NEW NORTRITERPENOID ISOLATED FROM ANTI-RHEUMATOID ARTHRITIC PLANT, TRIPTERYGIUM-WILFORDII, MODULATES TUMOR-GROWTH AND NEOVASCULARIZATION

Preparations of Tripterygium wilfordii, ''Thunder God vine'', have bee n used in China to treat rheumatoid arthritis. Rheumatoid arthritis, a s well as solid tumors, is closely associated with neovascularization. Antiarthritic drugs therefore may modulate tumor growth as well as ne ovascularization. We found that a compound purified from T. wilfordii, the nortriterpenoid, demethylzeylasteral (TZ-93), inhibited the proli feration of vascular endothelial cells approximately 30 times more eff ectively than it did for the proliferation of human tumor cells. In in vitro assays using bovine aortic endothelial cells, TZ-93 at non-toxi c doses inhibited cell migration, expression of urokinase-type plasmin ogen activator (uPA) mRNA and uPA activity. Exogenous addition of uPA restored the inhibitory effect of TZ-93 on cell migration. In dorsal a ir-sac assays in BALB/c mice, the oval administration of 3 mg/kg/day T Z-93 for 5 days partially inhibited, and 30 mg/kg/day almost completel y abrogated, the development of capillary networks induced by human he patoblastoma cells. Similarly, 0.3 mg/kg/day TZ-93 partially inhibited , and 3 or 30 mg/kg/day almost completely blocked, the growth of mouse B16-F10 melanoma cells in a tumor implantation assay. The highest dos e of TZ-93 significantly reduced the growth of well-vascularized tumor s with volumes of more than 500 mm(3). TZ-93 treatment of tumor-bearin g mice significantly decreased the density of microvessels in the tumo rs. We conclude that TZ-93 may be useful in treating highly vasculariz ed and metastatic tumors as well as other angiogenic diseases. (C) 199 7 Wiley-Liss, Inc.