title: Translational strategies exploiting TNF-alpha that sensitize tumors to radiation therapy.
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.
authors.affiliation: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Mauceri
authors.forename: M A
authors.initials: MA
authors.lastname: Beckett
authors.forename: H
authors.initials: H
authors.lastname: Liang
authors.forename: H G
authors.initials: HG
authors.lastname: Sutton
authors.forename: S
authors.initials: S
authors.lastname: Pitroda
authors.forename: E
authors.initials: E
authors.lastname: Galka
authors.forename: E
authors.initials: E
authors.lastname: Efimova
authors.forename: T
authors.initials: T
authors.lastname: Darga
authors.forename: N N
authors.initials: NN
authors.lastname: Khodarev
authors.forename: C R
authors.initials: CR
authors.lastname: King
authors.forename: M C
authors.initials: MC
authors.lastname: Posner
authors.forename: S
authors.initials: S
authors.lastname: Hellman
authors.forename: D W
authors.initials: DW
authors.lastname: Kufe
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D000068800:Etanercept; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D009368:Neoplasm Transplantation; D011838:Radiation-Sensitizing Agents; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014964:X-Ray Therapy
chemical_list: D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011838:Radiation-Sensitizing Agents; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept