1. ¹Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy
2. ²Laboratory of Molecular Oncology, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy
3. ³Institute of Medical Virology, University of Zurich, Zurich, Switzerland
4. ⁴Children's Hospital, Harvard Medical School, Boston, MA, USA
5. ⁵Animal Models Facility, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy
6. ⁶Immunopharmacology Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy

Correspondence: Dr DM Noonan, Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, c/o Centro di Biotecnologie Avanzate, Largo Rosanna Benzi, 10, 16132 Genova, Italy

Received 15 January 2003; Accepted 19 September 2003.

Abstract

IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN- 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-^-/- and CXCR3^-/- knockout mice, indicating that NK- and/or T-cell-initiated IFN--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.