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27 March 2018 Amelioration of Head and Neck Radiation-Induced Mucositis and Distant Marrow Suppression in Fanca–/– and Fancg–/– Mice by Intraoral Administration of GS-Nitroxide (JP4-039)
John Willis, Michael W. Epperly, Renee Fisher, Xichen Zhang, Donna Shields, Wen Hou, Hong Wang, Song Li, Peter Wipf, Kalindi Parmar, Eva Guinan, Justin Steinman, Joel S. Greenberger
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Abstract

Squamous cell carcinomas of the head and neck are appearing with increased frequency in both marrow transplanted and non-transplanted Fanconi anemia (FA) patients. FA patients commonly display radiosensitivity of epithelial tissues, complicating effective radiotherapy. Fancd2–/– mice (C57BL/6J and 129/Sv background) demonstrate epithelial tissue sensitivity to single-fraction or fractionated irradiation to the head and neck and distant marrow suppression (abscopal effect), both ameliorated by intraoral administration of the mitochondrial-targeted antioxidant, GS-nitroxide, JP4-039. We now report that mice of two other FA genotypes, Fancg–/– (B6) and the most prevalent human genotype Fanca–/– (129/Sv), also demonstrate: 1. reduced longevity of hematopoiesis in long-term bone marrow cultures; 2. radiosensitivity of bone marrow stromal cell lines; and 3. head and neck radiation-induced severe mucositis and abscopal suppression of distant marrow hematopoiesis. Intraoral administration of JP4-039/F15, but not non-mitochondrial-targeted 4-amino-Tempo/F15 or F15 alone, prior to each radiation treatment ameliorated both local and abscopal radiation effects. Head and neck irradiated TGF-β-resistant SMAD3–/– (129/Sv) mice and double-knockout SMAD3–/– Fancd2–/– (129/Sv) mice treated daily with TGF-β receptor antagonist, LY364947, still displayed abscopal bone marrow suppression, implicating a non-TGF-β mechanism. Thus, amelioration of both local normal tissue radiosensitivity and distant marrow suppression by intraoral administration of JP4-039 in Fancg–/– and Fanca–/– mice supports a clinical trial of this locally administered normal tissue radioprotector and mitigator during head and neck irradiation in FA patients.

©2018 by Radiation Research Society.
John Willis, Michael W. Epperly, Renee Fisher, Xichen Zhang, Donna Shields, Wen Hou, Hong Wang, Song Li, Peter Wipf, Kalindi Parmar, Eva Guinan, Justin Steinman, and Joel S. Greenberger "Amelioration of Head and Neck Radiation-Induced Mucositis and Distant Marrow Suppression in Fanca–/– and Fancg–/– Mice by Intraoral Administration of GS-Nitroxide (JP4-039)," Radiation Research 189(6), 560-578, (27 March 2018). https://doi.org/10.1667/RR14878.1
Received: 3 July 2017; Accepted: 1 February 2018; Published: 27 March 2018
JOURNAL ARTICLE
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