© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 12, 921-929,
June 20, 2001
© 2001 Oxford University Press
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Epidermal Growth Factor Receptor as a Genetic Therapy Target for Carcinoma Cell Radiosensitization
Affiliations of authors: G. Lammering, Department of Radiation Oncology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, and Department of Radiation Oncology, Heinrich-Heine University, Duesseldorf, Germany; T. H. Hewit, W. T. Hawkins, J. N. Contessa, P.-S. Lin, K. Valerie, P. Dent, R. B. Mikkelsen, R. K. Schmidt-Ullrich, Department of Radiation Oncology, Medical College of Virginia Campus, Virginia Commonwealth University; D. B. Reardon, School of Pharmacy, University of Louisiana, Monroe.
Correspondence to: Rupert K. Schmidt-Ullrich, M.D., Department of Radiation Oncology, Medical College of Virginia Campus, Virginia Commonwealth University, P.O. Box 980058, 401 College St., Richmond, VA 23298–0058 (e-mail: rullrich{at}hsc.vcu.edu).
Background: Exposure of human cancer cells to ionizing radiation activates the epidermal growth factor receptor (EGFR), which, in turn, mediates a cytoprotective response that reduces the cells' sensitivity to ionizing radiation. Overexpression of a dominant-negative EGFR mutant, EGFR-CD533, disrupts the cytoprotective response by preventing radiation-induced activation of the receptor and its downstream effectors. To investigate whether gene therapy with EGFR-CD533 has the potential to increase tumor cell radiosensitivity, we introduced an adenoviral vector containing EGFR-CD533 into xenograft tumors in nude mice and evaluated the tumor response to ionizing radiation. Methods: Xenograft tumors established from the human mammary carcinoma cell line MDA-MB-231 were transduced via infusion with the adenoviral vector Ad-EGFR-CD533 or a control vector containing the 
-galactosidase gene, Ad-LacZ. The transduced tumors were then exposed to radiation in the therapeutic dose range, and radiation-induced EGFR activation was assessed by examining the tyrosine phosphorylation of immunoprecipitated EGFR. Radiosensitization was determined in vitro by colony-formation assays. All statistical tests were two-sided. Results: The transduction efficiency of MDA-MB-231 tumors by Ad-LacZ was 44%. Expression of EGFR-CD533 in tumors reduced radiation-induced EGFR activation by 2.94-fold (95% confidence interval [CI] = 2.23 to 4.14). The radiosensitivity of Ad-EGFR-CD533-transduced tumors was statistically significantly higher (46%; P<.001) than that of Ad-LacZ-transduced tumors, yielding a dose-enhancement ratio of 1.85 (95% CI = 1.54 to 2.51). Conclusions: Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.
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