A prescreening system for potential antiproliferative agents: implications for local treatment strategies of postangioplasty restenosis.
BACKGROUND
Recent advances in the understanding of the biology of restenosis indicate that it is predominantly caused by a multifactorial stimulation of smooth muscle cell proliferation. The aim of this study was to investigate the in vitro effect of five potential antiproliferative agents on smooth muscle cells from human atherosclerotic femoral arteries.


RESULTS
Primary stenosing plaque material of 24 patients (aged 63 +/- 14 years) and restenosing plaque material of 7 patients (aged 65 +/- 9 years) was selectively extracted from femoral arteries by the Simpson atherectomy device. Cells were isolated by enzymatic disaggregation and identified as smooth muscle cells by positive reaction with smooth muscle alpha-actin. Dalteparin sodium (0.001-100 anti-Xa units/ml), cyclosporine A (0.005-500 micrograms/ml), colchicine (0.00004-4 pg/ml), etoposide (0.002-200 micrograms/ml), and doxorubicin (0.0005-50 micrograms/ml) were added to the cultures. Six days after seeding, cells were trypsinized and cell number was measured by a cell counter. All five agents tested exhibited a significant inhibition of smooth muscle cell proliferation (P < 0.001). After an incubation time of 48 h, the cytoskeletal components, alpha-actin, vimentin, and microtubules were investigated. At peak concentrations, all five tested agents except dalteparin sodium caused severe damage to the cytoskeleton.


CONCLUSIONS
All five potential antiproliferative agents exhibited a significant inhibition of smooth muscle cell proliferation. The development of new intravascular delivery systems may open the way for local antiproliferative treatment strategies in interventional cardiology.
Voisard
R
R
Department of Cardiology, Angiology, Nephrology, and Pneumology, University of Ulm, Federal Republic of Germany.
Seitzer
U
U
Baur
R
R
Dartsch
P C
PC
Osterhues
H
H
Höher
M
M
Hombach
V
V
D000199:Actins / Q000187:drug effects; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000800:Angioplasty, Balloon; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003078:Colchicine / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D017985:Dalteparin / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D005263:Femoral Artery; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006074:Gout Suppressants / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008870:Microtubules / Q000187:drug effects; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D012008:Recurrence; D014746:Vimentin / Q000187:drug effects
D000199:Actins; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D005343:Fibrinolytic Agents; D006074:Gout Suppressants; D007166:Immunosuppressive Agents; D014746:Vimentin; D005047:Etoposide; D004317:Doxorubicin; D016572:Cyclosporine; D017985:Dalteparin; D003078:Colchicine