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J Am Coll Cardiol, 2000; 35:1969-1976
© 2000 by the American College of Cardiology Foundation
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EXPERIMENTAL STUDIES

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

Christian Herdeg, MD*, Martin Oberhoff, MD*, Andreas Baumbach, MD*, Andreas Blattner*, Dorothea I. Axel, PhD*, Stephen Schröder, MD*, Helmut Heinle, PhD* and Karl R. Karsch, MD, FACC*

* Division of Cardiology, Department of Medicine, and the Department of Physiology, University of Tuebingen, Tuebingen, Germany

Manuscript received February 23, 1999; revised manuscript received December 10, 1999, accepted February 3, 2000.

Reprint requests and correspondence: Dr. Christian Herdeg, Division of Cardiology, Department of Medicine, University of Tuebingen, Otfried-Mueller-Str.10, D-72076 Tuebingen, Germany
christian.herdeg{at}med.uni-tuebingen.de

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 potent antitumor activity. It influences the cytoskeleton equilibrium by increasing the assembly of altered microtubules, thereby inducing cellular modifications that result in reduced proliferation, migration and signal transduction.

METHODS

Before the in vivo study, delivery efficiency was determined with radiolabeled paclitaxel in porcine hearts. After induction of a defined plaque in the right carotid arteries of 76 New Zealand rabbits by electrical stimulation, 27 animals underwent balloon dilation and subsequent local paclitaxel delivery (10 ml, 10 µmol/liter) with a double-balloon catheter. Twenty-nine animals served as control with angioplasty only, 10 animals underwent 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 significantly 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 balloon-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 mm2, control: 1.071, 1.338 and 1.206 mm2, respectively). Tubulin staining and electron microscopy revealed changes in microtubule assembly, which were limited to the intimal area. Vasocontractile function after paclitaxel treatment showed major impairment.

CONCLUSIONS

Local delivery of paclitaxel resulted in reduced neointimal stenosis and enlargement in vessel size. Both these effects contribute to a preservation of vessel shape and are likely to be caused by a structural alteration of the cytoskeleton.

Abbreviations and Acronyms
  ANOVA = analysis of variance
  BD = balloon dilation
  BRDU = bromodeoxyuridine
  LAD = left anterior descending artery
  LDD = local drug delivery
  SMC = smooth muscle cell




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