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation. In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity.ConclusionsThe addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.
Highlights
The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported
Combination of olaparib with whole thorax radiation increases oesophageal toxicity in A/J mice A fractionated dose of 25 Gy (5 × 5 Gy) and a biologically equivalent single dose of 13 Gy24 were chosen for thoracic radiation in these studies as pilot studies had shown that these doses have significant anti-tumour activity in the A/J model that could potentially be increased by combination treatment
In order to further mitigate potential toxicity in subsequent experiments, we reduced the dose of olaparib to 50 mg/kg given 1 h before radiation, a dose/schedule that we had previously shown to be effective in increasing the anti-tumour activity of radiation in human lung cancer xenograft models and shown evidence of oesophageal toxicity when whole thorax irradiation was combined with 50 mg/kg olaparib in C57BL6 mice.[11,12]
Summary
The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. RESULTS: Enhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity. Poly(ADP-ribose) polymerase 1 (PARP-1) is able to detect radiation-induced DNA SSBs, and recruit DNA repair proteins to facilitate DNA repair.[1] Following radiation, inhibition of PARP-1 inhibits SSB DNA repair, which can inhibit DNA synthesis leading to collapsed replication forks, increased DNA double-strand breaks and the subsequent cell death.[2] PARP inhibition has been shown to enhance the effects of radiotherapy in various pre-clinical tumour models including lung cancer,[3,4,5,6] breast cancer,[4] prostate cancer and colon cancer.[7]
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