Abstract
The purpose of this study was to determine whether systemic administration of interferon-alpha (IFN-alpha) can inhibit liver metastasis produced in nude mice by human colon cancer cells. KM12L4 (IFN-alpha-sensitive) or KM12L4 IFN(R) (IFN-alpha-resistant) cells were injected into the spleen of nude mice. Seven days later, the mice were treated with subcutaneous (s.c.) injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, or 7 times/week). Significant inhibition of tumor growth, vascularization and expression of basic fibroblast growth factor (bFGF) or matrix metalloproteinase-9 (MMP-9) mRNA and protein occurred in mice given daily injections of IFN-alpha. Kinetic analysis of therapy showed that daily s.c. administrations of 10,000 units of IFN-alpha induced apoptosis in liver metastasis-associated endothelial cells, followed by inhibition of tumor cell division and apoptosis of tumor cells. These data suggest that the antiangiogenic activity of IFN-alpha-2a depends on frequent administration of the optimal biologic dose.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / pathology*
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Dose-Response Relationship, Drug
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Down-Regulation
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Fibroblast Growth Factor 2 / biosynthesis
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Humans
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Immunohistochemistry
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In Situ Hybridization
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In Situ Nick-End Labeling
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Interferon Type I / therapeutic use*
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Interferon alpha-2
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Interferon-alpha / therapeutic use*
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Kinetics
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Liver Neoplasms / blood supply
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / secondary*
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Male
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Matrix Metalloproteinase 8 / biosynthesis
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Mice
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Mice, Nude
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Neoplasm Metastasis
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Neovascularization, Pathologic*
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Platelet Endothelial Cell Adhesion Molecule-1 / biosynthesis
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Proliferating Cell Nuclear Antigen / biosynthesis
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RNA, Messenger / metabolism
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Recombinant Proteins
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Spleen / metabolism
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Time Factors
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Tumor Cells, Cultured
Substances
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Interferon Type I
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Interferon alpha-2
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Interferon-alpha
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Platelet Endothelial Cell Adhesion Molecule-1
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Proliferating Cell Nuclear Antigen
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RNA, Messenger
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Recombinant Proteins
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Fibroblast Growth Factor 2
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Matrix Metalloproteinase 8