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4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.

Abstract
4-[3,5-bis(trimethylsilyl)benzamido] Benzoic acid (TAC-101) has potent antiproliferative, antiangiogenic, and antitumor effects in vitro and in vivo. These effects might be due to TAC-101 binding to retinoic acid receptor alpha (RAR-alpha) and interfering with the binding of activator protein-1 (AP-1) to DNA. However, little is known about the detailed mechanism of TAC-101 function. We investigated the mechanism of the antiangiogenic effect of TAC-101 using a rat hepatic metastatic model in vivo and DLD-1 human colon cancer cells in vitro. Liver metastases were induced by portal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 (8 mg/kg) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density (MVD) and vascular endothelial growth factor (VEGF). TAC-101 significantly reduced both MVD and VEGF expression. Northern blot analysis and ELISA indicated that TAC-101 efficiently inhibited production of VEGF mRNA and protein in DLD-1 cells in a time- and dose-dependent manner. These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF.
AuthorsNoritaka Minagawa, Yoshifumi Nakayama, Yuzuru Inoue, Koji Onitsuka, Takefumi Katsuki, Yosuke Tsurudome, Kazunori Shibao, Keiji Hirata, Tatsuhiko Sako, Naoki Nagata, Shinji Ohie, Kimitoshi Kohno, Hideaki Itoh
JournalOncology research (Oncol Res) Vol. 14 Issue 9 Pg. 407-14 ( 2004) ISSN: 0965-0407 [Print] United States
PMID15490972 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Angiogenesis Inhibitors
  • Benzoates
  • TAC 101
  • Trimethylsilyl Compounds
  • Vascular Endothelial Growth Factor A
Topics
  • Angiogenesis Inhibitors (pharmacology, therapeutic use)
  • Animals
  • Benzoates (pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Colonic Neoplasms (drug therapy, metabolism)
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic (drug effects, physiology)
  • Humans
  • Liver Neoplasms, Experimental (drug therapy, metabolism, secondary)
  • Neovascularization, Pathologic (drug therapy, metabolism)
  • Rats
  • Rats, Inbred F344
  • Trimethylsilyl Compounds (pharmacology, therapeutic use)
  • Vascular Endothelial Growth Factor A (antagonists & inhibitors, biosynthesis, genetics)

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