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

• Published in: Radiation oncology investigations Vol. 7; no. 4; p. 204
• Main Authors: Stickle, R L, Epperly, M W, Klein, E, Bray, J A, Greenberger, J S
• Format: Journal Article
• Language: English
• Published: United States 1999
• Subjects: Animals; DNA - genetics; DNA Primers - chemistry; Drug Delivery Systems; Esophagitis - enzymology; Esophagitis - etiology; Esophagitis - pathology; Esophagitis - prevention & control; Esophagus - enzymology; Esophagus - radiation effects; Gene Expression Regulation, Enzymologic; Genetic Therapy; Liposomes; Male; Mice; Mice, Inbred C3H; Plasmids; Polymerase Chain Reaction; Radiation Injuries, Experimental - enzymology; Radiation Injuries, Experimental - etiology; Radiation Injuries, Experimental - pathology; Radiation Injuries, Experimental - prevention & control; Superoxide Dismutase - administration & dosage; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Transgenes
• ISSN: 1065-7541
• DOI: 10.1002/(SICI)1520-6823(1999)7:4<204::AID-ROI2>3.0.CO;2-S

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 irradiation was carried out to attempt to prevent irradiation esophagitis. In control noninjected male C3H/HeNsd mice, esophagitis was induced by single fraction 3,500 cGy irradiation. Histopathology at 4 days revealed vacuole formation in squamous lining cells, separation of the squamous layer from the underlying muscle layer, ulceration at 7 days, and dehydration and death by 30 days. MnSOD plasmid/liposome complex-injected mice showed transcription of the human MnSOD transgene message in esophageal squamous lining cells by nested reverse transcriptase-polymerase chain reaction (RT-PCR) increased MnSOD biochemical activity 24 h after injection, decreased vacuole formation at day 4 (P < 0.001) after 3,500 cGy thoracic irradiation, and improved survival (P = 0.0009). In contrast, groups of mice receiving LacZ (bacterial beta-galactosidase gene) plasmid/liposome complexes or liposomes containing no DNA before 3,500 cGy irradiation showed an unaltered irradiation histopathology 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, showed increased survival, compared with irradiated control or LacZ plasmid/liposome groups. Thus, overexpression of the human MnSOD transgene in the esophagus can prevent irradiation-induced esophagitis in the mouse model.