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

Intraesophageal administration of manganese superoxide dismutase-plasmid/li posome (MnSOD-PL) prior to single fraction radiation has been shown to prot ect mice from lethal esophagitis. In our study, C3H/HeNsd mice received fra ctionated radiation in two protocols: (i) 18 Gy daily for four days with Mn SOD-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 th e same schedules. We measured thiol depletion and lipid peroxidation (LP) i n whole esophagus and tested the effectiveness of a new plasmid, hemaggluti nin (RA) epitope-tagged MnSOD (HA/MnSOD). In fractionation protocols, mice receiving MnSOD-PL, but not LacZ-PL (200 mul of plasmid/liposomes containin g 200 mug of plasmid DNA), showed a significant reduction in morbidity, dec reased weight loss, and improved survival. Four and seven days after 37 Gy single fraction radiation, the esophagus demonstrated a significant increas e in peroxidized lipids and reduction in overall antioxidant levels, reduce d thiols, and decreased glutathione (GSH). These reductions were modulated by MnSOD-PL administration. The HA-MnSOD plasmid product was detected in th e basal layers of the esophageal epithelium 24 hr after administration and provided significant radiation protection compared to glutathione peroxidas e-plasmid/liposome (GPX-PL), or liposomes containing MnSOD protein, vitamin E, co-enzyme Q10, or 21-aminosteroid. Thus, MnSOD-PL administration signif icantly improved tolerance to fractionated radiation and modulated radiatio n effects on levels of GSH and lipid peroxidation (LP). These studies provi de further support for translation of MnSOD-PL treatment into human esophag eal radiation protection. (C) 2001 Wiley-Liss, Inc.