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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抗癌剂，并在多种类型的癌症治疗中发挥作用。 RA影响肿瘤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（三甲基甲硅烷基）苯甲酰胺基]苯甲酸 (TAC-101) 是一种新型视黄苯甲酸衍生物，对视黄酸受体 (RAR)-α 和 -β 具有特异性结合亲和力。 TAC-101 在体外和体内具有有效的抗增殖、抗血管生成和抗肿瘤作用。然而，人们对TAC-101功能的详细机制知之甚少。在此，我们研究TAC-101的抗血管生成作用和诱导细胞凋亡的机制。将 RCN-9 大鼠结肠癌细胞经口注射到 F344 大鼠体内诱导肝转移。每周 5 天口服 TAC-101，持续 4 周，然后通过免疫组织化学方法评估肝肿瘤的微血管密度 (MVD) 和血管内皮生长因子 (VEGF)。使用单链 DNA 的免疫组织化学评估肝肿瘤的细胞凋亡指数 (A.I.)。还对增殖指数 (P.I.)、Fas 和 Fas 配体进行了免疫组织化学评估。此外，在 DLD-1 人结肠癌细胞系中使用 FACScan 分析对 TAC-101 的体外细胞凋亡进行评估。TAC-101 显着降低 MVD 和 VEGF 表达。 Northern blot 分析和 ELISA 表明，TAC-101 以时间和剂量依赖性方式有效抑制 DLD-1 细胞中 VEGF mRNA 和蛋白的产生。 TAC-101 显着降低肝转移肿瘤的 P. I.，但增加 A. I.。 TAC-101不影响Fas配体的表达，但明显增加转移性肿瘤中Fas的表达。此外，TAC-101 在体外以时间依赖性方式诱导 DLD-1 细胞早期凋亡。这些发现表明，TAC-101 可能通过干扰肿瘤 VEGF 的产生来抑制结肠癌的进展和转移。此外，TAC-101 可能部分通过增强 Fas 表达来诱导细胞凋亡。较少的