Abstract
Thalidomide, when administered orally, is an inhibitor of angiogenesis in the basic fibroblast growth factor (bFGF)-induced rabbit cornea micropocket assay. We now show in the mouse that thalidomide given intraperitoneally but not orally significantly inhibits bFGF-induced and vascular endothelial growth factor (VEGF)-induced corneal neovascularization. We further demonstrate that this inhibition is independent from thalidomide's ability to suppress tumor necrosis factor-alpha (TNF-alpha) production. Experiments examining thalidomide's enantiomers reveal-that the S(-)-enantiomer has the strongest antiangiogenic activity in VEGF-induced and bFGF-induced corneal neovascularization. Structure activity studies suggest that thalidomide's anti-angiogenic activity is related to the open ring metabolites resulting from hydrolysis. Together these data support a correlation between thalidomide's antiangiogenic and teratogenic activities.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Cornea / blood supply*
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Corneal Neovascularization / etiology
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Corneal Neovascularization / prevention & control*
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Endothelial Growth Factors
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Female
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Fibroblast Growth Factor 2
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Glutamates / therapeutic use
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Injections, Intraperitoneal
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Lymphokines
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Mice
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Mice, Inbred C57BL
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Structure-Activity Relationship
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Teratogens / chemistry
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Teratogens / pharmacology*
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Thalidomide / analogs & derivatives
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Thalidomide / chemistry
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Thalidomide / pharmacology*
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Thalidomide / therapeutic use
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Glutamates
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Lymphokines
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N-phthalimidino glutaric acid
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Teratogens
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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2-(2,6-dioxopiperidin-3-yl)phthalimidine
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N-phthaloylglutamic acid
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Thalidomide