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

在结直肠癌中，转移是一个严重影响死亡率的问题。约40%的晚期结直肠癌患者发生肝转移。如果肝转移减少，晚期结直肠癌患者的预后将会改善。肿瘤转移是通过复杂和多步骤的过程完成的。为了研究这一复杂的转移过程，我们建立了一套大鼠肝转移的磁共振成像(MRI)时程评估系统。我们还建立了利用内皮细胞进行侵袭实验的方法。近年来，维甲酸(RA)是最受期待的抗癌药物之一，对肿瘤的治疗有多种作用机制。在动物模型系统中，RA已被证明可以抑制各种上皮组织的癌变。RAS对肿瘤的作用机制可能与其对肿瘤细胞增殖和分化的影响有关。TAc-101是一种新型的合成RA、Severa…在裸鼠体内实验和体外实验中，更多的L报道了TAC-101的抗肿瘤活性和抗转移活性。(1)每日口服TAC-101对小鼠肝转移有明显抑制作用。(2)TAC-101治疗组大鼠肝转移瘤的微血管密度明显低于对照组。(3)TAC-101治疗组大鼠肝转移瘤血管内皮细胞生长因子(VEGF)表达明显低于对照组。(4)TAC-101治疗组大鼠肝转移瘤细胞凋亡指数明显高于对照组。(5)TAC-101治疗组大鼠肝转移瘤Fas表达明显高于对照组。提示TAC-101对肝转移的抑制作用可能是通过抑制血管生成抑制血管生成和通过Fas诱导细胞凋亡来实现的。较少

In colorectal cancer, metastasis is a critical problem which adversely affects mortality rates. About 40% of patients with advanced colorectal cancer developed hepatic metastasis. If the hepatic metastasis will be reduced, the prognosis of the patients with advanced colorectal cancer will be improved. Cancer metastasis is completed through complex and multistep processes. We developed an evaluate system of hepatic metastasis in rats by magnetic resonance imaging (MRI) in time course to investigate this complex metstatic processes. We also developed the invasion assay method using endothelial cell. Recently, retinoic acid (RA) is one of the most expected anti-cancer agents, and has several mechanism on cancer therapy. RA have been shown to supress carcinogenesis in various epithelial tissues in animal model systems. The mechanism of action of RAs on tumors seems to be related to their effects on proliferation and differentiation of the tumor cells. TAC-101 is a novel synthesic RA.Severa … More l reports indicated the anti-tumor activity and anti-metastatic activity of TAC-101 on the experiments using nude mice in vivo and the experiments in vitro. (1) Daily oral administration of TAC-101 resulted in a significant inhibition of hepatic metastasis. (2) MVD of the hepatic metastatic tumor in the rats treated with TAC-101 was significantly decreased as compared with that of control rats. (3) vascural endothelial growth factor (VEGF) expression of the hepatic metastatic tumor treated with TAC-101 was reduced as compared with that of control rats. (4) The apoptotic index of the hepatic metastatic tumors in the rats treated with TAC-101 was significantly increased as compared with that of the control rats. (5) Fas expression of the hepatic metastatic tumor in the rats treated with TAC-101 was remarkably increased as compared with that of control rats. These data indicate that the inhibitory effect of the hepatic metastasis by TAC-101 is the inhibitory effect of angiogenesis via the supression of VEGF expression and also induction of apoptosis via FAS. Less