1. ¹Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA
2. ²Department of Surgery, The University of Chicago, Chicago, IL, USA
3. ³GenVec Inc., Gaithersburg, MD, USA
4. ⁴Department of Medicinal Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Correspondence: Dr RR Weichselbaum, Department of Radiation and Cellular Oncology, Duchossois Center for Advanced Medicine, 5758 S. Maryland Avenue, MC 9006, Chicago, IL 60637, USA. E-mail: rrw@radonc.uchicago.edu

⁵These authors contributed equally to this study.

Received 27 June 2008; Accepted 24 July 2008; Published online 31 October 2008.

Abstract

TNFerade is a radioinducible adenoviral vector expressing tumor necrosis factor- (TNF-) (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- 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-, or in mice receiving anti-TNF- exhibited radiosensitivity. These results show that tumor-associated endothelium is the principal target for Ad.Egr-TNF radiosensitization and implicate TNF- signaling in tumor radiosensitivity.