The Effects of Paclitaxel on the Three Phases of Restenosis

PURPOSE: We sought to evaluate the growth-modulating potential of paclitaxel on cultured human arterial smooth muscle cells depending on the administered dose. MATERIAL AND METHODS: For all experiments human arterial smooth muscle cells (SMCs) were used. SMCs were either cultured for 5 days or for 20 days with paclitaxel (doses: 10(-7) M, 10(-8) M, 10(-9) M). For a total period of 20 days, proliferation kinetics of the SMC were analyzed. To assess the clonogenic activity of the SMC colony-forming assays were performed. Drug- and dose-dependent cell cycle changes were analyzed by flow cytometry. The effect on cell migration was examined in a 2-chamber migration system. The effects of paclitaxel on the synthesis of tenascin were examined via immunofluorescence. RESULTS: Depending on the dose administered, paclitaxel proved to inhibit SMC proliferation effectively when administered during the total period of 20 days. When incubated for 5 days with doses of paclitaxel ranging between 10(-8) M and 10(-9) M, SMCs showed clear signs of regeneration. When being incubated with 10(-7) M of paclitaxel, however, SMCs reacted with a reduction in cell proliferation, a reduced clonogenic activity, and a drug-induced G2/M phase block. SMC migration was inhibited effectively as well as extracellular matrix formation. CONCLUSION: Paclitaxel is a potent inhibitor of SMC proliferation, SMC migration, and extracellular matrix formation in vitro, with all three phases of the restenosis process inhibited effectively.