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Translational strategies exploiting TNF-α that sensitize tumors to radiation therapy

Cancer Gene Therapy volume 16, pages 373–381 (2009)Cite this article

Abstract

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

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Acknowledgements

We thank Dr Shang Lin for statistical analyses and Samuel Luka for technical assistance. This research was funded by Grant CA111423 from the NCI, Ludwig Center for Metastasis Research, the Center for Radiation Therapy, and a gift from Mr and Mrs Vincent Foglia. Dr Weichselbaum and Dr Kufe have an interest in GenVec and are consultants to GenVec. Dr King is employed by GenVec.

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Author notes

  1. H J Mauceri and M A Beckett: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA

    H J Mauceri, M A Beckett, H Liang, H G Sutton, S Pitroda, E Efimova, T Darga, N N Khodarev, S Hellman & R R Weichselbaum

  2. Department of Surgery, The University of Chicago, Chicago, IL, USA

    E Galka & M C Posner

  3. GenVec Inc., Gaithersburg, MD, USA

    C R King

  4. Department of Medicinal Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    D W Kufe

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  1. H J Mauceri
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Correspondence to R R Weichselbaum.

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Mauceri, H., Beckett, M., Liang, H. et al. Translational strategies exploiting TNF-α that sensitize tumors to radiation therapy. Cancer Gene Ther 16, 373–381 (2009). https://doi.org/10.1038/cgt.2008.86

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