Comparative characterization of cellular and molecular anti-restenotic profiles of paclitaxel and sirolimus

Rainer Wessely; Birgit Blaich; Rachida Siham BelAiba; Sabine Merl; Agnes Görlach; Adnan Kastrati; Albert Schömig

doi:10.1160/TH06-10-0586

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 97(06): 1003-1012
DOI: 10.1160/TH06-10-0586

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Comparative characterization of cellular and molecular anti-restenotic profiles of paclitaxel and sirolimus

Implications for local drug delivery

Rainer Wessely

¹Deutsches Herzzentrum, Department of Cardiology / 1. Medizinische Klinik rechts der Isar, University of Technology, Munich, Germany

,

Birgit Blaich

¹Deutsches Herzzentrum, Department of Cardiology / 1. Medizinische Klinik rechts der Isar, University of Technology, Munich, Germany

,

Rachida Siham BelAiba

²Deutsches Herzzentrum, Department of Pediatric Cardiology, University of Technology, Munich, Germany

,

Sabine Merl

¹Deutsches Herzzentrum, Department of Cardiology / 1. Medizinische Klinik rechts der Isar, University of Technology, Munich, Germany

,

Agnes Görlach

²Deutsches Herzzentrum, Department of Pediatric Cardiology, University of Technology, Munich, Germany

,

Adnan Kastrati

¹Deutsches Herzzentrum, Department of Cardiology / 1. Medizinische Klinik rechts der Isar, University of Technology, Munich, Germany

,

Albert Schömig

¹Deutsches Herzzentrum, Department of Cardiology / 1. Medizinische Klinik rechts der Isar, University of Technology, Munich, Germany

› Institutsangaben

Abstract

Summary

Pleiotropic anti-restenotic properties of drugs that are eluted from coated stents are critical for efficacy and safety. Little is known about comparative drug properties in appropriate human coronary target cell lines for the two compounds that are utilized on FDA-approved drug-eluting stent (DES) platforms, paclitaxel (PTX) and sirolimus (SRL). Target cell lines that play a pivotal role for the pathogenesis of restenosis and vascular healing include human coronary artery smooth muscle (CASMC) and endothelial cells (CAEC). PTX and SRL inhibited CASMC and CAEC proliferation and migration efficiently. However, there was a differential effect on proliferation and migration in CAEC with a more profound inhibition of both parameters by PTX, even at low dosages. Induction of cytotoxicity and apoptosis was pronounced in PTX- and very modest in SRL-treated CASMC and CAEC. PTX increased eNOS activity and nitric oxide (NO) release from CAEC. Neutrophilic leukocyte activation and transmigration, which should be avoided since it may precipitate adverse coronary events such as restenosis and stent thrombosis, was suppressed by SRL, whereas PTX tended to increase neutrophilic leucocyte activity. Therefore, although the primary drug target, inhibition of mitogen-mediated CASMC proliferation, is effectively accomplished by both drugs, auxiliary pharmacological properties that are crucial for the anti-restenotic drug effect and vascular healing are considerably different between PTX and SRL. In comparison with PTX, SRL shows minor interference with endothelial cell proliferation and migration, lower levels of cytotoxicity and apoptosis, a broader therapeutic range and distinctive immunosuppressive properties.

Keywords

endothelium - Drug-eluting stent - paclitaxel - sirolimus - smooth muscle cell

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Referenzen

References
1 Marban E. Translation, translation, translation: circulation research in cardiology's new golden age. Circ Res 2005; 96: 4-5.
2 Stone GW, Ellis SG, Cox DA. et al. A polymerbased, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004; 350: 221-231.
3 Moses JW, Leon MB, Popma JJ. et al. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349: 1315-1323.
4 Wessely R, Hengst L, Jaschke B. et al. A central role of interferon regulatory factor-1 for the limitation of neointimal hyperplasia. Hum Mol Genet 2003; 12: 177-187.
5 Jaschke B, Michaelis C, Milz S. et al. Local statin therapy differentially interferes with smooth muscle and endothelial cell proliferation and reduces neointima on a drug-eluting stent platform. Cardiovasc Res 2005; 68: 483-492.
6 Wollert KC, Taga T, Saito M. et al. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. J Biol Chem 1996; 271: 9535-9545.
7 Jaschke B, Milz S, Vogeser M. et al. Local cyclindependent kinase inhibition by flavopiridol inhibits coronary artery smooth muscle cell proliferation and migration: Implications for the applicability on drugeluting stents to prevent neointima formation following vascular injury. FASEB J 2004; 18: 1285-1287.
8 Kishimoto T, Jutila M, Butcher E. Identification of a human peripheral lymph node homing receptor: a rapidly down-regulated adhesion molecule. Proc Natl Acad Sci USA 1990; 87: 2244-2248.
9 Kahn J, Ingraham R, Shirley F. et al. Membrane proximal cleavage of L-selectin: identification of the cleavage site and a 6-kD transmembrane peptide fragment of L-selectin. J Cell Biol 1994; 125: 461-470.
10 Rathel TR, Leikert JJ, Vollmar AM. et al. Application of 4,5-diaminofluorescein to reliably measure nitric oxide released from endothelial cells in vitro. Biol Proced Online 2003; 5: 136-142.
11 Klemke RL, Leng J, Molander R. et al. CAS/Crk coupling serves as a „molecular switch“ for induction of cell migration. J Cell Biol 1998; 140: 961-972.
12 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115-126.
13 Hao H, Gabbiani G, Bochaton-Piallat M-L. Arterial smooth muscle cell heterogeneity: implications for atherosclerosis and restenosis development. Arterioscler Thromb Vasc Biol 2003; 23: 1510-1520.
14 Hwang C-W, Wu D, Edelman ER. Physiological transport forces govern drug distribution for stentbased delivery. Circulation 2001; 104: 600-605.
15 Farb A, Burke AP, Kolodgie FD. et al. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation 2003; 108: 1701-1706.
16 Dimmeler S, Zeiher AM. Nitric oxide-an endothelial cell survival factor. Cell Death Differ 1999; 6: 964-8.
17 Rossig L, Fichtlscherer B, Breitschopf K. et al. Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J Biol Chem 1999; 274: 6823-6826.
18 Wessely R, Schömig A, Kastrati A. Sirolimus and paclitaxel on polymer-based drug-eluting stents: similar but different. J Am Coll Cardiol 2006; 47: 708-714.
19 Joner M, Finn AV, Farb A. et al. Pathology of drugeluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48: 193-202.
20 Hao H, Gabbiani G, Camenzind E. et al. Phenotypic modulation of intima and media smooth muscle cells in fatal cases of coronary artery lesion. Arterioscler Thromb Vasc Biol 2006; 26: 326-332.
21 Orlandi A, Ehrlich HP, Ropraz P. et al. Rat aortic smooth muscle cells isolated from different layers and at different times after endothelial denudation show distinct biological features in vitro. Arterioscler Thromb Vasc Biol 1994; 14: 982-989.
22 O'Connor P. Mammalian G1 and G2 phase checkpoints. Cancer Surv 1997; 29: 151-182.
23 Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13: 1501-1512.
24 Pardee AB. G1 events and regulation of cell proliferation. Science 1989; 246: 603-608.
25 Abal M, Andreu JM, Barasoain I. Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets 2003; 3: 193-203.
26 Bhalla KN. Microtubule-targeted anticancer agents and apoptosis. Oncogene 2003; 22: 9075-9086.
27 El-Deiry W, Tokino T, Velculescu VE. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993; 75: 817-825.
28 Blagosklonny MV, Schulte TW, Nguyen P. et al. Taxol induction of p21WAF1 and p53 requires c-raf-1. Cancer Res 1995; 55: 4623-4626.
29 Wang TH, Wang HS, Soong YK. Paclitaxel-induced cell death: where the cell cycle and apoptosis come together. Cancer 2000; 88: 2619-2628.
30 Grube E, Lansky A, Hauptmann KE. et al. Highdose 7-hexanoyltaxol-eluting stent with polymer sleeves for coronary revascularization: One-year results from the SCORE randomized trial. J Am Coll Cardiol 2004; 44: 1368-1372.
31 Ho YS, Wang YJ, Lin JK. Induction of p53 and p21/WAF1/CIP1 expression by nitric oxide and their association with apoptosis in human cancer cells. Mol Carcinog 1996; 16: 20-31.
32 Ramanathan B, Jan K-Y, Chen C-H. et al. Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res 2005; 65: 8455-8460.
33 Farb A, Sangiorgi G, Carter AJ. et al. Pathology of acute and chronic coronary stenting in humans. Circulation 1999; 99: 44-52.
34 Virmani R, Farb A, Guagliumi G. et al. Drug-eluting stents: caution and concerns for long-term outcome. Coron Artery Dis 2004; 15: 313-318.
35 Virmani R, Guagliumi G, Farb A. et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious?. Circulation 2004; 109: 701-705.
36 Avery RK. Cardiac-allograft vasculopathy. N Engl J Med 2003; 349: 829-830.
37 Tsuzuki S, Toyama-Sorimachi N, Kitamura F. et al. FK506 (tacrolimus) inhibits extravasation of lymphoid cells by abrogating VLA-4/VCAM-1 mediated transendothelial migration. FEBS Lett 1998; 430: 414-418.
38 Finn AV, Kolodgie FD, Harnek J. et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus and paclitaxel eluting stents. Circulation 2005; 112: 270-278.
39 Sardella G, De Luca L, Di Roma A. et al. Comparison between sirolimus- and paclitaxel-eluting stent in T-cell subsets redistribution. Am J Cardiol 2006; 97: 494-498.
40 Kastrati A, Dibra A, Eberle S. et al. Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artery disease: meta-analysis of randomized trials. J Am Med Assoc 2005; 294: 819-825.