TY - JOUR
T1 - Effects of drug combinations on smooth muscle cell proliferation
T2 - An isobolographic analysis
AU - Parry, Tom J.
AU - Thyagarajan, Rathna
AU - Argentieri, Dennis
AU - Falotico, Robert
AU - Siekierka, John
AU - Tallarida, Ronald J.
PY - 2006/2/17
Y1 - 2006/2/17
N2 - 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.
AB - 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.
KW - Drug combination
KW - Isobolographic analysis
KW - Sirolimus
KW - Vascular smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=33644513715&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2005.12.042
DO - 10.1016/j.ejphar.2005.12.042
M3 - Article
C2 - 16448648
AN - SCOPUS:33644513715
SN - 0014-2999
VL - 532
SP - 38
EP - 43
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -