Abstract | PURPOSE: METHODS AND MATERIALS: The antitumor effects of fractionated irradiation (5 Gy × 4) in combination with BMN673 were evaluated in nude mice bearing established Calu-6 human lung cancer xenografts. The normal tissue response was evaluated in C57BL6 mice that were treated with BMN673 or AZD2281 combined with fractionated irradiation, 5 Gy × 4, delivered to the whole thorax. Body weight and histology of the esophagus and skin in the field of irradiation were examined. The DNA damage response in the esophagus and skin was assessed by γH2AX immunohistochemistry. RESULTS: While PARP inhibition enhanced irradiation-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 irradiation-induced DNA damage in the esophagus and skin. CONCLUSIONS: Although PARP inhibition enhanced the antitumor response to fractionated irradiation, it also enhanced the irradiation response in replicating normal tissues. Therefore, our study suggests that additional caution may be warranted in the clinical development of combination therapies using PARP inhibitors and radiation therapy, in particular where the field of irradiation includes the esophagus.
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Authors | Luiza Madia Lourenco, Yanyan Jiang, Neele Drobnitzky, Marcus Green, Fiona Cahill, Agata Patel, Yasmin Shanneik, John Moore, Anderson J Ryan |
Journal | International journal of radiation oncology, biology, physics
(Int J Radiat Oncol Biol Phys)
Vol. 100
Issue 3
Pg. 767-775
(03 01 2018)
ISSN: 1879-355X [Electronic] United States |
PMID | 29413287
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017. Published by Elsevier Inc. |
Chemical References |
- H2AX protein, human
- Histones
- Phthalazines
- Piperazines
- Poly(ADP-ribose) Polymerase Inhibitors
- Radiation-Sensitizing Agents
- talazoparib
- olaparib
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Topics |
- Animals
- Combined Modality Therapy
(adverse effects)
- DNA Damage
- Esophagus
(drug effects, radiation effects)
- Female
- Heterografts
- Histones
(analysis)
- Humans
- Lung Neoplasms
(radiotherapy)
- Mice
- Mice, Inbred C57BL
- Mice, Nude
- Organs at Risk
(radiation effects)
- Phthalazines
(pharmacology)
- Piperazines
(pharmacology)
- Poly(ADP-ribose) Polymerase Inhibitors
(pharmacology)
- Radiation Injuries, Experimental
(pathology)
- Radiation-Sensitizing Agents
(pharmacology)
- Skin
(drug effects, radiation effects)
- Weight Loss
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