The novel tubulin-binding drug BTO-956 inhibits R3230Ac mammary carcinoma growth and angiogenesis in Fischer 344 rats

BTO-956 [methyl-3,5-diiodo-4-(4 ' -methoxyphenoxy)-benzoate], a novel tubul in-binding drug and thyroid hormone analogue, was originally round to inhib it human carcinoma cell proliferation in vitro and to have potent growth de lay activity in human breast and ovarian carcinoma xenografts in nude mice. Here we report that BTO-956 given to Fischer 344 rats also inhibits cornea l angiogenesis and the growth and neovascularization of the R3230Ac rat mam mary carcinoma tumor implanted in skin-fold window chambers. Hydron pellets containing recombinant human basic fibroblast growth factor (50 ng) and Su cralfate (20 mug) were implanted into surgically created corneal micropocke ts (day 0). BTO-956 was administrated by oral gavage (500 mg/kg, twice a da y for 6 days) on days 1-6 (controls received vehicle alone). On day 7, rats received retrogade infusions of India ink via the thoracic aorta to visual ize the corneal vasculature. Digitized images of slide-mounted corneas from control and treated animals were taken with a microscope. For the tumor gr owth and angiogenesis study, small pieces of R3230Ac tumor from a donor rat were implanted into surgically prepared window chambers (day 0). BTO-956 w as given during days 5-11, and images of the tumors and their vasculature w ere recorded on day 12. No body weight loss was observed in either study. B TO-956 significantly inhibited corneal angiogenesis (by 50-80%), as assesse d by measurements of limbal circumference displaying neovascularization, ve ssel length, vascularized area, and vascular area density. In the window ch amber assay, tumors from treated animals were > 50% smaller than tumors in control animals. In addition, vascular length densities in peripheral tumor zones were 30% less in treated compared with control animals. Together, th ese findings demonstrate that BTO-956 can inhibit angiogenesis induced by a growth factor in the rat cornea and in the peripheral area of implanted tu mors, where tumor angiogenesis is most active.