Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model

Abstract

Background The 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. Methods To 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. 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. Conclusions The addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.

A high-throughput focused collimator for OAR-sparing preclinical proton FLASH studies: commissioning and validation

“…The custom collimator subject of this study is intended to be used in investigating the effect of radiation-induced normal tissue damage by delivering 17.5-22.5 Gy to a single lung of 10-12 week of age C57L/J mice (hemithorax irradiation), and is designed to produce irradiation fields similar to those used in the comparable kV x-ray hemithoracic irradiation technique (Down et al 1986, Jackson et al 2010, Jiang et al 2021. Maximal sparing of the contra-lateral lung, the mediastinum, and gut is critical to avoid gastro-intestinal acute radiation syndrome or pulmonary-cardiac toxicity, which can result in premature animal death.…”

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

“…Inhibitors for vital proteins (mTOR) and signaling pathways (hedgehog signaling or CD73/adenosine) have been incorporated into nanomedicines to indirectly increase ROS deposition and augment the microenvironmental stress. 120,121 Inhibitors for DNA repair (olaparib), 122 enhancers for RT-induced apoptosis (perifosine), 123 and disrupters for the cell cycle (proflavine hemisulfate, gemcitabine, and pentoxifylline) and the NAD + metabolism are the family members of radiosensitizers, 124,125 as they directly or indirectly improve the therapeutic outcome of RT.…”

Radiation-induced persistent DNA damage response and late toxicity in cardiac tissue

“…We previously reported development of inflammatory oesophagitis in the A/J mouse approximately one week after thoracic irradiation 13 . The development of inflammation-induced events following irradiation suggest that the A/J mouse is a useful model for the evaluation of other early and late toxicities from radiotherapy.…”

“…The A/J mouse has been shown to develop relevant pathophysiological adverse events to radiotherapy including pneumonitis following thoracic radiation therapy 12 . We previously reported development of inflammatory oesophagitis in the A/J mouse approximately one week after thoracic irradiation 13 . The development of inflammation-induced events following irradiation suggest that the A/J mouse is a useful model for the evaluation of other early and late toxicities from radiotherapy.…”