Co-Authors:
Pines, M., Institute of Animal Science, Agricultural Research Organization, Volcani Center, Bet Dagan, Israel, Institute of Animal Science, ARO, Volcani Center, Bet Dagan 50250, Israel
Vlodavsky, I., Department of Oncology, Hadassah University Hospital, Jerusalem, Israel
Nagler, A., Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel
Abstract:
At present, halofuginone is the only known inhibitor of collagen synthesis that is type specific. Halofuginone was found to inhibit collagen α1 (I) gene expression and collagen synthesis in vitro in cell cultures and in various animal models in vivo characterized by excessive deposition of collagen, which results in fibrosis. Toxicity studies both in animals and in normal volunteers revealed no major side effects. Halofuginone was successfully used topically in a patient with chronic graft-versus-host disease and at present is being tested in a clinical trial of patients with scleroderma. Collagen is an important component of the stroma and is involved in endothelial cell migration and assembly to form and recruit new blood vessels - angiogenesis. Both stromal support and angiogenesis are critical for tumor growth. Based on this rationale, using various tumor models such as bladder carcinoma, prostate cancer, and glioma, we demonstrated that inhibition of collagen α1 (I) gene expression by halofuginone caused inhibition of angiogenesis, which resulted in arrest of tumor growth. Thus, inhibition of collagen type I synthesis provides an attractive new target for cancer therapy. Many of the possible targets for halofuginone therapy pose enormous clinical problems, most of them without solutions. The ability of extremely low concentrations of halofuginone, given orally, locally or injected intraperitoneally, to inhibit collagen α1 (I) synthesis specifically and transiently at the transcriptional level suggests that this compound fulfills the criteria for a successful and effective antifibrotic and anticancer therapy. (C) 2000 Wiley-Liss, Inc.
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