TY - JOUR
T1 - GS-nitroxide (JP4-039)-mediated radioprotection of human fanconi anemia cell lines
AU - Bernard, Mark E.
AU - Kim, Hyun
AU - Berhane, Hebist
AU - Epperly, Michael W.
AU - Franicola, Darcy
AU - Zhang, Xichen
AU - Houghton, Frank
AU - Shields, Donna
AU - Wang, Hong
AU - Bakkenist, Christopher J.
AU - Frantz, Marie Celine
AU - Forbeck, Erin M.
AU - Goff, Julie P.
AU - Wipf, Peter
AU - Greenberger, Joel S.
PY - 2011/11
Y1 - 2011/11
N2 - Fanconi anemia (FA) is an inherited disorder characterizedby defective DNA repair and cellular sensitivity to DNAcrosslinking agents. Clinically, FA is associated with highrisk for marrow failure, leukemia and head and necksquamous cell carcinoma (HNSCC). Radiosensitivity in FApatients compromises the use of total-body irradiation forhematopoietic stem cell transplantation and radiationtherapy for HNSCC. A radioprotector for the surroundingtissue would therefore be very valuable during radiotherapyfor HNSCC. Clonogenic radiation survival curves weredetermined for pre- or postirradiation treatment with theparent nitroxide Tempol or JP4-039 in cells of four FApatient-derived cell lines and two transgene-correctedsubclonal lines. FancG-/- (PD326) and FancD2-/- (PD20F)patient lines were more sensitive to the DNA crosslinkingagent mitomycin C (MMC) than their transgene-restoredsubclonal cell lines (both P , 0.0001). FancD2-/- cells weremore radiosensitive than the transgene restored subclonalcell line (n2.0 6 0.7 and 4.7 6 2.2, respectively, P 0.03).In contrast, FancG-/- cells were radioresistant relative to thetransgene-restored subclonal cell line (n 9.4 6 1.5 and 2.26 05, respectively, P0.001). DNA strand breaks measuredby the comet assay correlated with radiosensitivity. Celllines from a Fanc-C and Fanc-A patients showed radiosensitivitysimilar to that of Fanc-D2-/- cells. A fluorophoretaggedJP4-039 (BODIPY-FL) analog targeted the mitochondriaof the cell lines. Preirradiation or postirradiationtreatment with JP4-039 at a lower concentration thanTempol significantly increased the radioresistance andstabilized the antioxidant stores of all cell lines. Tempolincreased the toxicity of MMC in FancD2-/- cells. These dataprovide support for the potential clinical use of JP4-039 fornormal tissue radioprotection during chemoradiotherapy inFA patients.
AB - Fanconi anemia (FA) is an inherited disorder characterizedby defective DNA repair and cellular sensitivity to DNAcrosslinking agents. Clinically, FA is associated with highrisk for marrow failure, leukemia and head and necksquamous cell carcinoma (HNSCC). Radiosensitivity in FApatients compromises the use of total-body irradiation forhematopoietic stem cell transplantation and radiationtherapy for HNSCC. A radioprotector for the surroundingtissue would therefore be very valuable during radiotherapyfor HNSCC. Clonogenic radiation survival curves weredetermined for pre- or postirradiation treatment with theparent nitroxide Tempol or JP4-039 in cells of four FApatient-derived cell lines and two transgene-correctedsubclonal lines. FancG-/- (PD326) and FancD2-/- (PD20F)patient lines were more sensitive to the DNA crosslinkingagent mitomycin C (MMC) than their transgene-restoredsubclonal cell lines (both P , 0.0001). FancD2-/- cells weremore radiosensitive than the transgene restored subclonalcell line (n2.0 6 0.7 and 4.7 6 2.2, respectively, P 0.03).In contrast, FancG-/- cells were radioresistant relative to thetransgene-restored subclonal cell line (n 9.4 6 1.5 and 2.26 05, respectively, P0.001). DNA strand breaks measuredby the comet assay correlated with radiosensitivity. Celllines from a Fanc-C and Fanc-A patients showed radiosensitivitysimilar to that of Fanc-D2-/- cells. A fluorophoretaggedJP4-039 (BODIPY-FL) analog targeted the mitochondriaof the cell lines. Preirradiation or postirradiationtreatment with JP4-039 at a lower concentration thanTempol significantly increased the radioresistance andstabilized the antioxidant stores of all cell lines. Tempolincreased the toxicity of MMC in FancD2-/- cells. These dataprovide support for the potential clinical use of JP4-039 fornormal tissue radioprotection during chemoradiotherapy inFA patients.
UR - http://www.scopus.com/inward/record.url?scp=80155193821&partnerID=8YFLogxK
U2 - 10.1667/RR2624.1
DO - 10.1667/RR2624.1
M3 - Article
C2 - 21939290
AN - SCOPUS:80155193821
SN - 0033-7587
VL - 176
SP - 603
EP - 612
JO - Radiation research
JF - Radiation research
IS - 5
ER -