Matsubara T, Saura R, Hirohata K, Ziff M
Department of Orthopedic Surgery, Kobe University School of Medicine, Japan.
J Clin Invest. 1989 Jan;83(1):158-67. doi: 10.1172/JCI113853.
To investigate the effects of D-penicillamine (D-Pen) on angiogenesis, we have studied the effects of this drug on in vitro proliferation of human endothelial cells (EC) and in vivo corneal neovascularization. D-Pen, in the presence of copper sulfate, suppressed tritiated thymidine ([3H]TdR) incorporation into EC in a dose-dependent manner. Significant inhibition was observed with D-Pen concentrations attainable in the serum and tissues of treated patients. Neither D-Pen nor copper ion alone significantly affected [3H]TdR incorporation into EC. The inhibition by D-Pen and copper was blocked by catalase (CAT) or horseradish peroxidase but not by boiled CAT or SOD. When rabbits were daily injected intravenously with D-Pen at the per kilogram dosage administered to rheumatoid patients, neovascularization as quantitated by the proliferation of corneal new blood vessels was significantly inhibited. These results suggest that hydrogen peroxide generated by D-Pen and copper exerts a pronounced antiangiogenic effect through inhibition of EC proliferation. It is, therefore, considered that D-Pen may suppress rheumatoid synovitis by reducing the number of small blood vessels available for the emigration of chronic inflammatory cells, and the proliferation of the synovial tissue.
为了研究D-青霉胺（D-Pen）对血管生成的影响，我们研究了该药物对人内皮细胞（EC）体外增殖以及体内角膜新生血管形成的作用。在硫酸铜存在的情况下，D-Pen以剂量依赖的方式抑制氚标记胸腺嘧啶核苷（[3H]TdR）掺入EC。在接受治疗患者的血清和组织中可达到的D-Pen浓度下观察到显著抑制作用。单独的D-Pen或铜离子均未显著影响[3H]TdR掺入EC。D-Pen和铜的抑制作用可被过氧化氢酶（CAT）或辣根过氧化物酶阻断，但不能被煮沸的CAT或超氧化物歧化酶阻断。当以给予类风湿患者的每千克剂量每日静脉注射D-Pen给兔子时，通过角膜新生血管增殖定量的新生血管形成受到显著抑制。这些结果表明，D-Pen和铜产生的过氧化氢通过抑制EC增殖发挥明显的抗血管生成作用。因此，认为D-Pen可能通过减少可供慢性炎症细胞迁移的小血管数量以及滑膜组织的增殖来抑制类风湿性滑膜炎。
