Local paclitaxel delivery for the prevention of restenosis: Biological effects and efficacy in vivo

OBJECTIVE The aim of this study was to evaluate the potential of paclitaxel to prevent restenosis in vivo. BACKGROUND Paclitaxel (Taxol) is a microtubule-stabilizing compound with po tent antitumor activity. It influences the cytoskeleton equilibrium by incr easing the assembly of altered microtubules, thereby inducing cellular modi fications that result in reduced proliferation, migration and signal transd uction. METHODS Before the in vivo study, delivery efficiency was determined with r adiolabeled paclitaxel in porcine hearts. After induction of a defined plaq ue in the right carotid arteries of 76 New Zealand rabbits by electrical st imulation, 27 animals underwent balloon dilation and subsequent local pacli taxel delivery (10 ml, 10 mu mol/liter) with a double-balloon catheter. Twe nty-nine animals served as control with angioplasty only, 10 animals underw ent local delivery of vehicle only (0.9% NaCl solution) and 10 animals were solely electrostimulated. Vessels were excised one, four, and eight weeks after intervention. RESULTS The extent of stenosis in paclitaxel-treated animals was significan tly reduced compared with balloon-dilated control animals (p = 0.0012, one, four and eight weeks after intervention: 14.6%, 24.6% and 20.5%, vs. 24.9% , 33.8% and 43.1%, respectively). Marked vessel enlargement compared with b alloon-dilated control animals could be observed (p = 0.0001, total vessel area after one, four and eight weeks: paclitaxel group: 1.983, 1.700 and 1. 602 mm(2), control: 1.071, 1.338 and 1.206 mm(2), respectively). Tubulin st aining and electron microscopy revealed changes in microtubule assembly, wh ich were limited to the intimal area. Vasocontractile function after paclit axel treatment showed major impairment. CONCLUSIONS Local delivery of paclitaxel resulted in reduced neointimal ste nosis and enlargement in vessel size. Both these effects contribute to a pr eservation of vessel shape and are likely to be caused by a structural alte ration of the cytoskeleton. (J Am Coll Cardiol 2000;35:1969-76) (C) 2000 by the American College of Cardiology.