Halofuginone: From veterinary use to human therapy

present, halofuginone is the only known inhibitor of collagen synthesis tha t is type specific. Halofuginone was found to inhibit collagen alpha(1)(I) gene expression and collagen synthesis in vitro in cell cultures and in var ious animal models in vivo characterized by excessive deposition of collage n, which results in fibrosis. Toxicity studies both in animals and in norma l volunteers revealed no major side effects. Halofuginone was successfully used topically in a patient with chronic graft-versus-host disease and at p resent is being tested in a clinical trial of patients with scleroderma. Co llagen is an important component of the stroma and is involved in endotheli al cell migration and assembly to form and recruit new blood vessels-angiog enesis. Both stromal support and angiogenesis are critical for tumor growth . Based on this rationale, using various tumor models such as bladder carci noma, prostate cancer, and glioma, we demonstrated that inhibition of colla gen alpha 1(I) gene expression by halofuginone caused inhibition of angioge nesis, which resulted in arrest of tumor growth. Thus, inhibition of collag en type I synthesis provides an attractive new target for cancer therapy. M any of the possible targets for halofuginone therapy pose enormous clinical problems, most of them without solutions. The ability of extremely low con centrations of halofuginone, given orally, locally or injected intraperiton eally, to inhibit collagen alpha(1) (I) synthesis specifically and transien tly at the transcriptional level suggests that this compound fulfills the c riteria for a successful and effective antifibrotic and anticancer therapy. Drug Dev. Res. 50:371-378, 2000. (C) 2000 Wiley-Liss, Inc.