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: Hebist Berhane, Ashwin Shinde, Ronny Kalash, Karen Xu, Michael W Epperly, Julie Goff, Darcy Franicola, Xichen Zhang, Tracy Dixon, Donna Shields, Hong Wang, Peter Wipf, Song Li, Xiang Gao, Joel S Greenberger
• Journal: Radiation research (Radiat Res) Vol. 182 Issue 1 Pg. 35-49 (Jul 2014) ISSN: 1938-5404 [Electronic] United States
• PMID: 24932534 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Fanconi Anemia Complementation Group D2 Protein
• JP4-039
• Liposomes
• Nitrogen Oxides
• RNA, Messenger
• Radiation-Protective Agents

Topics

• Animals
• Bone Marrow (drug effects, immunology, radiation effects)
• Cell Count
• Cell Line
• Fanconi Anemia Complementation Group D2 Protein (deficiency)
• Female
• Femur (immunology)
• Head (radiation effects)
• Hematopoietic Stem Cells (cytology, drug effects, radiation effects)
• Liposomes
• Male
• Mice
• Mouth (drug effects, radiation effects)
• Mucositis (prevention & control)
• Neck (radiation effects)
• Nitrogen Oxides (administration & dosage, pharmacology)
• RNA, Messenger (genetics, metabolism)
• Radiation Injuries, Experimental (prevention & control)
• Radiation Tolerance (drug effects)
• Radiation-Protective Agents (administration & dosage, pharmacology)