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Investigation of the inhibitory mechanism of the hepatic metastasis in the colorectal carcinoma by synthesic retinoid, TAC-101

合成类维生素A TAC-101抑制结直肠癌肝转移的机制研究

基本信息

批准号：
14571249
负责人：
ITOH Hideaki
金额：
$ 1.73万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

The presence of hepatic metastasis is one of the most important prognostic factors in colorectal cancer. This suggests that more effective suppressor of the progression and metastasis of colon cancer would significantly improve prognosis. Recently, RA (retinoic acid) has shown to be a potentially powerful anti-cancer agent, and acts in several types of cancer therapy. The mechanism of RA's affect on tumors appears to be related to its effects on proliferation and differentiation of tumor cells. 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101) is a novel retinobenzoic acid derivative and has a specific binding affinity to the retinoic acid receptors (RAR)-α and -β. TAC-101 has potent anti-proliferative, anti-angiogenic, and anti-tumor effects in vitro and in vivo. However, little is known about the detailed mechanism of TAC-101 function.Here, we investigate the mechanism of the anti-angiogenic effect and apoptosis induction of TAC-101. Hepatic metastases were induced by por … More tal injection of RCN-9 rat colonic cancer cells into F344 rats. TAC-101 was orally administered 5 days per week for four weeks, then liver tumors were immunohistochemically evaluated for microvascular density (MVD) and vascular endothelial growth factor (VEGF). Apoptotic index (A.I.) in the hepatic tumors was evaluated using immunohistochemistry for single-stranded DNA. The proliferative index (P.I.), Fas and Fas ligand were also immunohistochemically evaluated. Moreover, evaluation of apoptosis by TAC-101 in vitro using FACScan analysis was performed in the DLD-1 human colon cancer cell line.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. TAC-101 significantly decreased P. I. but increased A. I. in the hepatic metastatic tumors. TAC-101 did not affect the expression of Fas ligand, but obviously increased the expression of Fas in the metastatic tumors. Moreover, TAC-101 induced early apoptosis in DLD-1 cells in a time dependent manner in vitro.These findings suggest that TAC-101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of VEGF. Moreover, TAC-101 may induced apoptosis partially through enhanced Fas expression. Less

肝转移的存在是结直肠癌最重要的预后因素之一。这表明，更有效地抑制结肠癌的进展和转移将显着改善预后。最近，RA（视黄酸）已被证明是一种潜在的强大的抗癌剂，并在几种类型的癌症治疗中发挥作用。RA对肿瘤作用的机制似乎与其对肿瘤细胞增殖和分化的影响有关。4-[3，5-双（三甲基硅基）苯甲酰氨基]苯甲酸（TAC-101）是一种新型的视黄酸衍生物，与视黄酸受体（RAR）-α和-β具有特异性结合。TAC-101在体外和体内具有强效的抗增殖、抗血管生成和抗肿瘤作用。然而，关于TAC-101作用的详细机制还知之甚少，本文主要探讨TAC-101抗血管生成和诱导细胞凋亡的作用机制。por诱导肝转移 ...更多信息将RCN-9大鼠结肠癌细胞注射到F344大鼠体内。每周5天口服TAC-101，持续4周，然后用免疫组织化学方法评估肝脏肿瘤的微血管密度（MVD）和血管内皮生长因子（VEGF）。凋亡指数（A.I.）用单链DNA免疫组化法评价肝肿瘤中的表达。增殖指数（P.I.），Fas和Fas配体也进行了免疫组化评价。此外，使用FACScan分析在体外对TAC-101在DLD-1人结肠癌细胞系中的凋亡进行评估，TAC-101显著降低MVD和VEGF表达。北方印迹分析和ELISA检测结果表明，TAC-101能有效抑制DLD-1细胞VEGF mRNA和蛋白的表达，并呈时间和剂量依赖性。TAC-101显著降低P.I.但增加了A。I.肝转移瘤中。TAC-101不影响Fas配体的表达，但明显增加转移瘤中Fas的表达。此外，TAC-101在体外可诱导DLD-1细胞发生早期凋亡，并呈时间依赖性，提示TAC-101可能通过干扰VEGF的产生而抑制结肠癌的进展和转移。此外，TAC-101可能部分通过增强Fas表达而诱导细胞凋亡。少