Tumor necrosis factor alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature.
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) alpha (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-alpha 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-alpha and X-irradiation occurs selectively within the tumor vessels.
Mauceri
H J
HJ
Department of Radiation and Cellular Oncology, Pritzker School of Medicine, University of Chicago, Illinois 60637, USA.
Hanna
N N
NN
Wayne
J D
JD
Hallahan
D E
DE
Hellman
S
S
Weichselbaum
R R
RR
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000528:radiation effects*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013927:Thrombosis / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha