3 years ago

PARP inhibition combined with thoracic radiation exacerbates esophageal and skin toxicity in C57BL6 mice

PARP inhibitors have been shown to enhance the radiosensitivity of cancer cells in vitro in a replication-dependent manner. Their in vivo radiosensitizing effects have also been demonstrated in preclinical tumor models. However, whether PARP inhibition can enhance the response to radiation in normal tissues has been largely neglected. We hypothesized that PARP inhibition might also potentiate the response of replicating normal tissues to radiation. In this study, we examined the normal tissue response in mice treated with PARP inhibitors (BMN673 or AZD2281) in combination with thoracic radiation. Methods and Materials Anti-tumor effects of fractionated radiation (5 Gy x 4) in combination with BMN673 were evaluated in nude mice bearing established Calu-6 human lung cancer xenografts. Normal tissue response was evaluated in C57BL6 mice that were treated with BMN673 or AZD2281 combined with fractionated 5 Gy x 4 radiation delivered to the whole thorax. Body weight and histology of the esophagus and skin in the field of irradiation were examined. DNA damage response in the esophagus and skin was assessed by γH2AX immunohistochemistry. Results Whilst PARP inhibition enhanced radiation-induced tumor growth inhibition in nude mice, it was also associated with significant body weight loss and increased damage to the esophagus and skin within the field of irradiation in C57BL6 mice. PARP inhibition compromised the repair of radiation-induced DNA damage in the esophagus and skin. Conclusion Although PARP inhibition enhanced the anti-tumor response to fractionated radiation, it also enhanced the radiation response in replicating normal tissues. Therefore, our study suggests that additional caution may be warranted in the clinical development of combination therapies utilizing PARP inhibitors and radiotherapy, in particular where the field of radiation includes the esophagus.

Teaser

PARP inhibitors have been demonstrated to potentiate the anti-tumor effect of radiation in preclinical studies. However, their effect on normal tissue response to radiation is unclear. Here we show that PARP inhibitors not only enhance radiation-induced tumor growth inhibition, but also enhance the response of the esophagus and skin to radiation. Therefore, caution may be warranted when combining PARP inhibition with radiotherapy that includes proliferating normal tissues.

Publisher URL: www.sciencedirect.com/science

DOI: S036030161734066X

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