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Departments of
* Oncology,
Bone Marrow Transplantation,
Pharmacology, and
§ Ophthalmology, Hadassah-Hebrew University Hospital, Jerusalem 91120; and
¶ Institute of Animal Science, the Volcany Center, Bet Dagan, Israel
1Correspondence: Department of Oncology, Hadassah Hospital, POB 12000, Jerusalem, 91120, Israel. E-mail: vlodavsk{at}cc.huji.ac.il
We have previously demonstrated that halofuginone, a low molecular
weight quinazolinone alkaloid, is a potent inhibitor of collagen
1(I) and matrix metalloproteinase 2 (MMP-2) gene expression.
Halofuginone also effectively suppresses tumor progression and
metastasis in mice. These results together with the well-documented
role of extracellular matrix (ECM) components and matrix degrading
enzymes in formation of new blood vessels led us to investigate the
effect of halofuginone on the angiogenic process. In a variety of
experimental system, representing sequential events in the angiogenic
cascade, halofuginone treatment resulted in profound inhibitory effect.
Among these are the abrogation of endothelial cell MMP-2 expression and
basement membrane invasion, capillary tube formation, and vascular
sprouting, as well as deposition of subendothelial ECM. The most
conclusive anti-angiogenic activity of halofuginone was demonstrated
in vivo (mouse corneal micropocket assay) by showing a
marked inhibition of basic fibroblast growth factor (bFGF) -induced
neovascularization in response to systemic administration of
halofuginone, either i.p. or in the diet. The ability of halofuginone
to interfere with key events in neovascularization, together with its
oral bioavailability and safe use as an anti-parasitic agent, make it a
promising drug for further evaluation in the treatment of a wide range
of diseases associated with pathological angiogenesis.—Elkin, M.,
Miao, H.-Q., Nagler, A., Aingorn, E., Reich, R., Hemo, I., Dou, H.-L.,
Pines, M., Vlodavsky, I. Halofuginone: a potent inhibitor of critical
steps in angiogenesis progression,
Key Words: neovascularization • type I collagen • halofuginone • matrix metalloproteinase-2 • extracellular matrix
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