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Tumor Necrosis Factor (TNF-) Gene Therapy Targeted by Ionizing Radiation Selectively Damages Tumor Vasculature¹

Departments of Radiation and Cellular Oncology [H. J. M., D. E. H., S. H., R. R. W.] and Surgery [N. N. H., J. D. W.], Pritzker School of Medicine, University of Chicago, Chicago, Illinois 60637

Intratumoral injection of an adenoviral vector containing radiation-inducible DNA sequences of the Egr-1 promoter linked to a cDNA encoding tumor necrosis factor (TNF) (Ad.Egr-TNF) enhances the tumoricidal action of ionizing radiation in a human epidermoid carcinoma xenograft (SQ-20B). The dominant histopathological feature in tumor-bearing animals treated with Ad.Egr-TNF and irradiation is extensive intratumoral vascular thrombosis and tumor necrosis. Thrombosis and necrosis are not observed in animals treated with either the viral construct encoding TNF- or radiation and did not occur in irradiated normal tissues adjacent to tumor in animals injected with Ad.Egr-TNF. To determine if the occlusive effects of Ad.Egr-TNF and X-irradiation were specific for tumor vessels, non-tumor-bearing mice were irradiated after receiving i.m. injection of Ad.Egr-TNF at viral titers 20–100 times greater than titers injected intratumorally. No vascular thrombosis was observed in the treated normal tissues. Combined Ad.Egr-TNF and radiation produced occlusion of tumor microvessels without significant normal tissue damage. Taken together, these data suggest that the interaction between radiation inducible TNF- and X-irradiation occurs selectively within the tumor vessels.

¹ Supported by The Daniel F. and Ada L. Rice Foundation, a gift from the Passis family, the Chicago Tumor Institute, the Center for Radiation Therapy, and NCI Grant CA41068.

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, MC 0085, 5841 South Maryland Avenue, University of Chicago, Chicago, IL 60637.

Received 7/18/96. Accepted 8/16/96.

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