Effects of MnSOD-plasmid liposome gene therapy on antioxidant levels in irradiated murine oral cavity orthotopic tumors.
Intraoral manganese superoxide dismutase (SOD2)-plasmid liposome (PL) radioprotective gene therapy prolongs the survival of mice with orthotopic oral cavity tumors within the irradiated field. To determine whether the mechanism involved effects in antioxidant pool, C57BL/6J mice bearing orthotopic oral cavity squamous cell carcinoma SCC-VII tumors received intraoral or intravenous MnSOD-PL gene therapy 24 h prior to 18 Gy irradiation to the head and neck region. Glutathione (GSH) levels and levels of radiation-generated nitric oxide and peroxynitrite were measured in orthotopic tumors and in adjacent oral mucosa. MnSOD-PL transfection of the SCC-VII tumor cells, but not normal embryo fibroblasts, produced acute radiosensitization. Furthermore, SCC-VII tumor cells demonstrated increased relative hydrogen peroxide (the product of MnSOD superoxide dismutation)-induced apoptosis in vitro. Radiation decreased levels of GSH and increased GPX in both tumor and normal cells in vitro, effects that were blunted by MnSOD-PL treatment. In vivo irradiation decreased GSH and GPX more effectively in tumors, and the decrease was not reversed by MnSOD-PL therapy. Intravenous but not intraoral administration of epitope-tagged hemagglutinin MnSOD-PL resulted in significant uptake in orthotopic tumors and decreased the levels of radiation-induced nitric oxide and peroxynitrite. Thus normal tissue radioprotective MnSOD-PL gene therapy radiosensitizes tumor cell lines in vitro and has a therapeutic effect on orthotopic tumors in part through its effects on tumor antioxidants.
Epperly
Michael W
MW
Department of Radiation Oncology, University of Pittsburgh Cancer Institute and School of Public Health, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Wegner
Rodney
R
Kanai
Anthony J
AJ
Kagan
Valerian
V
Greenberger
Emily E
EE
Nie
Suhua
S
Greenberger
Joel S
JS
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D015316:Genetic Therapy; D006861:Hydrogen Peroxide / Q000633:toxicity; D008081:Liposomes; D051379:Mice; D009055:Mouth / Q000378:metabolism / Q000528:radiation effects; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009566:Nitrates / Q000378:metabolism; D010957:Plasmids / Q000235:genetics*; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors
D000975:Antioxidants; D008081:Liposomes; D009566:Nitrates; C039642:peroxynitric acid; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase