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