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 mi cropocket assay. We now show in the mouse that thalidomide given intra peritoneally but not orally significantly inhibits bFGF-induced and va scular endothelial growth factor (VEGF)-induced corneal neovasculariza tion, We further demonstrate that this inhibition is independent from thalidomide's ability to suppress tumor necrosis factor-alpha (TNF-alp ha) 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 a ctivity studies suggest that thalidomide's anti-angiogenic activity is related to the open ring metabolites resulting from hydrolysis. Toget her these data support a correlation between thalidomide's antiangioge nic and teratogenic activities. (C) 1997 Academic Press Limited.