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Biological Profiling of Drugs for Treatment of In‐stent Restenosis
Author(s) -
Lavigne Mark C.,
Queen Jillian,
Kunkel Eric,
Berg Ellen,
Kamath Kalpana,
Palasis Maria,
Barry James,
Eppihimer Michael J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1148.1
Subject(s) - paclitaxel , restenosis , thrombomodulin , sirolimus , dexamethasone , pharmacology , medicine , cancer research , chemistry , platelet , stent , thrombin , chemotherapy
To elucidate the actions of drugs that are useful in treating in‐stent restenosis, we compared the activities of both Paclitaxel and Sirolimus against dexamethasone, actinomycin D, or 17β‐estradiol in a panel of human cell‐based assays that model biological processes involved in restenosis. Paclitaxel and Sirolimus each inhibited endothelial cell (EC) and vascular smooth muscle cell (VSMC) growth, while dexamethasone promoted VSMC proliferation. Sirolimus and actinomycin D each decreased tissue remodeling markers in ECs and fibroblasts. Paclitaxel had no remarkable effects, while dexamethasone enhanced PAI‐1 expression. Paclitaxel did not affect T cell activation or peripheral blood mononuclear cell (PBMC)/T cell CD40/CD40 ligand and MCP‐1 expression. Sirolimus, 17β‐estradiol, dexamethasone, and actinomycin D each inhibited one or more of these inflammatory markers. In VSMC cultures, Paclitaxel up‐regulated thrombomodulin and decreased tissue factor expression. In contrast, Sirolimus increased tissue factor expression, but had no effect on thrombomodulin in cultures containing ECs and PBMCs. Dexamethasone, 17β‐estradiol, and actinomycin D each had little or no effect on these thrombosis factors. These results suggest that drugs considered for future use in DES platforms should inhibit VSMC proliferation to afford clinical efficacy with in‐stent restenosis. Further optimization would include drug actions that are not directed at ECs so as to permit proper vascular healing following DES deployment.