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Spatial and temporal control of gene therapy using ionizing radiation

Nature Medicine volume 1, pages 786–791 (1995)Cite this article

Abstract

Activation of transcription of the Egr-1 gene by X-rays is regulated by the promoter region of this gene. We linked the radiation-inducible promoter region of the Egr-1 gene to the gene encoding the radiosensitizing and tumoricidal cytokine, tumour necrosis factor-α (TNF-α) and used a replication-deficient adenovirus to deliver the Egr-TNF construct to human tumours growing in nude mice. Combined treatment with Ad5.Egr-TNF and 5,000 cGy (rad) resulted in increased intratumoral TNF-α production and increased tumour control compared with treatment with Ad5.Egr-TNF alone or with radiation alone. The increase in tumour control was achieved without an increase in normal tissue damage when compared to tissue injury from radiation alone. Control of gene transcription by iohizing radiation in vivo represents a novel method of spatial and temporal regulation of gene-based medical treatments.

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References

  1. Culver, K. & Blaese, R.M. Gene therapy for cancer. Trends Genet 10, 174–178 (1994).

    Article  CAS  Google Scholar 

  2. Anderson, W. Gene therapy for cancer. Hum. Gene Ther. 5, 1–2 (1994).

    Article  Google Scholar 

  3. Takaku, F. Clinical application of cytokines for cancer treatment. Oncology 51, 123–128 (1994).

    Article  CAS  Google Scholar 

  4. Patel, P., Flemming, C., Russell, S., Eccles, S. & Collins, M. Cytokine gene transfer as a therapeutic strategy. J. Immunother. 14, 310–313 (1993).

    Article  CAS  Google Scholar 

  5. Kasahara, N., Dozy, A. & Kan, Y. Tissue-specific targeting of retroviral vectors through ligand-receptor interactions. Science 266, 1373–1376 (1994).

    Article  CAS  Google Scholar 

  6. Manome, Y., Abe, M., Hagen, M., Fine, H. & Kufe, D. Enhancer sequences of the DF3 gene regulate expression of the herpes simplex virus thymidine kinase gene. Cancer Res. 54, 5408–5413 (1994).

    CAS  PubMed  Google Scholar 

  7. Old, L.J. Tumour necrosis factor. Science 230, 630–636 (1985).

    Article  CAS  Google Scholar 

  8. Larrick, J.W. & Wright, S.C. Cytotoxic mechanism of tumour necrosis factor-α. FASEB J. 4, 3215–3223 (1990).

    Article  CAS  Google Scholar 

  9. Wright, S. & Larrick, J. Apoptosis and DNA fragmentation precede TNF-induced cytolysis in U937 cells. J. cell. Biochem. 48, 344–355 (1992).

    Article  CAS  Google Scholar 

  10. Laster, S., Wood, J. & Gooding, L. TNF can induce both apoptic and necrotic forms of cell lysis. J. Immun. 141, 2629–2634 (1988).

    CAS  PubMed  Google Scholar 

  11. Sersa, G., Willingham, V. & Milas, L. Anti-tumour effects of tumour necrosis factor alone or combined with radiotherapy. Int. J. Cancer 42, 129–134 (1988).

    Article  CAS  Google Scholar 

  12. Hallahan, D.E., Spriggs, D.R., Beckett, M.A., Kufe, D.W. & Weichselbaum, R.R. Increased tumour necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc. natn. Acad. Sci. U.S.A. 86, 10104–10107 (1989).

    Article  CAS  Google Scholar 

  13. Hallahan, D.E., Beckett, M.A., Kufe, D. & Weichselbaum, R.R. The interaction between recombinant human tumour necrosis factor and radiation in 13 human tumour cell lines. Int. J. Rad. One. biol. Phys. 19, 69–74 (1990).

    Article  CAS  Google Scholar 

  14. Weichselbaum, R. et al. Radiation targeting of gene therapy preferentially radiosensitizes tumour cells. Cancer Res. 54, 4266–4269 (1994).

    CAS  PubMed  Google Scholar 

  15. Wong, G., McHugh, T., Weber, R. & Goeddel, D. Tumour necrosis factor selectively sensitizes human immunodeficiency virus-infected cells to heat and radiation. Proc. natn. Acad. Sci. U.S.A. 88, 4372–4376 (1991).

    Article  CAS  Google Scholar 

  16. Gridley, D., Hammond, S. & Liwnicz, B. Tumour necrosis factor-alpha augments radiation effects against human colon tumour xenografts. Anticancer Res. 14, 1107–1112 (1994).

    CAS  PubMed  Google Scholar 

  17. Huang, P. et al. The effect of combining rhTNF with radiation on tumour control of human glioblastoma multiforme xenograft in nude mice. Int. J. Radiat. Oncol, biol. Phys. (in the press).

  18. Hallahan, D., Weichselbaum, R., Kufe, D. & Vokes, E. Phase I trial of tumour necrosis factor combined with radiotherapy. Cancer J. (in the press).

  19. Herrlich, P., Ponta, H. & Rahmsdorf, H. DNA damaged-induced gene expression: signal transduction and relation to growth factor signaling. Rev. Physiol. Biochem. Pharmacol. 119, 187–223 (1992).

    Article  CAS  Google Scholar 

  20. Weichselbaum, R.R., Hallahan, D.E. & Chen, G.T.Y. Biological and Physical Basis of Radiation Oncology. in Cancer Medicine (eds Holland, J. F. et al) 539–565 (Lea and Febiger, Malvern, Pennsylvania, 1993).

    Google Scholar 

  21. Holbrook, N. & Fornace, A. Response to adversity: molecular control of gene activation following genotoxic stress. New Biol. 3, 825–833 (1991).

    CAS  PubMed  Google Scholar 

  22. Boothman, D., Bouvard, I. & Hughes, E. Identification and characterization of X-ray-induced proteins in human cells. Cancer Res. 49, 2871–2878 (1989).

    CAS  PubMed  Google Scholar 

  23. Hallahan, D. et al. Radiation signalling mediated by Jun activation following dissociation from the Jun inhibitor. J. biol Chem. 268, 4903–4907 (1993).

    CAS  PubMed  Google Scholar 

  24. Datta, R. et al. Ionizing radiation activates transcription of the Egr-1 gene via CArG elements. Proc. natn. Acad. Sci. U.S.A. 89, 10149–10153 (1992).

    Article  CAS  Google Scholar 

  25. Brach, M., Sherman, M., Gunji, H., Weichselbaum, R. & Kufe, D. Ionizing radiation stimulates NF-κB binding activity in human myeloid leukemia cells. J. clin. Invest. 88, 691–695 (1991).

    Article  CAS  Google Scholar 

  26. Hallahan, D.E. et al Protein kinase-C mediates x-ray inducibility of nuclear signal transducers, egr-1 and c-jun. Proc. natn. Acad. Sci. U.S.A. 88, 2152–2160 (1991).

    Google Scholar 

  27. McGrory, Bautista & Graham . A simple technique for the rescue of early region I mutations into adenovirus typr 5. Virology 163, 614–617 (1988).

    Article  CAS  Google Scholar 

  28. Jones, N. & Shenk, T. Isolation of Ad5 mutants defective for transformation. Cell 17, 683–689 (1979).

    Article  CAS  Google Scholar 

  29. Weichselbaum, R.R., Dahlberg, W. & Little, J.B. Inherently radioresistant cells exist in some human tumours. Proc. natn. Acad. Sci. U.S.A. 82, 4732–4735 (1985).

    Article  CAS  Google Scholar 

  30. Kasid, U. et al. Effect of anti-sense c-raf-1 on tumourgenicity and radiation sen-stivity of a human squamous cell carcinoma. Science 243, 1354–1356 (1989).

    Article  CAS  Google Scholar 

  31. Gorcyca, W., Gong, J. & Darzynkiewicz, Z. Detection of DNA strandbreaks in individual apoptotic cells by the in situ terminal deoxynucleotidyl transferase and nick translation assay. Cancer Res. 53, 1945–1951 (1993).

    Google Scholar 

  32. Meyn, R.E. et al. Biochemical modulation of radiation-induced apoptosis in murine lympohoma cells. Radiat. Res. 136, 327–334 (1993).

    Article  CAS  Google Scholar 

  33. Amin, R., Wilmott, R., Schwartz, Y., Trapnell, B. and Stark, J. Replication-deficient adenovirus induces expression of interlukin-8 by airway epithelial cells in vitro. Hum. Gene Ther. 6, 145–153 (1995).

    Article  CAS  Google Scholar 

  34. Kruskal, W.H. & Wallis, W.A. Use of ranks in one-criterion variance analysis. J. Am. Star. Assoc. 47, 583–621 (1952).

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Radiation and Cellular Oncology,

    Dennis E. Hallahan, Helena J. Mauceri, Lisa P. Seung, Edward J. Dunphy, Samuel Hellman & Ralph R. Weichselbaum

  2. Pritzker School of Medicine, MC0085, University of Chicago, j5841 S. Maryland Ave., Chicago, Illinois, 60637, USA

    Dennis E. Hallahan, Helena J. Mauceri, Lisa P. Seung, Edward J. Dunphy, Samuel Hellman & Ralph R. Weichselbaum

  3. Department of Surgery, University of Chicago, Chicago, Illinois

    Jeffrey D. Wayne & Nader N. Hanna

  4. Department of Anesthesia and Critical Care, University of Chicago, Chicago, Illinois

    Alicia Toledano

  5. Division of Cancer Pharmacology, Dana Farber Cancer Institute, 44 Binney St, Boston, Massachusetts, 02115, USA

    Donald W. Kufe

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Hallahan, D., Mauceri, H., Seung, L. et al. Spatial and temporal control of gene therapy using ionizing radiation. Nat Med 1, 786–791 (1995). https://doi.org/10.1038/nm0895-786

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