Lu Haiyan, Lin Chen, Zheng Zhibing, Li Song, Guo Shunxing, Zhang Xueyan, Fu Ming, Liang Xiao, Wu Min
National Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
J Pharmacol Sci. 2005 Apr;97(4):533-40. doi: 10.1254/jphs.fp0040761.
Z24, a small molecular compound with similar chemical structure to SU5416 designed and synthesized by our lab, has been proved to be an angiogenesis inhibitor. In this study, Z24 was shown to induce human umbilical venous endothelial cell (HUVEC) apoptosis confirmed by morphologic changes including the presence of apoptotic bodies, significant apoptotic sub-G1 peak upon flow-cytometric analysis, formation of DNA ladders upon agarose gel electrophoresis, and TUNEL (TdT mediated X-dUTP nick-end labeling) results. Systemic administration of Z24 at non-toxic dose in nude mice resulted in inhibition of subcutaneous tumor growth of human colon cancer HCT-8, while it did not inhibit this cell line in vitro, with 100-fold more potent growth-inhibition against endothelial cells. The immunohistochemical results showed that the microvessel density of tumor tissue of the Z24 group was significantly lower than that of the control groups (P<0.05), which supported its anti-angiogenic property. We further found that Z24 inhibited the pulmonary metastasis of mouse lung adenocarcinoma LA795, with fewer surface lung metastases (89.6%, P<0.0001) and decreased lung weights (38.5%, P<0.01) compared to the vehicle group. All these findings support that Z24 is a promising angiogenesis inhibitor for limiting tumor growth and metastasis.
Z24是我们实验室设计合成的一种化学结构与SU5416相似的小分子化合物，已被证明是一种血管生成抑制剂。在本研究中，Z24被证明可诱导人脐静脉内皮细胞（HUVEC）凋亡，这通过形态学变化得以证实，包括凋亡小体的存在、流式细胞术分析时显著的凋亡亚G1峰、琼脂糖凝胶电泳时DNA梯带的形成以及TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）结果。以无毒剂量对裸鼠进行Z24全身给药可抑制人结肠癌HCT - 8的皮下肿瘤生长，而它在体外对该细胞系无抑制作用，对内皮细胞的生长抑制作用强100倍。免疫组化结果显示，Z24组肿瘤组织的微血管密度显著低于对照组（P<0.05），这支持了其抗血管生成特性。我们进一步发现，Z24抑制小鼠肺腺癌LA795的肺转移，与载体组相比，肺表面转移灶更少（89.6%，P<0.0001）且肺重量减轻（38.5%，P<0.01）。所有这些发现都支持Z24是一种有潜力的血管生成抑制剂，可限制肿瘤生长和转移。
