Effects of thalidomide and related metabolites in a mouse corneal model of neovascularization.
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.
Kenyon
B M
BM
Department of Surgery, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Browne
F
F
D'Amato
R J
RJ
D000284:Administration, Oral; D000818:Animals; D003315:Cornea / Q000098:blood supply*; D016510:Corneal Neovascularization / Q000209:etiology / Q000517:prevention & control*; D016228:Endothelial Growth Factors; D005260:Female; D016222:Fibroblast Growth Factor 2; D005971:Glutamates / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D008222:Lymphokines; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000737:chemistry / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D005971:Glutamates; D008222:Lymphokines; C108154:N-phthalimidino glutaric acid; D013723:Teratogens; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C001079:2-(2,6-dioxopiperidin-3-yl)phthalimidine; C034741:N-phthaloylglutamic acid; D013792:Thalidomide