Effectiveness of combined modality radiotherapy of orthotopic human squamous cell carcinomas in Nu/Nu mice using cetuximab, tirapazamine and MnSOD-plasmid liposome gene therapy.
Hypoxic regions limit the radiocontrollability of head and neck carcinomas. Whether or not combinations of plasmid/liposome mediated overexpression of normal tissue protective manganese superoxide dismutase (MnSOD), cetuximab (C225), and the hypoxic cytotoxin tirapazamine (TPZ) enhanced radiotherapeutic effects was tested in a CAL-33 orthotopic mouse cheek tumor model. The tumor volume continued to increase in the control (untreated) mice, with a ninefold increase by 10 days when the tumors exceeded 2 cm(3). The mice receiving 14 Gy only showed reduced tumor growth to 3.1+/-0.1 fold at day 10. The mice receiving MnSOD-PL, C225, TPZ plus 14 Gy had the best outcome with 0.7+/-0.1 fold increase in tumor volume by 10 days (p=0.015) compared to irradiation only. The addition of MnSOD-PL, TPZ, and C225 to irradiation optimized the therapeutic ratio for the local control of hypoxic region-containing CAL-33 orthotopic tumors.
Department of Radiation Oncology, University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Michael W
MW
Epperly
Stephen Y
SY
Lai
Anthony J
AJ
Kanai
Neal
N
Mason
Brian
B
Lopresi
Tracey
T
Dixon
Darcy
D
Franicola
Yunyun
Y
Niu
William R
WR
Wilson
Joel S
JS
Greenberger
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D004307:Dose-Response Relationship, Radiation; D015316:Genetic Therapy; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009569:Nitric Oxide / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D018714:Radiotherapy, Adjuvant; D013482:Superoxide Dismutase / Q000235:genetics*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008081:Liposomes; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D000077704:Tirapazamine; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D000068818:Cetuximab