Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Ionizing radiation: a genetic switch for cancer therapy

Cancer Gene Therapy volume 13, pages 1–6 (2006)Cite this article

Abstract

Gene therapy of cancer represents a promising but challenging area of therapeutic research. The discovery of radiation-inducible genes led to the concept and development of radiation-targeted gene therapy. In this approach, promoters of radiation-inducible genes are used to drive transcription of transgenes in the response to radiation. Constructs in which the radiation-inducible promoter elements activate a transgene encoding a cytotoxic protein are delivered to tumors by adenoviral vectors. The tumoricidal effects are then localized temporally and spatially by X-rays. We review the conceptual development of TNFerade™, an adenoviral vector containing radiation-inducible elements of the early growth response-1 promoter upstream of a cDNA encoding human tumor necrosis factor-α. We also summarize the preclinical work and clinical trials utilizing this vector as a treatment for diverse solid tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR . Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci USA 1989; 86(24): 10104–10107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hallahan DE, Beckett MA, Kufe D, Weichselbaum RR . The interaction between recombinant human tumor necrosis factor and radiation in 13 human tumor cell lines. Int J Radiat Oncol Biol Phys 1990; 19(1): 69–74.

    Article  CAS  PubMed  Google Scholar 

  3. Datta R, Rubin E, Sukhatme V, Qureshi S, Hallahan D, Weichselbaum RR, Kufe DW . Ionizing radiation activates transcription of the EGR1 gene via CArG elements. Proc Natl Acad Sci USA 1992; 89(21): 10149–10153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Weichselbaum RR, Hallahan DE, Sukhatme VP, Kufe DW . Gene therapy targeted by ionizing radiation. Int J Radiat Oncol Biol Phys 1992; 24(3): 565–567.

    Article  CAS  PubMed  Google Scholar 

  5. Weichselbaum RR, Hallahan DE, Beckett MA, Mauceri HJ, Lee H, Sukhatme VP et al. Gene therapy targeted by radiation preferentially radiosensitizes tumor cells. Cancer Res 1994; 54(16): 4266–4269.

    CAS  PubMed  Google Scholar 

  6. Seung LP, Mauceri HJ, Beckett MA, Hallahan DE, Hellman S, Weichselbaum RR . Genetic radiotherapy overcomes tumor resistance to cytotoxic agents. Cancer Res 1995; 55(23): 5561–5565.

    CAS  PubMed  Google Scholar 

  7. Mauceri HJ, Hanna NN, Wayne JD, Hallahan DE, Hellman S, Weichselbaum RR . Tumor necrosis factor-alpha (TNF-alpha) gene therapy targeted by ionizing radiation selectively damages tumor vasculature. Cancer Res 1996; 56(19): 4311–4314.

    CAS  PubMed  Google Scholar 

  8. Hallahan DE, Mauceri HJ, Seung LP, Dunphy EJ, Wayne JD, Hanna NN et al. Spatial and temporal control of gene therapy using ionizing radiation. Nat Med 1995; 1(8): 786–791.

    Article  CAS  PubMed  Google Scholar 

  9. Chung TD, Mauceri HJ, Hallahan DE, Yu JJ, Chung S, Grdina WL et al. Tumor necrosis factor-alpha-based gene therapy enhances radiation cytotoxicity in human prostate cancer. Cancer Gene Ther 1998; 5(6): 344–349.

    CAS  PubMed  Google Scholar 

  10. Staba MJ, Mauceri HJ, Kufe DW, Hallahan DE, Weichselbaum RR . Adenoviral TNF-alpha gene therapy and radiation damage tumor vasculature in a human malignant glioma xenograft. Gene Therapy 1998; 5(3): 293–300.

    Article  CAS  PubMed  Google Scholar 

  11. Weichselbaum RR, Kufe D . Gene therapy of cancer. Lancet 1997; 349(Suppl 2): SII10–SII12.

    Article  PubMed  Google Scholar 

  12. Mauceri HJ, Hanna NN, Beckett MA, Gorski DH, Staba MJ, Stellato KA et al. Combined effects of angiostatin and ionizing radiation in antitumour therapy. Nature 1998; 394(6690): 287–291.

    Article  CAS  PubMed  Google Scholar 

  13. Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ . Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 1998; 4(4): 408–414.

    Article  CAS  PubMed  Google Scholar 

  14. Nose K, Shibanuma M, Kikuchi K, Kageyama H, Sakiyama S, Kuroki T . Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. Eur J Biochem 1991; 201(1): 99–106.

    Article  CAS  PubMed  Google Scholar 

  15. Sodhi A, Gupta P . Increased release of hydrogen peroxide (H2O2) and superoxide anion (O2-) by murine macrophages in vitro after cis-platin treatment. Int J Immunopharmacol 1986; 8(7): 709–714.

    Article  CAS  PubMed  Google Scholar 

  16. Senturker S, Tschirret-Guth R, Morrow J, Levine R, Shacter E . Induction of apoptosis by chemotherapeutic drugs without generation of reactive oxygen species. Arch Biochem Biophys 2002; 397(2): 262–272.

    Article  PubMed  Google Scholar 

  17. Armanios M, Xu R, Forastiere AA, Haller DG, Kugler JW, Benson III AB . Adjuvant chemotherapy for resected adenocarcinoma of the esophagus, gastro-esophageal junction, and cardia: phase II trial (E8296) of the Eastern Cooperative Oncology Group. J Clin Oncol 2004; 22(22): 4495–4499.

    Article  CAS  PubMed  Google Scholar 

  18. Macdonald JS . Clinical overview: adjuvant therapy of gastrointestinal cancer. Cancer Chemother Pharmacol 2004; 54(Suppl 1): S4–S11.

    CAS  PubMed  Google Scholar 

  19. Mancini R, Tedesco M, Garufi C, Filippini A, Arcieri S, Caterino M et al. Hepatic arterial infusion (HAI) of cisplatin and systemic fluorouracil in the treatment of unresectable colorectal liver metastases. Anticancer Res 2003; 23(2C): 1837–1841.

    CAS  PubMed  Google Scholar 

  20. Park JO, Lopez CA, Gupta VK, Brown CK, Mauceri HJ, Darga TE et al. Transcriptional control of viral gene therapy by cisplatin. J Clin Invest 2002; 110(3): 403–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lopez CA, Kimchi ET, Mauceri HJ, Park JO, Mehta N, Murphy KT et al. Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity. Mol Cancer Ther 2004; 3(9): 1167–1175.

    Article  CAS  PubMed  Google Scholar 

  22. Yamini B, Yu X, Gillespie GY, Kufe DW, Weichselbaum RR . Transcriptional targeting of adenovirally delivered tumor necrosis factor-alpha by temozolomide in experimental glioblastoma. Cancer Res 2004; 64(18): 6381–6384.

    Article  CAS  PubMed  Google Scholar 

  23. Rasmussen H, Rasmussen C, Lempicki M, Durham R, Brough D, King CR et al. TNFerade Biologic: preclinical toxicology of a novel adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor-α gene. Cancer Gene Ther 2002; 9(11): 951–957.

    Article  CAS  PubMed  Google Scholar 

  24. Kufe D, Weichselbaum R . Radiation therapy: activation for gene transcription and the development of genetic radiotherapy-therapeutic strategies in oncology. Cancer Biol Ther 2003; 2(4): 326–329.

    Article  CAS  PubMed  Google Scholar 

  25. Lienard D, Ewalenko P, Delmotte JJ, Renard N, Lejeune FJ . High-dose recombinant tumor necrosis factor alpha in combination with interferon gamma and melphalan in isolation perfusion of the limbs for melanoma and sarcoma. J Clin Oncol 1992; 10(1): 52–60.

    Article  CAS  PubMed  Google Scholar 

  26. Thom AK, Alexander HR, Andrich MP, Barker WC, Rosenberg SA, Fraker DL . Cytokine levels and systemic toxicity in patients undergoing isolated limb perfusion with high-dose tumor necrosis factor, interferon gamma, and melphalan. J Clin Oncol 1995; 13(1): 264–273.

    Article  CAS  PubMed  Google Scholar 

  27. Senzer N, Mani S, Rosemurgy A, Nemunaitis J, Cunningham C, Guha C et al. TNFerade biologic, an adenovector with a radiation-inducible promoter, carrying the human tumor necrosis factor alpha gene: a phase I study in patients with solid tumors. J Clin Oncol 2004; 22(4): 592–601.

    Article  CAS  PubMed  Google Scholar 

  28. Mundt AJ, Vijayakumar S, Nemunaitis J, Sandler A, Schwartz H, Hanna N et al. A Phase I trial of TNFerade biologic in patients with soft tissue sarcoma in the extremities. Clin Cancer Res 2004; 10(17): 5747–5753.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was sponsored in part by the Varian corporation and the University of Chicago Center for Radiation Therapy.

Author information

Author notes

  1. J J Mezhir and K D Smith: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, The University of Chicago Hospitals, Chicago, IL, USA

    J J Mezhir, K D Smith, M C Posner & B Yamini

  2. Mary Crowley Medical Research Center, Sammons Cancer Center, Dallas, TX, USA

    N Senzer

  3. Department of Medicine, and the Department of Pharmacology, Harvard Medical School, Dana Farber Cancer Institute, Boston, Massachusetts, USA

    D W Kufe

  4. Department of Radiation Oncology, The University of Chicago Hospitals, Chicago, IL, USA

    R R Weichselbaum

Authors
  1. J J Mezhir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K D Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M C Posner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N Senzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Yamini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D W Kufe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R R Weichselbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R R Weichselbaum.

Additional information

Conflict of Interest

GenVec Inc. provided the adenoviral vectors used in the studies reported herein. RRW and DWK are consultants for GenVec Inc. and hold interest in the company.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mezhir, J., Smith, K., Posner, M. et al. Ionizing radiation: a genetic switch for cancer therapy. Cancer Gene Ther 13, 1–6 (2006). https://doi.org/10.1038/sj.cgt.7700879

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700879

Keywords

This article is cited by

Search

Advanced search

Quick links