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Genetic Radiotherapy Overcomes Tumor Resistance to Cytotoxic Agents¹

Department of Radiation and Cellular Oncology and The Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637

We report that radiation enhances gene therapy of a radioresistant tumor by upregulating the induction of a chimeric gene encoding a radiosensitizing protein, tumor necrosis factor (TNF-). We ligated the radiation-inducible CArG elements of the radiation-inducible Egr-1 promoter/enhancer region upstream to the transcriptional start site of the human TNF cDNA (pE425-TNF). This construct was transfected using cationic liposomes into the variant murine fibrosarcoma cell line, P4L. The P4L cell line was both radioresistant (D₀ = 188) and resistant to TNF. After a single intratumoral injection of 10 µg of pE425-TNF in cationic liposomes and two 20-Gy doses of irradiation, mean tumor volumes were significantly reduced in P4L tumors as compared to those receiving either pE425-TNF in liposomes or radiation alone (P = 0.01). TNF protein in P4L tumors was induced by radiation as high as 29 times control levels and remained detectable for 14 days. Our data indicate that combined gene therapy using liposomes, together with ionizing radiation to locally activate the induction of a radiosensitizing protein, is successful at overcoming resistance to both TNF and radiation.

¹ This work was supported by the Daniel F. and Ada L. Rice Foundation; The Chicago Tumor Institute; The Center for Radiation Therapy; National Cancer Institute Grants CA58508 and CA41068; and NIH Grant 5T32CA09273.

² To whom requests for reprints should be addressed, at Department of Radiation and Cellular Oncology, University of Chicago Medical Center, 5841 South Maryland Avenue, Box 442, Chicago, IL 60637.

Received 9/ 8/95. Accepted 10/30/95.

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