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A novel low molecular weight VEGF receptor-binding antagonist, VGA1102, inhibits the function of VEGF and in vivo tumor growth

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Abstract

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 [125I]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 IC50 values of 0.66±0.07 and 0.61±0.16 μM, respectively. VGA1102 (10 μM) exhibited inhibitory activity against VEGF-induced receptor autophosphorylation. VGA1102 also inhibited VEGF-induced growth of rat liver sinusoidal endothelial cells (IC50=0.89±0.16 μM) 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.

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Abbreviations

BSA:

bovine serum albumin

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

fetal bovine serum

Flt-1:

fms-like tyrosine kinase

HUVEC:

human umbilical vein endothelial cells

ILS:

increase in lifespan

KDR/Flk-1:

kinase insert domain containing receptor/fetal liver kinase

MEM:

minimum essential medium

MST:

median survival time

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

PBS:

phosphate-buffered saline

VEGF:

vascular endothelial growth factor

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Authors and Affiliations

  1. Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, 331-9530, Saitama, Japan

    Yasuji Ueda, Takehiro Yamagishi, Kazunori Samata, Hisao Ikeya, Noriko Hirayama, Tadayasu Okazaki, Sumi Nishihara, Koshi Arai, Shiro Nakaike & Makoto Tanaka

  2. Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, 108-8639, Tokyo, Japan

    Sachiko Yamaguchi & Masabumi Shibuya

Authors
  1. Yasuji Ueda
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  2. Takehiro Yamagishi
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  12. Makoto Tanaka
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Correspondence to Yasuji Ueda.

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Ueda, Y., Yamagishi, T., Samata, K. et al. A novel low molecular weight VEGF receptor-binding antagonist, VGA1102, inhibits the function of VEGF and in vivo tumor growth. Cancer Chemother Pharmacol 54, 16–24 (2004). https://doi.org/10.1007/s00280-004-0763-8

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  • DOI: https://doi.org/10.1007/s00280-004-0763-8

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