Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells

Kevin W.H. Yee, Marcus Schittenhelm, Anne Marie O'Farrell, Ajia R. Town, Laura McGreevey, Troy Bainbridge, Julie M. Cherrington, Michael C. Heinrich

    Research output: Contribution to journalArticle

    106 Scopus citations

    Abstract

    Fetal liver tyrosine kinase 3 internal tandem duplication (FLT3 ITD) mutations are the most common molecular abnormality associated with adult acute myeloid leukemia (AML). To exploit this molecular target, a number of potent and specific FLT3 kinase inhibitors have been developed and are currently being tested in early phase clinical trials of patients with refractory AML. To explore the efficacy of combining a FLT3 inhibitor with standard AML chemotherapy drugs, we tested the effect of combining the FLT3 inhibitor SU11248 with cytarabine or daunorubicin on the proliferation and survival of cell lines expressing either mutant (FLT3 ITD or FLT3 D835V) or wild-type (WT) FLT3. SU11248 had additive-to-synergistic inhibitory effects on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin. The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis. SU11248 inhibited the proliferation of primary AML myelobiasts expressing mutant FLT3 ITD but not WT FLT3 protein. Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein. These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results.

    Original languageEnglish (US)
    Pages (from-to)4202-4209
    Number of pages8
    JournalBlood
    Volume104
    Issue number13
    DOIs
    StatePublished - Dec 15 2004

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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  • Cite this

    Yee, K. W. H., Schittenhelm, M., O'Farrell, A. M., Town, A. R., McGreevey, L., Bainbridge, T., Cherrington, J. M., & Heinrich, M. C. (2004). Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. Blood, 104(13), 4202-4209. https://doi.org/10.1182/blood-2003-10-3381