Prevention of irradiation-induced esophagitis by plasmid/liposome deliveryof the human manganese superoxide dismutase transgene

Esophagitis is a major toxicity of radiation therapy for nonsmall-cell lung cancer. Intraesophageal injection of manganese superoxide dismutase (MnSOD ) plasmid/liposome complexes (1 mg of the pRK5-MnSOD plasmid containing the human MnSOD transgene in a 0.15 ml volume of lipofectin) before irradiatio n was carried out to attempt to prevent irradiation esophagitis. In control noninjected male C3H/HeNsd mice, esophagitis was induced by single fractio n 3,500 cGy irradiation. Histopathology at 4 days revealed vacuole formatio n in squamous lining cells, separation of the squamous layer from the under lying muscle layer, ulceration at 7 days, and dehydration and death by 30 d ays. MnSOD plasmid/liposome complex-injected mice showed transcription of t he human MnSOD transgene message in esophageal squamous lining cells by nes ted reverse transcriptase-polymerase chain reaction (RT-PCR) increased MnSO D biochemical activity 24 h after injection, decreased vacuole formation at day 4 (P < 0.001) after 3,500 cGy thoracic irradiation, and improved survi val (P = 0.0009). In contrast, groups of mice receiving LacZ (bacterial bet a-galactosidase gene) plasmid/liposome complexes or liposomes containing no DNA before 3,500 cGy irradiation showed an unaltered irradiation histopath ology and decreased survival. Mice receiving intraesophageal MnSOD plasmid/ Liposomes followed 8 h later by human equivalent doses of Taxol (1.4 mg/kg ) and carboplatin (2.5 mg/kg), then 15 h later 3,300 cGy irradiation, showe d increased survival, compared with irradiated control or LacZ plasmid/lipo some groups. Thus, overexpression of the human MnSOD transgene in the esoph agus can prevent irradiation-induced esophagitis in the mouse model. Radiat . Oncol. Invest. 7:204-217, 1999. (C) 1999 Wiley-Liss, Inc.