Direct in vitro evidence and in vivo analysis of the antiangiogenesis effects of interleukin 12

As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunode...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2000-02, Vol.60 (4), p.1111-1116
Main Authors: DUDA, D. G, SUNAMURA, M, LOZONSCHI, L, KODAMA, T, EGAWA, S.-I, MATSUMOTO, G, SHIMAMURA, H, SHIBUYA, K, TAKEDA, K, MATSUNO, S
Format: Article
Language:English
Subjects:
3T3 Cells
Angiogenesis Inhibitors - pharmacology
Animals
Antineoplastic agents
Biological and medical sciences
Cytokines - biosynthesis
Cytokines - genetics
Humans
Immunotherapy
Interleukin-12 - pharmacology
Male
Medical sciences
Mice
Mice, SCID
Neoplasms, Experimental - blood supply
Neovascularization, Pathologic - prevention & control
Pharmacology. Drug treatments
Tumor Cells, Cultured
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Summary:As an antitumor agent, interleukin-12 (IL-12) has been revealed to be a key regulator of the immune response, particularly that involving CTL and natural killer (NK) cells. We report herein the antiangiogenesis effect of IL-12 on human as well as murine tumors in NK-depleted severe-combined immunodeficient mice using fibroblasts genetically engineered to secrete this cytokine. Although the in vitro growth of tumor cells was not affected by the presence of IL-12, coinoculation of IL-12-secreting fibroblasts strongly inhibited tumor growth in immunodeficient mice. The neovascularization surrounding the tumor was remarkably inhibited in the area in which the IL-12-secreting fibroblasts were implanted, resulting in the suppression of tumor growth. Lectin staining in tumor sample sections also showed a significant reduction in the number of vessels. The RNA expression of IFN-gamma and its inducible antiangiogenic chemokine IFN gamma-inducible protein 10 was stimulated in endothelial cells cultured with IL-12. It was also found that IL-12 down-regulated the expression of the endothelial cell mitogens vascular endothelial growth factor and basic fibroblast growth factor. The antitumor effects of IL-12 were accompanied by interesting histological changes consisting of a high degree of keratinization and apoptosis and a decrease in the proliferation rate of human tumors and extensive necrosis in the murine ones.
ISSN:0008-5472
1538-7445