title: Intraoral Mitochondrial-Targeted GS-Nitroxide, JP4-039, Radioprotects Normal Tissue in Tumor-Bearing Radiosensitive Fancd2(-/-) (C57BL/6) Mice.
abstract: We evaluated normal tissue specific radioprotection of the oral cavity in radiosensitive Fanconi Anemia (FA) Fancd2(-/-) mice with orally established tumors using mitochondrial-targeted GS-nitroxide (JP4-039). Adult (10-12 weeks old) Fancd2(+/+), Fancd2(+/-) and Fancd2(-/-) mice (C57BL/6 background) and subgroups with orally established TC-1 epithelial cell tumors received a single fraction of 28 Gy or four daily fractions of 8 Gy to the head and neck. Subgroups received JP4-039 in F15 emulsion (F15/JP4-039; 0.4 mg/mouse), 4-amino-Tempo in F15 emulsion (F15/4-amino-Tempo; 0.2 mg/mouse) or F15 emulsion alone prior to each irradiation. Oral mucosa of Fancd2(-/-) mice showed baseline elevated RNA transcripts for Sod2, p53, p21 and Rad51 (all P < 0.0012) and suppressed levels of Nfkb and Tgfb, (all P < 0.0020) compared with Fancd2(+/+) mice. The oral mucosa in tumor-bearing mice of all genotypes showed decreased levels of p53 and elevated Tgfb and Gadd45a (P ≤ 0.0001 for all three genotypes). Intraoral F15/JP4-039, but not F15/4-amino-Tempo, modulated radiation-induced normal tissue transcript elevation, ameliorated mucosal ulceration and reduced the depletion of antioxidant stores in oral cavity tissue of all genotypes, but did not radioprotect tumors. Mitochondrial targeting makes F15/JP4-039 an effective normal tissue radioprotector for Fancd2(-/-) mice, as well as wild-type mice.
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Ashwin
authors.initials: A
authors.lastname: Shinde
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.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Byung Han
authors.initials: BH
authors.lastname: Rhieu
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Ronny
authors.initials: R
authors.lastname: Kalash
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Karen
authors.initials: K
authors.lastname: Xu
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Julie
authors.initials: J
authors.lastname: Goff
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Epperly
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Darcy
authors.initials: D
authors.lastname: Franicola
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Xichen
authors.initials: X
authors.lastname: Zhang
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Donna
authors.initials: D
authors.lastname: Shields
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: c  Chemistry and Bioengineering.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.affiliation: b  Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115; and Departments of.
authors.forename: Kalindi
authors.initials: K
authors.lastname: Parmar
authors.affiliation: b  Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115; and Departments of.
authors.forename: Eva
authors.initials: E
authors.lastname: Guinan
authors.affiliation: d  Environmental/Occupational Health.
authors.forename: Valerian
authors.initials: V
authors.lastname: Kagan
authors.affiliation: d  Environmental/Occupational Health.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tyurin
authors.affiliation: e  Otolaryngology and.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: f  School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: f  School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: a  Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213;
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000528:radiation effects*; D009061:Mouth Mucosa / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects*; D009062:Mouth Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D009589:Nitrogen Oxides / Q000008:administration & dosage*; D058958:Organs at Risk; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; C544775:JP4-039; D009589:Nitrogen Oxides; D011837:Radiation-Protective Agents