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

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 (control:0.35+/-0.04mm2, low-dose:0.23+/-0.04mm2 and mid-dose:0.19+/-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 (placebo:3.02+/-0.34, low-dose:2.24+/-0.54 and mid-dose:1.47+/-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 (control:71+/-9, low-dose:73+/-9, mid-dose:54+/-14 and high-dose:53+/-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.

Inhibition of Basic Fibroblast Growth Factor Induced Corneal Angiogenesis by a Farnesyl Transferase Inhibitor

Farnesyl transferase inhibitors(FTI) disrupt fanesylation of ras protein and thus, suppress tumor growth in vivo, To determine whether FTI extracted from Cinnamomum Cassia Blume(CB2`-ph) interferes with angiogenesis, we studied the effect of CB2`-ph on rabbit corneal angiogenesis induced by basic fibroblast growth factor(bFGF). A hydrogel disk containing 1000ng of bFGF was implanted intrastromally in the superior cornea of 12 NZW rabbit eyes. All eyes received a second intrastromal disk, randomized to contain either 40 micro gram of CB2`-ph(n=6) or phosphate-buffered saline(PBS)(n=6). Both disks were positioned side-by-side, 1.2mm from the superior limbus. Each eye was examined daily by two masked of new blood vessels. At 3, 5, and 7 days postimplantation of bFGF disks, eyes treated with CB2`-ph showed mean angiogenesis score of 6.0 +/- 4.8, 25.6 +/- 23.9 and 38.1 +/- 28.3, respectively, while PBS-treated controls scored 10.4 +/- 9.2, 27.2 +/- 16.7, and 39.0 +/- 22.8, respectively(p>0.4, Wilcoxon signed rank test). In a rabbit corneal pocket assay, CB2`-ph appears to be ineffective against bFGF-induced corneal angiogenesis in the model.

Inhibition of Corneal Angiogenesis by a Farnesyl Transferase Inhibitor

Farnesyl transferase inhibitor(FTI) disrupt farnesylation of ras protein and thus, suppress tumor growth in vivo. The ras oncogene is thought to contribute to tumor development directly by promoting tumor cell proliferation and indirectly by stimulating vascular endothelial growth from Cinnamomum Cassia Blume(CB2`-ph) interferes with angiogenesis, we studied the effect of CB2`-ph on rabbit corneal angiogenesis induced by VEGF. A hygrogel disk containing 250ng of VEGF was implated intrastromally in the superior cornea of 16 NZW rabbit eyes. All eyes received a second intrastromal disk, randomized to contain either 40 micro gram of CB2`-ph(n=8) or phosphate-buffered saline(PBS)(n=8). Both disks were positioned side-by-side, 1.2mm from the superior limbus. Each eye was examined daily by two masked observers and assigned an angiogenesis score based on number and length of new blood vessels. At 3, 5 and 7 days postimplantation of VEGF disks, eyes treated with CB2`=ph showed mean angiogenesis score of 2.0 +/- 1.7, 13.4 +/- 6.6 and 23.8 +/- 11.3, respectively, while PBS=treated controls scored 8.6 +/- 4.4, 30.3 +/- 20.8 and 52.2 +/- 26.9, respectively(p<0.05, Wilcoxon signed rank test). In a rabbit corneal pocket assay, CB2`-ph appears to be effective on VEGF-induced corneal angiogenesusis in the model.