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Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy

Gene Therapy volume 11, pages 284–291 (2004)Cite this article

Abstract

IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-γ and angiostatic CXCR3 chemokine ligands. Naked DNA intramuscular injection of an expression vector plasmid producing IL-12 resulted in significant, well-tolerated elevation of serum IL-12 levels. Injection of the IL-12 plasmid at least 2 days, and up to 20 days, before subcutaneous injection of matrigel with angiogenic factors resulted in strong prevention of angiogenesis in both C57/bl and nude mice. A single injection of the IL-12 plasmid contemporarily with the matrigel or 2 days after resulted in partial, statistically not significant, inhibition. Control plasmid injection did not affect either angiogenesis or angiogenesis inhibition by IL-12 protein in vivo. Angiogenesis inhibition was observed in NK cell-depleted C57/bl and nude mice as well as in IFN-γ−/− and CXCR3−/− knockout mice, indicating that NK- and/or T-cell-initiated IFN-γ-chemokine cascades were not involved in the angiogenesis inhibition observed in vivo. Finally, IL-12 plasmid DNA gene transfer significantly prevented the growth and vascularization of highly angiogenic KS-Imm Kaposi's sarcoma and TS/A murine mammary carcinoma tumors in nude and/or syngeneic mice. These data suggest that a preventive gene therapy approach using antiangiogenic cytokines can effectively inhibit tumor angiogenesis and KS, representing an example of angioimmunoprevention.

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Acknowledgements

These studies were supported by grants from the AIRC (Associazione Italiana per la Ricerca sul Cancro), the Istituto Superiore di Sanità – Progetto Italia–USA sulla Terapia dei Tumori and – Progetto AIDS, the Ministero della Salute – Progetto Finalizzato, the MIUR – Progetto Strategico, the MURST and the Compagnia di San Paolo. We are grateful to Simona Minghelli and Amleto De Santanna for the histology preparations, to Anna Rapetti for expert secretarial assistance and Monica Barabino for data searches.

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Authors and Affiliations

  1. Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy

    M Morini, G Lorusso & DM Noonan

  2. Laboratory of Molecular Oncology, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy

    A Albini

  3. Institute of Medical Virology, University of Zurich, Zurich, Switzerland

    K Moelling

  4. Children's Hospital, Harvard Medical School, Boston, MA, USA

    B Lu

  5. Animal Models Facility, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy

    M Cilli

  6. Immunopharmacology Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy

    S Ferrini

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  1. M Morini
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Morini, M., Albini, A., Lorusso, G. et al. Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy. Gene Ther 11, 284–291 (2004). https://doi.org/10.1038/sj.gt.3302175

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