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Tumor-targeted gene delivery of tumor necrosis factor-α induces tumor necrosis and tumor regression without systemic toxicity

Cancer Gene Therapy volume 9, pages 673–680 (2002)Cite this article

Abstract

We have recently developed surface-shielded transferrin–polyethylenimine (Tf–PEI)/DNA delivery systems that target reporter gene expression to distant tumors after systemic application. In the present study, we used surface-shielded Tf–PEI/DNA complexes for delivering the gene for a highly potent cytokine, tumor necrosis factor-α (TNFα). TNFα is known for its ability to induce hemorrhagic tumor necrosis and tumor regression. However, the therapeutic application of TNFα is hampered by its high systemic toxicity dictating the need to target TNFα activity to the tumor. Systemic application of surface-shielded Tf–PEI complexes with the TNFα gene resulted in preferential expression of TNFα in the tumor without detectable TNFα serum levels, in contrast to the application of nontargeted complexes. Tumor-targeted TNFα gene delivery induced pronounced hemorrhagic tumor necrosis and inhibition of tumor growth in three murine tumor models of different tissue origins, Neuro2a neuroblastoma, MethA fibrosarcoma, and M-3 melanoma, with complete tumor regressions observed in the MethA model. No systemic TNF-related toxicity was observed due to the localization of the TNFα activity to the tumor. Targeted gene therapy may be an attractive strategy applicable to highly active, yet toxic, molecules such as TNFα.

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Acknowledgements

We thank Alexandra Schreiber, Brenda Rohrhan, and Vanessa Rössler for excellent technical help, Gerhard Wallner for the TNFα bioassay, and Iduna Fichtner (Max-Delbrück Center) for kindly providing the MethA cells.

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Authors and Affiliations

  1. Boehringer Ingelheim Austria, Vienna, Austria

    Ralf Kircheis, Elinborg Ostermann, Christine Magin-Lachmann, Lionel Wightman, Malgorzata Kursa & Ernst Wagner

  2. Department of Clinical Pharmacology, Section of Experimental Oncology, University of Vienna, Vienna, Austria

    Markus F Wolschek

  3. Department of Internal Medicine IV, Division of Gastroenterology and Hepatology, University of Vienna, Vienna, Austria

    Markus F Wolschek & Cornelia Lichtenberger

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  1. Ralf Kircheis
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  2. Elinborg Ostermann
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Correspondence to Ralf Kircheis.

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Kircheis, R., Ostermann, E., Wolschek, M. et al. Tumor-targeted gene delivery of tumor necrosis factor-α induces tumor necrosis and tumor regression without systemic toxicity. Cancer Gene Ther 9, 673–680 (2002). https://doi.org/10.1038/sj.cgt.7700487

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