Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated radiation

Int J Cancer. 2001 Aug 20;96(4):221-31. doi: 10.1002/ijc.1023.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Biomarkers
  • Cells, Cultured
  • Chromatography, High Pressure Liquid
  • Dinoprost / metabolism
  • Dose-Response Relationship, Drug
  • Epitopes / metabolism
  • Esophagitis / etiology*
  • Esophagitis / prevention & control*
  • Fatty Acids, Unsaturated / metabolism
  • Female
  • Hemagglutinins / metabolism
  • Lac Operon
  • Lipid Metabolism
  • Lipid Peroxidation / radiation effects
  • Liposomes / therapeutic use*
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Plasmids / therapeutic use*
  • Radiotherapy / adverse effects
  • Superoxide Dismutase / chemistry
  • Superoxide Dismutase / therapeutic use*
  • Time Factors

Substances

  • Biomarkers
  • Epitopes
  • Fatty Acids, Unsaturated
  • Hemagglutinins
  • Liposomes
  • Dinoprost
  • Superoxide Dismutase
  • parinaric acid