Halofuginone has recently been shown to inhibit
tumor progression of various types of
cancers. The antitumoral effect was associated with decreased
tumor angiogenesis rather than a direct
cytostatic effect on the
tumor cells. The antiangiogenic action of the
drug could be related to its inhibition of
collagen type I synthesis, inhibition of
matrix metalloproteinases (
MMPs), or via both mechanisms because both
collagen synthesis and
MMP activity have been shown to be involved in angiogenesis.
Vascular endothelial growth factor (
VEGF), in addition to its effect on endothelial cell proliferation, has been shown to be a potent inducer of
MMP expression. Because von Hippel-Lindau (VHL)-associated
tumors express high levels of
VEGF, it was of interest to ascertain the potential usefulness of
halofuginone for treatment of these
tumors.
Pheochromocytoma tissue fragments obtained at surgery from a VHL type 2a patient were propagated s.c. in male BALB/c nu/nu (nude) mice. For experiments, 2-3-mm
tumor fragments were transplanted secondarily s.c. to nude mice. Two treatment groups received
halofuginone in standard lab chow at 3 and 5 ppm; control animals received regular chow. All groups were followed for 6 weeks after
transplantation. A marked and significant diminution of
tumor size and weight was observed in the
drug-treated animals (>90% reduction of mean
tumor volume for both the 3 and 5 ppm groups). In vivo magnetic resonance imaging analysis of
tumors in
halofuginone-treated animals showed a significant reduction of vascular functionality. Immunohistochemical studies revealed decreased
collagen type I levels and vascular density in treated
tumors and
gelatinase assays of
tumor extracts revealed a reduction of MMP-2 and MMP-9 activity in
halofuginone-treated cells. Taken together, our data indicate that
therapy directed at blocking
MMP activity (presumably related to excessive
VEGF expression in VHL) and reduction of
type I collagen deposition curtails angiogenesis and thereby presumably
tumor growth in this model system.