Angiocidal effect of Cyclosporin A: a new therapeutic approach for pathogenic angiogenesis.
OBJECTIVE
Angiogenesis is essential in the development of several disorders such as cancer, arthritis, and autoimmune diseases. Several agents prevent angiogenesis but only a few destroy established angiogenesis. In this study we tested whether local or systemic administration of Cyclosporin A (CyA) would inhibit as well as destroy established angiogenesis in an in vivo assay of angiogenesis.


METHODS
We utilized an in vivo assay of angiogenesis in which an angiogenic mixture of Matrigel, FGF, VEGF, and heparin was injected subcutaneously into mice. Angiogenesis in the subcutaneous plugs was quantified by ANOVA. CyA or the vehicle for CyA was administered to the experimental or the control groups by three routes: by addition to the angiogenic mixture, by local injection into the angiogenic plug at various time points or by systemic administration at high doses. Angiogenesis was quantified by pointing method and expressed as an angiogenic index (AI).


RESULTS
In control animals the subcutaneous plug of Matrigel with the angiogenic mixture revealed exuberant angiogenesis at day 4 and day 7. This angiogenesis was completely inhibited when CyA was included in the angiogenic mixture; the vehicle for CyA had no such effect. Angiogenesis that had progressed was found to regress after local subcutaneous injection of CyA at day 4 and 7. Similar regression of angiogenesis was noted when CyA was administered systemically after allowing angiogenesis to proceed for 4 days.


CONCLUSIONS
Our experiments strongly suggest that CyA is both angiocidal and angiostatic in vivo. These results provide a basis for future therapy directed against established angiogenesis in malignancies and autoimmune diseases.
Wilasrusmee
C
C
Department of Surgery, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. racwl@mahidol.ac.th
Yusupov
I
I
Ondocin
P
P
Bruch
D
D
Kittur
S
S
Wilasrusmee
S
S
Kittur
D S
DS
D000818:Animals; D003094:Collagen / Q000633:toxicity; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D016220:Fibroblast Growth Factor 1 / Q000633:toxicity; D005500:Follow-Up Studies; D006493:Heparin / Q000633:toxicity; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D007797:Laminin / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011509:Proteoglycans / Q000633:toxicity; D012867:Skin / Q000098:blood supply*; D042461:Vascular Endothelial Growth Factor A / Q000633:toxicity
D004338:Drug Combinations; D007166:Immunosuppressive Agents; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D016220:Fibroblast Growth Factor 1; C059485:matrigel; D016572:Cyclosporine; D006493:Heparin; D003094:Collagen