title: Amelioration of radiation-induced oral cavity mucositis and distant bone marrow suppression in fanconi anemia Fancd2-/- (FVB/N) mice by intraoral GS-nitroxide JP4-039.
abstract: The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2(-/-) mice, comparing this to Fancd2(+/-) and Fancd2(+/+) mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10-12-week-old mice, of FVB/N background Fancd2(-/-), Fancd2(+/-) and Fancd2(+/+) were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2(-/-) mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2(+/+) mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2(-/-) mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2(+/+) mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2(-/-) mice compared to Fancd2(+/+) controls. Fancd2(-/-) mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head- and neck-irradiated Fancd2(+/+) mice. In radiosensitive Fancd2(-/-) mice, biomarkers of both local oral cavity and distant marrow radiation toxicity were ameliorated by intraoral JP4-039/F15. We propose that Fancd2(-/-) mice are a valuable radiosensitive animal model system, which can be used to evaluate potential radioprotective agents.
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Hebist
authors.initials: H
authors.lastname: Berhane
authors.forename: Ashwin
authors.initials: A
authors.lastname: Shinde
authors.forename: Ronny
authors.initials: R
authors.lastname: Kalash
authors.forename: Karen
authors.initials: K
authors.lastname: Xu
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.forename: Julie
authors.initials: J
authors.lastname: Goff
authors.forename: Darcy
authors.initials: D
authors.lastname: Franicola
authors.forename: Xichen
authors.initials: X
authors.lastname: Zhang
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon
authors.forename: Donna
authors.initials: D
authors.lastname: Shields
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology / Q000528:radiation effects*; D002452:Cell Count; D002460:Cell Line; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000172:deficiency*; D005260:Female; D005269:Femur / Q000276:immunology; D006257:Head / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008081:Liposomes; D008297:Male; D051379:Mice; D009055:Mouth / Q000187:drug effects / Q000528:radiation effects*; D052016:Mucositis / Q000517:prevention & control*; D009333:Neck / Q000528:radiation effects; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; C544775:JP4-039; D008081:Liposomes; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D011837:Radiation-Protective Agents