Effects of drug combinations on smooth muscle cell proliferation: An isobolographic analysis

Tom J. Parry, Rathna Thyagarajan, Dennis Argentieri, Robert Falotico, John Siekierka, Ronald J. Tallarida

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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.

Original languageEnglish
Pages (from-to)38-43
Number of pages6
JournalEuropean Journal of Pharmacology
Issue number1-2
StatePublished - 17 Feb 2006


  • Drug combination
  • Isobolographic analysis
  • Sirolimus
  • Vascular smooth muscle


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