Abstract
BackgroundFullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells.MethodsIn vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for γH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry.ResultsDF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer γH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls.ConclusionsDF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.
Highlights
Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors
We found that human tumor cells and immortalized fibroblasts are only protected at the highest achievable concentrations of DF-1, the magnitude of this protection was small with dose modifying factors at a surviving fraction of 0.1 of 1.1
In vitro studies To determine the effects of DF-1 on tumor cell and fibroblast radiosensitivity, clonogenic survival analysis was performed in the MRC5, DU145, and MiaPaCa-2 cell lines
Summary
Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. Several compounds have been described that protect tissues from exposure to ionizing radiation. The majority of agents protect against acute radiation damage are antioxidants which effectively scavenge free radicals, preventing indirect DNA damage, the predominant cause of cell death after exposure to ionizing radiation. To categorize agents that alter normal tissue radiation response, the terms radioprotectors, radiation mitigators, and treatment have recently been adopted[1,2]. Chemical radioprotectors exert their protective effects through scavenging of free radicals[3]. Other compounds have been found to have radio-
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