title: Metformin exhibits radiation countermeasures efficacy when used alone or in combination with sulfhydryl containing drugs.
abstract: Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, administered 30 min prior to irradiation, were used as positive controls. Treatment of MEF, HMEC and SA-NH cells with metformin elevated survival levels by 1.4-, 1.5- and 1.3-fold compared to 1.9-, 1.8- and 1.6-fold for these same cells treated with WR1065, respectively. Metformin (250 mg/kg) was effective in protecting splenic cells from a 7 Gy dose in vivo (protection factor = 1.8). Amifostine (400 mg/kg), administered 30 min prior to irradiation resulted in a 2.6-fold survival elevation, while metformin administered 24 h after irradiation in combination with NAC (400 mg/kg), MESNA (300 mg/kg) or captopril (200 mg/kg) enhanced survival by 2.6-, 2.8- and 2.4-fold, respectively. Each of these agents has been approved by the FDA for human use and each has a well characterized human safety profile. Metformin alone or in combination with selected sulfhydryl agents possesses radioprotective properties when administered 24 h after radiation exposure comparable to that observed for amifostine administered 30 min prior to irradiation making it a potentially useful agent for radiation countermeasures use.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Illinois 60637.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Miller
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Murley
authors.forename: David J
authors.initials: DJ
authors.lastname: Grdina
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000627:therapeutic use; D054508:Acute Radiation Syndrome / Q000473:pathology / Q000517:prevention & control*; D004999:Amifostine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000528:radiation effects; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015080:Mesna / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012509:Sarcoma / Q000473:pathology; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D016166:Free Radical Scavengers; D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds; D008687:Metformin; D002216:Captopril; D004999:Amifostine; D015080:Mesna; D000111:Acetylcysteine
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