Fanconi anemia mouse genotype-specific mitigation of total body irradiation by GS-nitroxide JP4-039

Abstract

Background/Aim: Radiation mitigator, GS-nitroxide, JP4-039, was evaluated for mitigation of total body irradiation (TBI) in Fanconi anemia (FA) Fancd2−/− (129/Sv), Fancg−/− (B6), and Fanca−/− (129/Sv) mice. Materials and Methods: JP4-039 dissolved in 30% 2-hydroxypropyl-β-cyclodextrin was injected intramuscularly 24 h after total body irradiation (9.25 Gy) into Fanca−/−, Fancd2−/− and Fancg−/− mice. Irradiation survival curves were performed in vitro using bone marrow stromal cell lines derived from Fanca−/−, Fancd2−/− and Fancg−/− mice. Results: FA mice demonstrate genotype specific differences in TBI mitigation by JP4-039. Radiation effects in derived bone marrow stromal cell lines in vitro were mitigated by drugs that block apoptosis, but not necroptosis or ferroptosis. Conclusion: FA mouse models are valuable for elucidating DNA repair pathways in cell and tissue responses to TBI, and the role of drugs that target distinct cell death pathways.