ANTI-ANGIOGENIC ACTIVITY OF ARACHIDONIC-ACID METABOLISM INHIBITORS INANGIOGENESIS MODEL SYSTEMS INVOLVING HUMAN MICROVASCULAR ENDOTHELIAL-CELLS AND NEOVASCULARIZATION IN MICE

We have established an in vitro angiogenesis model using human omental microvascular endothelial (HOME) cells, in which epidermal growth fac tor (EGF) or transforming growth factor-alpha (TGF-alpha) stimulated c ell migration and tube formation. In this study, we examined whether a lpha-guaiaconic acid (GR-12) and its synthetic 20 derivatives showed i nhibition of cell migration and tubular formation of HOME cells. We fo und that GR-12 inhibits arachidonic acid metabolism, while GR-12 and o ne derivative, GS-01, inhibit tubular formation of endothelial cells i n our model system. Confluent monolayers of HOME cells were damaged wi th a razor blade and incubated with or without TGF-alpha; HOME cell mi gration was stimulated about 1.5-fold over control values in the prese nce of TGF-alpha. Treatment of HOME cells with GR-12 or GS-01 inhibite d both spontaneous and TGF-alpha-stimulated migration. GR-12 or GS-01 inhibited TGF-alpha-induced HOME-cell tube formation in type-1 collage n gels. We examined whether these compounds could modulate tubular for mation of HOME cells induced by human cancer cells. Enhanced tube form ation of HOME cells by co-cultured esophageal cancer cells was almost completely inhibited by co-administration of GR-12 or GS-01. Both comp ounds also inhibited formation of tubular networks of HOME cells on Ma trigels. We also examined anti-angiogenic activity of these compounds in an in vivo model system of tumor angiogenesis in mice. In this syst em, GS-01 inhibited development of capillary networks at a rate compar able to that of a well-known anti-angiogenic compound, fumagillin, but GR-12 did not. The inhibitor of arachidonic acid metabolism is thus e xpected to modulate tumor angiogenesis. (C) 1993 Wiley-Liss, Inc.