TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) GENE-THERAPY TARGETED BY IONIZING-RADIATION SELECTIVELY DAMAGES TUMOR VASCULATURE

Intratumoral injection of an adenoviral vector containing radiation-in ducible DNA sequences of the Egr-1 promoter linked to a cDNA encoding tumor necrosis factor (TNF) alpha (Ad.Egr-TNF) enhances the tumoricida l action of ionizing radiation in a human epidermoid carcinoma xenogra ft (SQ-20B). The dominant histopathological feature in tumor-bearing a nimals treated with Ad.Egr-TNF and irradiation is extensive intratumor al vascular thrombosis and tumor necrosis, Thrombosis and necrosis are not observed in animals treated with either the viral construct encod ing TNF-alpha or radiation and did not occur in irradiated normal tiss ues adjacent to tumor in animals injected with Ad.Egr-TNF. To determin e if the occlusive effects of Ad.Egr-TNF and X-irradiation were specif ic for tumor vessels, non-tumor-bearing mice were irradiated after rec eiving i.m. injection of Ad.Egr-TNF at viral titers 20-100 times great er than titers injected intratumorally. No vascular thrombosis was obs erved in the treated normal tissues. Combined Ad.Egr-TNF and radiation produced occlusion of tumor microvessels without significant normal t issue damage. Taken together, these data suggest that the interaction between radiation inducible TNF-alpha and X-irradiation occurs selecti vely within the tumor vessels.