Paclitaxel: an anti-cancer agent for the prevention of restenosis? Resultsfrom experimental in vitro and in vivo studies

Paclitaxel, a potent anti-tumor agent, shifts the cytoskeleton equilibrium towards assembly of altered and extraordinarily stable microtubules. These cellular modifications lead to reduced proliferation, migration, and signal transduction. It is highly lipophilic, which pro motes a rapid cellular up take, and has a long-lasting effect in the cell due to the structural alter ation of the cytoskeleton. This makes paclitaxel a promising candidate for local drug deliver!, intended to address the proliferative and migratory pr ocesses involved in restenosis. In this article, results of our in vitro an d in vivo studies with paclitaxel are presented. Cell culture experiments w ith monocultures of human arterial smooth muscle cells as well as co-cultur es with human endothelial cells showed that paclitaxel leads to an almost c omplete growth inhibition within a dose range of 1.0-10.0 mu mol/l, even af ter a short (20 min) single dose application. The comparison of an active, semi-active, and passive delivery system (porous balloon, microporous ballo on, and double balloon) favored the double balloon for the following in viv o experiments. Tubulin staining and electron microscopy enabled visualizati on of paclitaxel-induced vessel wall alterations. In the rabbit model, loca lly delivered paclitaxel resulted in reduced neointima formation and enlarg ement in vessel size; in the pig model, however, after stenting, this inhib ition was nor significant. Both reduced proliferation and enlargement in ve ssel size contribute to a presentation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton, which is also suppo rted by vascular contraction force experiments.