1. 4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor.
- Author
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Minagawa N, Nakayama Y, Inoue Y, Onitsuka K, Katsuki T, Tsurudome Y, Shibao K, Hirata K, Sako T, Nagata N, Ohie S, Kohno K, and Itoh H
- Subjects
- Angiogenesis Inhibitors pharmacology, Animals, Benzoates pharmacology, Cell Line, Tumor, Colonic Neoplasms metabolism, Dose-Response Relationship, Drug, Gene Expression Regulation, Neoplastic physiology, Humans, Liver Neoplasms, Experimental drug therapy, Liver Neoplasms, Experimental metabolism, Liver Neoplasms, Experimental secondary, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Rats, Rats, Inbred F344, Trimethylsilyl Compounds pharmacology, Vascular Endothelial Growth Factor A biosynthesis, Vascular Endothelial Growth Factor A genetics, Angiogenesis Inhibitors therapeutic use, Benzoates therapeutic use, Colonic Neoplasms drug therapy, Gene Expression Regulation, Neoplastic drug effects, Trimethylsilyl Compounds therapeutic use, Vascular Endothelial Growth Factor A antagonists & inhibitors
- 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.
- Published
- 2004
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