Takano S, Gately S, Jiang J B, Brem S
Division of Neurological Surgery, Northwestern Memorial Hospital and School of Medicine, Chicago, Illinois.
J Pharmacol Exp Ther. 1994 Nov;271(2):1027-33.
Tumor growth is dependent upon angiogenesis. There is an intense search for pharmacological inhibitors of angiogenesis as a novel approach to treat angiogenic diseases, e.g., arthritis, diabetic retinopathy or cancer. A series of compounds, originally studied as potential protein kinase C inhibitors, included the diaminoanthraquinone NSC 639366 (1-[[3-(diethylamino)-2-hydroxypropyl]amino]-4-[(2,3- epoxypropyl)amino]-9,10-anthracenedione fumaric acid salt) (SPC-100097), was found to reversibly inhibit bovine endothelial cell growth with an IC50 that ranged between 1 and 4 nM. NSC 639366 reversibly inhibited endothelial cell migration, particularly endothelial cells stimulated by the potent angiogenic molecule, basic fibroblast growth factor. The activity of secreted urokinase-type plasminogen activator and active interstitial collagenase, but not gelatinase, was inhibited by NSC 639366. In vivo, angiogenesis was significantly inhibited by NSC 639366 by using the chick chorioallantoic membrane or the rat corneal bioassay. Two analogs of NSC 639366 did not inhibit endothelial cell growth. These experiments introduce a novel compound that could be clinically useful against angiogenic diseases and encourage further development of compounds that inhibit the plasminogen-plasmin system known to be a key regulator of angiogenesis.
肿瘤生长依赖于血管生成。人们正在积极寻找血管生成的药理学抑制剂，作为治疗血管生成性疾病（如关节炎、糖尿病视网膜病变或癌症）的新方法。一系列最初作为潜在蛋白激酶C抑制剂进行研究的化合物，包括二氨基蒽醌NSC 639366（1-[[3-(二乙氨基)-2-羟丙基]氨基]-4-[(2,3-环氧丙基)氨基]-9,10-蒽二酮富马酸盐）（SPC-100097），被发现能可逆地抑制牛内皮细胞生长，其IC50在1至4 nM之间。NSC 639366可逆地抑制内皮细胞迁移，尤其是被强效血管生成分子碱性成纤维细胞生长因子刺激的内皮细胞。NSC 639366抑制分泌型尿激酶型纤溶酶原激活剂和活性间质胶原酶的活性，但不抑制明胶酶的活性。在体内，通过鸡胚绒毛尿囊膜或大鼠角膜生物测定法，NSC 639366能显著抑制血管生成。NSC 639366的两种类似物不抑制内皮细胞生长。这些实验引入了一种可能对血管生成性疾病具有临床应用价值的新型化合物，并鼓励进一步开发抑制已知为血管生成关键调节因子的纤溶酶原-纤溶酶系统的化合物。
