title: Effects of drug combinations on smooth muscle cell proliferation: an isobolographic analysis.
abstract: Although sirolimus is a potent inhibitor of vascular smooth muscle cell (VSMC) proliferation and is effective at preventing restenosis in the majority of clinical revascularization procedures employing sirolimus-eluting stents, some VSMC may escape the antiproliferative effects of sirolimus. The present study examines the effects of combining sirolimus with other known cell cycle-specific antiproliferative agents (cladribine, topotecan or etoposide) on cultured coronary artery VSMC proliferation and utilizes a novel isobolographic approach to determine whether sirolimus/antiproliferative agent combinations produce subadditive, additive or supraadditive potentiation of antiproliferative activity. All agents were found to inhibit coronary artery VSMC proliferation in a dose-dependent manner. Cladribine was found to potentiate the antiproliferative activity of sirolimus in either an additive or supraadditive manner, depending upon the cladribine concentration. Topotecan potentiated the sirolimus antiproliferative activity by simple additivity while etoposide yielded subadditive potentiation. The present results demonstrate the utility of isobolographic analysis for identifying and optimizing antiproliferative drug combinations.
authors.affiliation: Johnson and Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477, USA. tparry@prdus.jnj.com
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Parry
authors.forename: Rathna
authors.initials: R
authors.lastname: Thyagarajan
authors.forename: Dennis
authors.initials: D
authors.lastname: Argentieri
authors.forename: Robert
authors.initials: R
authors.lastname: Falotico
authors.forename: John
authors.initials: J
authors.lastname: Siekierka
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Tallarida
mesh_terms: D000465:Algorithms; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017338:Cladribine / Q000494:pharmacology; D003331:Coronary Vessels / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology
chemical_list: D006131:Growth Inhibitors; D017338:Cladribine; D005047:Etoposide; D019772:Topotecan; D020123:Sirolimus