Effects of abciximab on key pattern of human coronary restenosis in vitro: impact of the SI/MPL-ratio.
BACKGROUND
The significant reduction of angiographic restenosis rates in the ISAR-SWEET study (intracoronary stenting and antithrombotic regimen: is abciximab a superior way to eliminate elevated thrombotic risk in diabetes) raises the question of whether abciximab acts on clopidogrel-independent mechanisms in suppressing neointimal hyperplasia. The current study investigates the direct effect of abciximab on ICAM-1 expression, migration and proliferation.


METHODS
ICAM-1: Part I of the study investigates in cytoflow studies the effect of abciximab (0.0002, 0.002, 0.02, 0.2, 2.0, and 20.0 microg/ml) on TNF-alpha induced expression of intercellular adhesion molecule 1 (ICAM-1). Migration: Part II of the study explored the effect of abciximab (0.0002, 0.002, 0.02, 0.2, 2.0, and 20.0 microg/ml) on migration of HCMSMC over a period of 24 h. Proliferation: Part III of the study investigated the effect of abciximab (0.0002, 0.002, 0.02, 0.2, 2.0, and 20.0 microg/ml) on proliferation of HUVEC, HCAEC, and HCMSMC after an incubation period of 5 days.


RESULTS
ICAM-1: In human venous endothelial cells (HUVEC), human coronary endothelial cells (HCAEC) and human coronary medial smooth muscle cells (HCMSMC) no inhibitory or stimulatory effect on expression of ICAM-1 was detected. Migration: After incubation of HCMSMC with abciximab in concentrations of 0.0002-2 microg/ml a stimulatory effect on cell migration was detected, statistical significance was achieved after incubation with 0.002 microg/ml (p < 0.05), 0.002 microg/ml (p < 0.001), and 0.2 microg/ml (p < 0.05). Proliferation: Small but statistically significant antiproliferative effects of abciximab were detected after incubation of HUVEC (0.02 and 2.0 microg/ml; p = 0.01 and p < 0.01), HCAEC (2.0 and 20.0 microg/ml; p < 0.05 and p < 0,01), and HCMSMC (2.0 and 20.0 microg/ml; p < 0.05 and p < 0.05). The significant inhibition (SI) of cell proliferation found in HCAEC and HCMSMC was achieved with drug concentrations more than 10 times beyond the maximal plasma level (MPL), resulting in a SI/MPL-ratio > 1.


CONCLUSIONS
Thus, the anti-restenotic effects of systemically administered abciximab reported in the ISAR-SWEET-study were not caused by a direct inhibitory effect on ICAM-1 expression, migration or proliferation.
Voisard
Rainer
R
Department of Internal Medicine II-Cardiology, University of Ulm, Robert-Kochstrasse 8, D-89081 Ulm, Germany. rainer.voisard@uni-ulm.de
Alan
Mustafa
M
von Müller
Lutz
L
Baur
Regine
R
Hombach
Vinzenz
V
D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000517:prevention & control*; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D018799:Intercellular Adhesion Molecule-1; D000077284:Abciximab