α-双炔失碳酯体内、外抑制血管生成

摘要

AIM: To study the antiangiogenic effect of α-anordrin (α-Ano), a partial. antagonist of estrogen receptor.METHODS: The in vivo inhibitory effect of α-Ano on angiogenesis was determined by microvascular density (MVD) in tumors and the chicken chorioallantoic membrane (CAM) model. The in vitro effects of α-Ano on proliferation, migration, and attachment of human umbilical vein endothelial cells (HUVEC) were assessed by trypan blue exclusion, wound-induced two-dimensional migration model, and their ability to adhere to type Ⅰcollagen, respectively. The possible involvement of nitric oxide (NO) in α-Ano antiangiogenic effect was determined by measuring NO content using fluorescent assay.RESULTS: α-Ano significantly inhibited the MVD in Lewis lung carcinoma model and this effect was correlated with its inhibition of the tumor growth. α-Ano also showed an inhibitory effect on the angiogenesis of CAM with the inhibitory rate of 53 % and such action of α-Ano could not be blocked by simultaneous administration of 17β-estrodiol, a typical agonist of estrogen receptor. In vitro studies showed that α-ANO obviously suppressed the proliferation and migration of HUVEC, but had no obvious effect on the attachment of HUVEC to the type Ⅰ collagen. Moreover, α-Ano significantly reduced the level of NO released by HUVEC in a dose-and time-dependent manner. CONCLUSION: α-Ano possesses an antiangiogenic effect, and this effect is mediated, at least in part, by reducing the NO content and subsequently inhibiting the proliferation and migration of endothelial cells.%目的：研究雌激素受体部分拮抗剂α-双炔失碳酯(α-Ano)对体内、外肿瘤血管生成的抑制作用.方法：在C57BL/6小鼠中观察Lewis肺癌的生长情况，用免疫组织化学方法观察肿瘤微血管密度(MVD)；在鸡胚绒毛膜尿囊膜(CAM)模型上观察药物对血管生成的影响；用台盼蓝排染法研究药物对人脐静脉内皮细胞(HUVEC)生长的作用；在体外观察了药物对HUVEC的由伤口引起的迁移和对胶原基质的粘附活性的影响；用荧光法间接测定一氧化氮(NO)水平.结果：α-Ano显著地抑制Lewis肺癌的MVD，同时抑制小鼠皮下接种的肿瘤生长，MVD的降低程度与肿瘤生长的抑制程度相关.α-ANO在CAM模型上也显示出对血管生成的抑制活性，抑制率达53％，17β-雌二醇对α-Ano抑制CAM血管生成的活性无明显拮抗作用；α-Ano对HUVEC的增殖和迁移活性有抑制作用，但对HUVEC对Ⅰ型胶原的粘附能力无明显影响.同时，α-Ano能够抑制HUVEC释放NO的水平，且具有时间和剂量依赖性.结论：α-Ano具有血管生成抑制活性，此作用是通过减少NO的释放，随后抑制内皮细胞的增殖和迁移而实现的.