Orally administered bovine lactoferrin systemically inhibits VEGF(165)-mediated angiogenesis in the rat

Lactoferrin (Lf) systemically suppresses tumor growth and metastasis by unk nown mechanisms. We have studied the effect of orally administered iron-uns aturated bovine Lf on angiogenesis induced by VEGF(165) and IL-1-alpha in a dult rats using the mesenteric-window angiogenesis assay. VEGF(165) is a ma jor angiogenic factor in most, if not all, tumors and other angiogenesis di seases of clinical relevance. A number of objective angiogenesis variables were analyzed using microscopic morphometry and image analysis. Lf treatmen t significantly inhibited the VEGF(165)-mediated response in terms of micro vessel spatial extension. overall vascularity and incidence of crossover. T he response to IL-1-alpha decreased significantly only in terms of microves sel crossover. In vitro, Lf exerted an antiproliferative effect on endothel ial cells. To our knowledge, Lf is the first endogenous protein that has be en shown to be antiangiogenic following oral administration. The oral admin istration of Lf thus appears to he of potential interest as an antiangiogen esis treatment modality in the clinical setting. Since tumor growth is angi ogenesis dependent, the extensive therapeutic potential warrants further st udy to elucidate the mechanisms responsible for the angiostatic effect of L f. (C) 2001 Wiley-Liss, Inc.