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Gene Therapy Targeted by Radiation Preferentially Radiosensitizes Tumor Cells¹

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 60637 [R. R. W., D. E. H., M. A. B., H. J. M., H. L.]; Section of Nephrology, Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02114 [V. P. S.]; and Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [D. W. K.]

Transcriptional regulation of the promoter/enhancer region of the Egr-1 gene is activated by ionizing radiation. We linked DNA sequences from the promotor region of Egr-1 to a complementary DNA sequence which encodes human tumor necrosis factor (TNF) , a radiosensitizing cytokine. The Egr-TNF construct was transfected into a human cell line of hematopoietic origin, HL525, which was used in an experimental animal system. HL525 (clone 2) cells containing the Egr-TNF construct which exhibits radiation induction of TNF- were injected into human xenografts of the radioresistant human squamous cell carcinoma cell line SQ-20B. Animals treated with radiation and clone 2 demonstrated an increase in tumor cures compared with animals treated with radiation alone or unirradiated animals given injections of clone 2 alone. No increase in local or systemic toxicity was observed in the combined treatment group. The combination of gene therapy and radiation therapy enhances tumor cures without increasing normal tissue toxicity and is a new paradigm for cancer treatment.

¹ This research was supported by a gift from the Daniel F. and Ada L. Rice Foundation; Grants CA 58505, CA 41068, and CA 42596 from the National Cancer Institute; the Center for Radiation Therapy; and a gift from the Passis family.

Received 6/ 2/94. Accepted 7/ 1/94.

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