The Effect of Farnesyl Transferase Inhibitor on the Proliferation of Vascular Smooth Muscle Cells and Neointima Formation

ABSTRACT

BACKGROUND AND OBJECTIVES: We tested the hypothesis that prolonged oral administration of farnesyl transferase inhibitor (FTI, LB42908a, MW=604, LG chemical, Korea) inhibits the proliferation and neointimal thickening of smooth muscle cells (SMC) in a rat carotid injury model. MATERIALS AND METHODS: Cultured rat aortic vascular SMCs were exposed to sequential concentrations of FTI, and the proliferation inhibition analyzed using the MTT assay. In the rat carotid injury model, the FTI, at 3 dose levels (low-dose;10mg/kg, bid;mid-dose;50mg/kg, bid;high-dose;100 mg/kg, bid), or as a placebo, was administered orally, twice a day for 14 days, starting from 30 minutes before injury, until sacrifice. The histo-morphometric analysis was performed. The immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) was performed for 3 days. RESULTS: FTI inhibited the PDGF or FBS-induced cellular proliferations in a dose dependently manner. In the rat carotid artery balloon injury model, the mean neointimal area was significantly less in the mid-dose group than in the placebo and low-dose groups (control0.35+/-0.04mm2, low-dose0.23+/-0.04mm2 and mid-dose0.19+/-0.04mm2, p<0.05), and the mean ratio of the neointima to medial areas were significantly less in the mid-dose group than in the placebo and low dose group (placebo3.02+/-0.34, low-dose2.24+/-0.54 and mid-dose1.47+/-0.31, p<0.05). The labeling index of the PCNA was significantly less in the mid-dose group than in the placebo and low-dose groups (control71+/-9, low-dose73+/-9, mid-dose54+/-14 and high-dose53+/-9, p<0.05). CONCLUSION: The FTI inhibits SMC proliferation in a dose dependent manner. The prolonged oral administration of FTI, for 14 days, is effective in reducing neointimal hyperplasia in the rat carotid balloon injury model.