Prevention of irradiation-induced esophagitis by plasmid/liposome delivery of 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 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.
Stickle
R L
RL
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Epperly
M W
MW
Klein
E
E
Bray
J A
JA
Greenberger
J S
JS
D000818:Animals; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000737:chemistry; D016503:Drug Delivery Systems; D004941:Esophagitis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004947:Esophagus / Q000201:enzymology / Q000528:radiation effects*; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy; D008081:Liposomes; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011833:Radiation Injuries, Experimental / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
D017931:DNA Primers; D008081:Liposomes; D004247:DNA; D013482:Superoxide Dismutase