Synergistic effects of troglitazone in combination with cytotoxic agents in acute myelogenous leukaemia cells.
We have previously shown that troglitazone (TG) induces apoptosis in acute myelogenous leukaemia (AML) cell lines. Here we show that normal bone marrow and mobilized peripheral blood progenitors are highly resistant to TG at concentrations up to 100 microM, while primary cultures of AML bone marrow show significant decline in viability at >7.5 microM TG. The combination of standard cytotoxic agents (daunorubicin, etoposide, and cytarabine) with TG is synergistic in six AML cell lines, with the strongest synergy being exhibited when cells are pretreated with TG for 24h prior to addition of the cytotoxic agent. Significant declines in IC(50) for the cytotoxic agents are seen at nanomolar concentrations of TG. The in vitro synergy between TG and the cytotoxic drugs used in AML therapy provides a basis for in vivo evaluation of these combinations.
Gu
Chunhong
C
Discipline of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ont., Canada M4N 3M5.
Ye
Teng
T
Wells
Richard A
RA
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D003630:Daunorubicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D020298:U937 Cells
D002839:Chromans; D045162:Thiazolidinediones; D003561:Cytarabine; D005047:Etoposide; D000077288:Troglitazone; D003630:Daunorubicin