TAS-301, AN INHIBITOR OF SMOOTH-MUSCLE CELL-MIGRATION AND PROLIFERATION, INHIBITS INTIMAL THICKENING AFTER BALLOON INJURY TO RAT CAROTID ARTERIES

The purpose of this study was to determine the efficacy and the possib le mechanism of action of a recently synthesized drug, TAS-301 [3-bis (4-methoxyphenyl)methylene-2-indolinone] on intimal formation in compa rison with those of tranilast, the clinical efficacy of which was repo rted earlier. Rat carotid arteries were injured using a balloon cathet er. Neointimal thickening, measured 14 days after injury, was reduced by the oral administration of TAS-301 in a dose-dependent fashion (3-1 00 mg/kg), and the effect of TAS-301 at, a dose of 100 mg/kg was signi ficantly greater than that of tranilast (300 mg/kg). Fewer cells were found on the intima of balloon-injured arteries of TAS-301-treated rat s than on arteries of tranilast-treated rats. In an in vitro assay, TA S-301 inhibited the migration of smooth muscle cells (SMCs) stimulated by platelet-derived growth factor-BE, insulin-like growth factor-1 or heparin-binding epidermal growth factor-like growth factor. In additi on, TAS-301 and tranilast reduced the proliferation of medial and inti mal SMCs at 4 and 8 days, respectively, after the injury. in vitro, TA S-301 inhibited basic fibroblast growth Factor-induced proliferation o f SMCs dose dependently. These findings indicate that TAS-301 shows a higher inhibitory potency on intimal formation than tranilast due to i nhibition of both migration of medial SMCs and proliferation of medial and intimal SMCs. Our results suggest that further evaluation of TAS- 301 as an inhibitor of postangioplasty intimal thickening is warranted .