Prevention of human smooth muscle cell proliferation without induction of apoptosis by the topoisomerase I inhibitor topotecan

Despite significant improvements in the treatment of atherosclerotic disease involving procedures such as angioplasty, bypass grafting, endartherectomy, or stent implantation, secondary failure due to late restenosis still occurs in 30-50% of individuals. Restenosis and later stages of atherosclerotic lesions arise from a complex series of fibroproliferative responses to Vascular injury that are triggered by potent growth-regulatory molecules and finally result in vascular smooth muscle cell proliferation, migration, and neointima formation. The aim of this study was to investigate the antiproliferative effects of the topoisomerase I inhibitor topotecan on human arterial coronary smooth muscle cells. Following incubation of cells with different drug concentrations, mitotic indices were measured by bromodeoxyuridine incorporation, while cellular mitochondrial activity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. Continuous incubation with topotecan for 7 days resulted in a complete and dose-dependent reduction of smooth muscle cell proliferation, and topotecan inhibited cell proliferation in the presence of growth factors as well. In contrast, mitochondrial activity was only partially decreased. Remarkably, although even short-term incubations for 20 min were sufficient to induce a long-lasting growth inhibition, topotecan did not induce apoptosis. Our results therefore suggest that, based on its drug profile, the topoisomerase I inhibitor topotecan may be a promising drug to inhibit restenosis occurring after coronary angioplasty with local devices. (C) 2000 Elsevier Science Inc. All rights reserved.