title: Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated radiation.
abstract: Intraesophageal administration of manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) prior to single fraction radiation has been shown to protect mice from lethal esophagitis. In our study, C3H/HeNsd mice received fractionated radiation in two protocols: (i) 18 Gy daily for four days with MnSOD-PL administration 24 hr prior to the first and third fraction, or (ii) 12 Gy daily for six days with MnSOD-PL 24 hr prior to the first, third, and fifth fraction. Control radiated mice received either no liposomes only or LacZ (bacterial beta-galactosidase gene)-plasmid/liposome (LacZ-PL) by the same schedules. We measured thiol depletion and lipid peroxidation (LP) in whole esophagus and tested the effectiveness of a new plasmid, hemagglutinin (HA) epitope-tagged MnSOD (HA-MnSOD). In fractionation protocols, mice receiving MnSOD-PL, but not LacZ-PL (200 microl of plasmid/liposomes containing 200 microg of plasmid DNA), showed a significant reduction in morbidity, decreased weight loss, and improved survival. Four and seven days after 37 Gy single fraction radiation, the esophagus demonstrated a significant increase in peroxidized lipids and reduction in overall antioxidant levels, reduced thiols, and decreased glutathione (GSH). These reductions were modulated by MnSOD-PL administration. The HA-MnSOD plasmid product was detected in the basal layers of the esophageal epithelium 24 hr after administration and provided significant radiation protection compared to glutathione peroxidase-plasmid/liposome (GPX-PL), or liposomes containing MnSOD protein, vitamin E, co-enzyme Q10, or 21-aminosteroid. Thus, MnSOD-PL administration significantly improved tolerance to fractionated radiation and modulated radiation effects on levels of GSH and lipid peroxidation (LP). These studies provide further support for translation of MnSOD-PL treatment into human esophageal radiation protection.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Epperly
authors.forename: V E
authors.initials: VE
authors.lastname: Kagan
authors.forename: C A
authors.initials: CA
authors.lastname: Sikora
authors.forename: J E
authors.initials: JE
authors.lastname: Gretton
authors.forename: S J
authors.initials: SJ
authors.lastname: Defilippi
authors.forename: D
authors.initials: D
authors.lastname: Bar-Sagi
authors.forename: J S
authors.initials: JS
authors.lastname: Greenberger
mesh_terms: D000818:Animals; D015415:Biomarkers; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D015237:Dinoprost / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000378:metabolism; D004941:Esophagitis / Q000209:etiology* / Q000517:prevention & control*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D006388:Hemagglutinins / Q000378:metabolism; D007763:Lac Operon; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000528:radiation effects; D008081:Liposomes / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000627:therapeutic use*; D011878:Radiotherapy / Q000009:adverse effects; D013482:Superoxide Dismutase / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D015415:Biomarkers; D000939:Epitopes; D005231:Fatty Acids, Unsaturated; D006388:Hemagglutinins; D008081:Liposomes; D015237:Dinoprost; D013482:Superoxide Dismutase; C013641:parinaric acid