Abstract
TNFerade is a radioinducible adenoviral vector expressing tumor necrosis factor-alpha (TNF-alpha) (Ad.Egr-TNF) currently in a phase III trial for inoperable pancreatic cancer. We studied B16-F1 melanoma tumors in TNF receptor wild-type (C57BL/6) and deficient (TNFR1,2-/- and TNFR1-/-) mice. Ad.Egr-TNF+IR inhibited tumor growth compared with IR in C57BL/6 but not in receptor-deficient mice. Tumors resistant to TNF-alpha were also sensitive to Ad.Egr-TNF+IR in C57BL/6 mice. Ad.Egr-TNF+IR produced an increase in tumor-associated endothelial cell apoptosis not observed in receptor-deficient animals. Also, B16-F1 tumors in mice with germline deletions of TNFR1,2, TNFR1 or TNF-alpha, or in mice receiving anti-TNF-alpha exhibited radiosensitivity. These results show that tumor-associated endothelium is the principal target for Ad.Egr-TNF radiosensitization and implicate TNF-alpha signaling in tumor radiosensitivity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line, Tumor
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Endothelial Cells / drug effects
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Endothelial Cells / physiology
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Etanercept
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Genetic Therapy / methods*
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Humans
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Immunoglobulin G / pharmacology
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Immunosuppressive Agents / pharmacology
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Melanoma, Experimental / therapy*
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Mice
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Neoplasm Transplantation
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Radiation-Sensitizing Agents*
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I / deficiency
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Receptors, Tumor Necrosis Factor, Type II / deficiency
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / metabolism*
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X-Ray Therapy*
Substances
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Immunoglobulin G
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Immunosuppressive Agents
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Radiation-Sensitizing Agents
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Tumor Necrosis Factor-alpha
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Etanercept