Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine.
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.
Matsubara
T
T
Department of Orthopedic Surgery, Kobe University School of Medicine, Japan.
Saura
R
R
Hirohata
K
K
Ziff
M
M
D002374:Catalase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003300:Copper / Q000494:pharmacology; D019327:Copper Sulfate; D004261:DNA Replication / Q000187:drug effects; D004220:Disulfides / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology*; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D010396:Penicillamine / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D004220:Disulfides; D013438:Sulfhydryl Compounds; D006052:Gold Sodium Thiomalate; D003300:Copper; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D002374:Catalase; D010396:Penicillamine; D019327:Copper Sulfate