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Inhibition of Bladder Carcinoma Angiogenesis, Stromal Support, and Tumor Growth by Halofuginone¹

Departments of Oncology [M. E., H-Q. M., I. V.], Pathology [I. A.], and Bone Marrow Transplantation [A. N.], Hadassah-Hebrew University Hospital, Jerusalem 91120; Department of Biological Chemistry, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904 [M. E., N. d-G., A. H.]; and Institute of Animal Science, the Volcany Center, Bet Dagan 50250 [M. P.], Israel

We have previously demonstrated that halofuginone, a widely used alkaloid coccidiostat, is a potent inhibitor of collagen 1(I) and matrix metalloproteinase 2 gene expression. Halofuginone also suppresses extracellular matrix deposition and cell proliferation. We investigated the effect of halofuginone on transplantable and chemically induced mouse bladder carcinoma. In both systems, oral administration of halofuginone resulted in a profound anticancerous effect, even when the treatment was initiated at advanced stages of tumor development. Although halofuginone failed to prevent proliferative preneoplastic alterations in the bladder epithelium, it inhibited further progression of the chemically induced tumor into a malignant invasive stage. Histological examination and in situ analysis of the tumor tissue revealed a marked decrease in blood vessel density and in both collagen 1(I) and H19 gene expression. H19 is regarded as an early marker of bladder carcinoma. The antiangiogenic effect of halofuginone was also demonstrated by inhibition of microvessel formation in vitro. We attribute the profound antitumoral effect of halofuginone to its combined inhibition of the tumor stromal support, vascularization, invasiveness, and cell proliferation.

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