The process of angiogenesis involves the formation of new blood vessels from established vasculature and is essential for progressive
tumor growth and
metastasis. Since
vascular endothelial growth factor (
VEGF) plays a pivotal role in
tumor angiogenesis, it is reasonable to expect that antagonizing
VEGF binding to its receptor may be effective in
cancer therapy. Our previous study found that a novel low molecular weight compound,
VGA1155, inhibited binding between
radioisotope-labelled
VEGF and cells overexpressing its two receptors, Flt-1 and KDR/Flk-1, that is, NIH3T3-Flt-1 and NIH3T3-KDR, respectively. In the present study, we investigated the anti-angiogenic effects of
VGA1155 based on
VEGF inhibition.
VGA1155 inhibited
VEGF-induced
DNA synthesis of human umbilical vein endothelial cells (HUVEC) and human
retinal endothelial cells (HREC) in a concentration-dependent manner.
VGA1155 also inhibited
VEGF-induced tube formation of HUVEC in vitro and
tumor angiogenesis toward B16-BL6
melanoma after orthotopic implantation into the skin of the back. On the other hand, VGA 1155 did not affect the proliferation of human
epidermoid carcinoma (KB) cells and mouse mammary
carcinoma (MM2) cells. It also had no effect on the activity of several cytosolic
kinases such as p55fyn and p56lck. These findings suggest that
VGA1155 inhibits endothelial cell growth and angiogenesis by inhibiting
VEGF function but not non-specific cytotoxicity.
VGA1155 thus exhibits promise as an antiangiogenic or anti-
tumor agent with fewer side-effects.