Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy.
IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-gamma 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-gamma(-/-) and CXCR3(-/-) knockout mice, indicating that NK- and/or T-cell-initiated IFN-gamma-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.
Morini
M
M
Tumor Progression Section, Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi, Genova, Italy.
Albini
A
A
Lorusso
G
G
Moelling
K
K
Lu
B
B
Cilli
M
M
Ferrini
S
S
Noonan
D M
DM
D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D010957:Plasmids / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000276:immunology; D012514:Sarcoma, Kaposi / Q000098:blood supply* / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D018664:Interleukin-12; D007371:Interferon-gamma