Vascular endothelial cell
growth factor (
VEGF) plays an important role in the processes of angiogenesis. Angiogenesis appears to be essential for the growth of solid
tumors and their
metastasis.
VEGF plays a principal role in
tumor angiogenesis. To identify a compound that inhibits the binding of
VEGF to its receptor, we used a high-throughput screening method and found that oxydibenzoic
acid derivatives inhibited
VEGF binding to its receptors. Among the active compounds, 5-[3-[4-(octadecyloxy)phenyl]propionylamino]-2,4'-oxydibenzoic
acid (
VGA1102) was selected based on its potent binding inhibitory activity.
VGA1102 inhibited [(125)I]
VEGF binding to both of two
VEGF receptor-transfected cell lines, NIH-Flt-1 and NIH-KDR/Flk-1, in a concentration-dependent manner, with IC(50) values of 0.66+/-0.07 and 0.61+/-0.16 micro M, respectively.
VGA1102 (10 micro M) exhibited inhibitory activity against
VEGF-induced receptor autophosphorylation.
VGA1102 also inhibited
VEGF-induced growth of rat liver sinusoidal endothelial cells (IC(50)=0.89+/-0.16 micro M) as well as
VEGF-induced tube formation of HUVEC in vitro.
VGA1102 reduced intradermal
VEGF-induced vascular permeability in guinea pigs. Treatment with
VGA1102 (50 mg/kg, i.p., days 0-20) significantly increased the lifespan of MM2-bearing mice with an increase in lifespan of >195.8%, and all such mice were long-term survivors on day 71. Furthermore,
VGA1102 (50 mg/kg, i.p.) administered daily suppressed the growth of nude mice transplanted with
LC-6 human
non-small-cell lung cancer. These results suggest that
VGA1102 inhibits
VEGF function resulting in inhibition of
tumor angiogenesis, which led to suppression of growth of human
tumors transplanted into nude mice.