Colon cancer therapy targeting specific charactetistics of tumor vessel.

由于血管生成在肿瘤生长中起着重要的作用，人们对肿瘤血管生成进行了各种研究和治疗。如果肿瘤血管的具体特征被发现，更有效的血管生成治疗可能会付诸实施。与正常血管相比，肿瘤血管大小不一，扭曲、缠绕、渗漏。这种改变可能是由于癌组织中增生活动过多或血管生成因子不平衡所致。我们关注血管生成素2/血管生成素1的平衡，用阿加曲班（新型抗凝剂）的抗血管生成作用检测了这种平衡在实验性癌血管生成中的改变。采用S-180肉瘤细胞和COLO320DM结肠癌细胞建立背气囊模型，测定其宏观血管结构、血管面积计数、cd34微血管密度、血管生成因子（Ang1、Ang2、VEGF）。采用Matrigel法检测HUVEC细胞的成管情况。阿加曲班对肿瘤血管生成有统计学抑制作用。由于阿加曲班在马提格尔试验中没有抑制HUVEC的管状形成，因此这种作用可能不是对内皮细胞的直接作用。在本实验模型中，肿瘤血管生成过程中Ang2 / Ang1比值始终升高，这种现象可能导致肿瘤血管结构异常。提示阿加曲班可能通过抑制肿瘤血管生成而具有抗肿瘤作用。此外，Ang2/Ang1比值的升高可能与肿瘤组织的抗血管生成作用有关。针对肿瘤血管一氧化氮合成异常，进行了另一实验。在相同的背气囊模型中，研究NO合成酶抑制剂N^ g -硝基- l-精氨酸甲酯（L-NAME）的抗血管生成作用及其与血管生成生长因子的关系。L-NAME可显著抑制肿瘤血管生成。肿瘤细胞周围组织中VEGF表达及mRNA水平显著降低。

Since it have been reported that angiogenesis plays an important role in cancer growth, various studies and therapies for tumor angiogenesis have been done. If specific charactetistics of tumor vessel find out, more effective atiangiogenic therapies may be put into practice. The tumor vessel is large and small, twisting, winding and leacky compared with normal vessel. This alterations may be caused by too much proliferative activity or unbalance of angiogenic factors in cancer tissues. We focus on Angiopoietin2/Angiopoietin1 balance, Alteration of this balance in experimental cancerous angiogenesis were examined with antiangiogenic effect of argatroban (new anticoagulant). Macroscopical Vascular structure, Count of vascular area, CD34microvessel density, angiogenic factor (Ang1,Ang2,VEGF) were measured in dorsal air sac model using S-180 sarcoma cell and COLO320DM colon cancer cell. Tube formation of HUVEC cells were tested by Matrigel. For adiministration of argatroban, tumor angiogenesis was statistically inhibited. Because Argatroban did not inhibited tube formation of HUVEC in martigel assey, this effect may not be direct action for endotherial cells. In this experiment model, the Ang2 to Ang1 ratio was always elevated during tumor angiogenesis, this phenomenon might caused abnormal tumor vasclular artitecture. These results suggest that Argatroban may have antitumor effect by inhibition of tumor angiogenesis. In addition, Rivision of Ang2/Ang1 ratio may related to antiangiogenic effect in cancer tissues.Focus on abnormal Nitric oxide synthesis of tumor vessel, Another experiment was done. In the same dorsal air sac model, N^G-nitro-L-arginine-methyl-ester (L-NAME), a NO synthase inhibitor was tested its anti-angiogenic effect with relationship between angiogenic growth factors. Administration of L-NAME significantly inhibited tumor angiogenesis. VEGF expression and mRNA levels in tissue surrounding tumor cells were significantly decreased.