Cancer Res. 2004 May 15;64(10):3586-92.
Blocking
angiogenesis and tumorigenesis with GFA-116, a
synthetic molecule that inhibits binding of vascular endothelial growth factor
to its receptor.
Sun J, Blaskovich
MA, Jain RK, Delarue
F, Paris D, Brem
S, Wotoczek-Obadia
M, Lin Q, Coppola D, Choi
K, Mullan
M, Hamilton AD, Sebti
SM.
Drug Discovery Program, H.
A small synthetic library of cyclohexapeptidomimetic calixarenes was prepared to identify disrupters of vascular
endothelial growth factor (VEGF) binding to its receptor that inhibits
angiogenesis. From this library, we discovered GFA-116, which potently inhibits
(125)I-VEGF binding to Flk-1 in Flk-1-overexpressing
NIH 3T3 cells and human prostate tumor cells with an IC(50) of 750 nM. This inhibition is highly selective for VEGF in that
(125)I- platelet-derived growth factor binding to its
receptor is not affected. GFA-116 inhibits VEGF-stimulated Flk-1 tyrosine phosphorylation and subsequent activation of Erk1/2 mitogen-activated protein kinases.
Furthermore, epidermal growth factor, platelet-derived growth factor, and
fibroblast growth factor-dependent stimulation of Erk1/2 phosphorylation
are not affected at concentrations as high as 10 microM.
In vitro, GFA-116 inhibits angiogenesis as measured by inhibition of migration
and formation of capillary-like structures by human endothelial cells as well
as suppression of microvessel outgrowth in rat aortic
rings and rat cornea angiogenesis. In vivo, GFA-116 (50 mpk/day)
inhibits tumor growth and angiogenesis as measured by CD31 staining of A-549
human lung tumors in nude mice. Furthermore, GFA-116 is also effective at
inhibiting tumor growth and metastasis to the lung of B16-F10 melanoma cells
injected into immunocompetent mice. Taken together,
these results demonstrate that a synthetic molecule capable of disrupting the binding
of VEGF to its receptor selectively inhibits VEGF-dependent signaling and
suppresses angiogenesis and tumorigenesis.
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Keywords: Angiogenesis, tumorogenesis, GFA-116, vascular, endothelial, growth factor, receptor, Cancer Res.