Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats
Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats
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DOI：
10.1172/jci118838
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发表时间：
1996-08-01
影响因子：
15.9
通讯作者：
Bouck, NP
中科院分区：
文献类型：
--
作者：
Volpert, OV;Ward, WF;Bouck, NP
巯甲丙脯酸是一种血管紧张素转换酶抑制剂，临床上广泛用于治疗高血压和充血性心力衰竭。在这里，卡托普利被证明是一种血管生成抑制剂，能够阻断大鼠角膜中诱导的新血管形成。Captopril直接和特异性作用于毛细血管内皮细胞，抑制其趋化性与双相剂量-反应曲线显示在临床可达到的剂量在10 μ M以下的初始下降和进一步缓慢下降的毫摩尔范围。卡托普利对内皮细胞迁移的抑制不是通过血管紧张素转换酶抑制介导的，而是被锌抑制。还观察到卡托普利对已知对血管生成至关重要的锌依赖性内皮细胞衍生的72-和92-kD金属蛋白酶的直接抑制。当对大鼠全身使用时，卡托普利抑制角膜新生血管形成，并显示出预期的血管生成抑制剂的抗肿瘤活性，减少癌前肝细胞致癌物诱导病灶中存在的有丝分裂的数量，并减缓体外细胞对卡托普利耐药的实验性纤维肉瘤的生长速率。这些数据定义这种广泛使用的药物作为一种新的新血管形成抑制剂，并提出了长期服用卡托普利的患者可能从其抗血管生成活性中获得意想不到的益处的可能性。
Captopril, an inhibitor of angiotensin converting enzyme, is widely used clinically to manage hypertension and congestive heart failure. Here captopril is shown to be an inhibitor of angiogenesis able to block neovascularization induced in the rat cornea. Captopril acted directly and specifically on capillary endothelial cells, inhibiting their chemotaxis with a biphasic dose-response curve showing an initial decrease at clinically achievable doses under 10 mu M and a further slow decline in the millimolar range. Captopril inhibition of endothelial cell migration was not mediated by angiotensin converting enzyme inhibition, but was suppressed by zinc. Direct inhibition by captopril of zinc-dependent endothelial cell-derived 72- and 92-kD metalloproteinases known to be essential for angiogenesis was also seen. When used systemically on rats captopril inhibited corneal neovascularization and showed the antitumor activity expected of an inhibitor of angiogenesis, decreasing the number of mitoses present in carcinogen-induced foci of preneoplastic liver cells and slowing the growth rate of an experimental fibrosarcoma whose cells were resistant to captopril in vitro. These data define this widely used drug as a new inhibitor of neovascularization and raise the possibility that patients on long term captopril therapy may derive unexpected benefits from its antiangiogenic activities.