Emerging Flt3 kinase inhibitors in the treatment of leukaemia

Bibliography

• MCCULLOCH EA, SMITH LJ, ALDER S: Cellular lineages in normal and leukemic hemopoiesis. Prog. Clin. Biol. Res. (1983) 134:229-244.
   PubMedGoogle Scholar
• GILLILAND DG, TALLMAN MS: Focus on acute leukemias. Cancer Cell (2002) 1:417-420.
   PubMed Web of Science ®Google Scholar
• TALLMAN MS, GILLILAND DG, ROWE JM: Drug therapy of acute myeloid leukemia. Blood (2005) 106(4):1154-1163. Erratum in: Blood (2005) 106(7):2243.
   PubMed Web of Science ®Google Scholar
• GILLILAND DG, GRIFFIN JD: Role of FLT3 in leukemia. Curr. Opin. Hematol. (2002) 9:274-281.
   PubMed Web of Science ®Google Scholar
• POPPE B, VANDESOMPELE J, SCHOCH C et al.: Expression analyses identify MLL as a prominent target of 11q23 amplification and support an etiologic role for MLL gain of function in myeloid malignancies. Blood (2004) 103:229-235.
   PubMed Web of Science ®Google Scholar
• STIREWALT DL, KOPECKY KJ, MESHINCHI S et al.: FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood (2001) 97:3589-3595.
   PubMed Web of Science ®Google Scholar
• STIREWALT DL, RADICH JP: The role of FLT3 in haematopoietic malignancies. Nat. Rev. Cancer (2003) 3:650-665.
   PubMed Web of Science ®Google Scholar
• THIEDE C, STEUDEL C, MOHR B et al.: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood (2002) 99:4326-4335.
   PubMed Web of Science ®Google Scholar
• FARAG SS, RUPPERT AS, MROZEK K et al.: Outcome of induction and postremission therapy in younger adults with acute myeloid leukemia with normal karyotype: a cancer and leukemia group B study. J. Clin. Oncol. (2005) 23:482-493.
   PubMed Web of Science ®Google Scholar
• BURNETT AK, GOLDSTONE AH, STEVENS RM et al.: Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children’s Leukaemia Working Parties. Lancet (1998) 351:700-708.
   PubMed Web of Science ®Google Scholar
• BUCHNER T, HIDDEMANN W, BERDEL WE et al.: Subgroup specific therapy effects in AML: AMLCG data. Ann. Hematol. (2004) 83(Suppl. 1):S100-S101.
   Google Scholar
• LYMAN SD, JAMES L, ZAPPONE J et al.: Characterization of the protein encoded by the flt3 (flk2) receptor-like tyrosine kinase gene. Oncogene (1993) 8:815-822.
   PubMed Web of Science ®Google Scholar
• MAROC N, ROTTAPEL R, ROSNET O et al.: Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene (1993) 8:909-918.
   PubMed Web of Science ®Google Scholar
• SMALL D, LEVENSTEIN M, KIM E et al.: STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells. Proc. Natl. Acad. Sci. USA (1994) 91:459-463.
   PubMed Web of Science ®Google Scholar
• MATTHEWS W, JORDAN CT, WIEGAND GW, PARDOLL D, LEMISCHKA IR: A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell (1991) 65:1143-1152.
   PubMed Web of Science ®Google Scholar
• GILLILAND DG, GRIFFIN JD: The roles of FLT3 in hematopoiesis and leukemia. Blood (2002) 100:1532-1542.
   PubMed Web of Science ®Google Scholar
• SCHMIDT-ARRAS D, SCHWABLE J, BOHMER FD, SERVE H: Flt3 receptor tyrosine kinase as a drug target in leukemia. Curr. Pharm. Des. (2004) 10:1867-1883.
   PubMed Web of Science ®Google Scholar
• BIRG F, COURCOUL M, ROSNET O et al.: Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood (1992) 80:2584-2593.
   PubMed Web of Science ®Google Scholar
• ROSNET O, BUHRING HJ, MARCHETTO S et al.: Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia (1996) 10:238-248.
   PubMed Web of Science ®Google Scholar
• CAROW CE, LEVENSTEIN M, KAUFMANN SH et al.: Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood (1996) 87:1089-1096.
   PubMed Web of Science ®Google Scholar
• NAKAO M, YOKOTA S, IWAI T et al.: Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia (1996) 10:1911-1918.
   PubMed Web of Science ®Google Scholar
• ARMSTRONG SA, MABON ME, SILVERMAN LB et al.: FLT3 mutations in childhood acute lymphoblastic leukemia. Blood (2004) 103:3544-3546.
   PubMed Web of Science ®Google Scholar
• HORIIKE S, YOKOTA S, NAKAO M et al.: Tandem duplications of the FLT3 receptor gene are associated with leukemic transformation of myelodysplasia. Leukemia (1997) 11:1442-1446.
   PubMed Web of Science ®Google Scholar
• YOKOTA S, KIYOI H, NAKAO M et al.: Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia (1997) 11:1605-1609.
   PubMed Web of Science ®Google Scholar
• STEUDEL C, WERMKE M, SCHAICH M et al.: Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia. Genes Chromosomes Cancer (2003) 37:237-251.
   PubMed Web of Science ®Google Scholar
• YAMAMOTO Y, KIYOI H, NAKANO Y et al.: Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood (2001) 97:2434-2439.
   PubMed Web of Science ®Google Scholar
• ABU-DUHIER FM, GOODEVE AC, WILSON GA et al.: Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia. Br. J. Haematol. (2001) 113:983-988.
   PubMed Web of Science ®Google Scholar
• SPIEKERMANN K, BAGRINTSEVA K, SCHOCH C et al.: A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. Blood (2002) 100:3423-3425.
   PubMed Web of Science ®Google Scholar
• KINDLER T, BREITENBUECHER F, KASPER S et al.: Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML). Blood (2005) 105:335-340.
   PubMed Web of Science ®Google Scholar
• JIANG J, PAEZ JG, LEE JC et al.: Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML. Blood (2004) 104:1855-1858.
   PubMed Web of Science ®Google Scholar
• HAYAKAWA F, TOWATARI M, KIYOI H et al.: Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene (2000) 19:624-631.
   PubMed Web of Science ®Google Scholar
• MIZUKI M, FENSKI R, HALFTER H et al.: Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood (2000) 96:3907-3914.
   PubMed Web of Science ®Google Scholar
• KELLY LM, LIU Q, KUTOK JL et al.: FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood (2002) 99:310-318.
   PubMed Web of Science ®Google Scholar
• KELLY LM, KUTOK JL, WILLIAMS IR et al.: PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc. Natl. Acad. Sci. USA (2002) 99:8283-8288.
   PubMed Web of Science ®Google Scholar
• SOHAL J, PHAN VT, CHAN PV et al.: A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood (2003) 101:3188-3197.
   PubMed Web of Science ®Google Scholar
• CHOUDHARY C, SCHWABLE J, BRANDTS C et al.: AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood (2005) 106(1):265-273.
   PubMed Web of Science ®Google Scholar
• GRUNDLER R, MIETHING C, THIEDE C, PESCHEL C, DUYSTER J: FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood (2005) 105(12):4792-4799.
   PubMed Web of Science ®Google Scholar
• KOTTARIDIS PD, GALE RE, FREW ME et al.: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood (2001) 98:1752-1759.
   PubMed Web of Science ®Google Scholar
• SCHNITTGER S, SCHOCH C, DUGAS M et al.: Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood (2002) 100:59-66.
   PubMed Web of Science ®Google Scholar
• BEGHINI A, PETERLONGO P, RIPAMONTI CB et al.: C-kit mutations in core binding factor leukemias. Blood (2000) 95:726-727.
   PubMed Web of Science ®Google Scholar
• CARE RS, VALK PJ, GOODEVE AC et al.: Incidence and prognosis of c-KIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br. J. Haematol. (2003) 121:775-777.
   PubMed Web of Science ®Google Scholar
• WHITMAN SP, ARCHER KJ, FENG L et al.: Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. (2001) 61:7233-7239.
   PubMed Web of Science ®Google Scholar
• SHIH LY, HUANG CF, WU JH et al.: Internal tandem duplication of FLT3 in relapsed acute myeloid leukemia: a comparative analysis of bone marrow samples from 108 adult patients at diagnosis and relapse. Blood (2002) 100:2387-2392.
   PubMed Web of Science ®Google Scholar
• MORENO I, MARTIN G, BOLUFER P et al.: Incidence and prognostic value of FLT3 internal tandem duplication and D835 mutations in acute myeloid leukemia. Haematologica (2003) 88:19-24.
   PubMed Web of Science ®Google Scholar
• SHEIKHHA MH, AWAN A, TOBAL K, LIU YIN JA: Prognostic significance of FLT3 ITD and D835 mutations in AML patients. Hematol. J. (2003) 4:41-46.
   PubMedGoogle Scholar
• FROHLING S, SCHLENK RF, BREITRUCK J et al.: Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood (2002) 100:4372-4380.
   PubMed Web of Science ®Google Scholar
• LIANG DC, SHIH LY, HUNG IJ et al.: Clinical relevance of internal tandem duplication of the FLT3 gene in childhood acute myeloid leukemia. Cancer (2002) 94:3292-3298.
   PubMed Web of Science ®Google Scholar
• TURNER AM, LIN NL, ISSARACHAI S, LYMAN SD, BROUDY VC: FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells. Blood (1996) 88:3383-3390.
   PubMed Web of Science ®Google Scholar
• WEISS A, SCHLESSINGER J: Switching signals on or off by receptor dimerization. Cell (1998) 94:277-280.
   PubMed Web of Science ®Google Scholar
• GRIFFITH J, BLACK J, FAERMAN C et al.: The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol. Cell (2004) 13:169-178.
   PubMed Web of Science ®Google Scholar
• SCHMIDT-ARRAS DE, BOHMER A, MARKOVA B et al.: Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. Mol. Cell. Biol. (2005) 25:3690-3703.
   PubMed Web of Science ®Google Scholar
• KIYOI H, OHNO R, UEDA R, SAITO H, NAOE T: Mechanism of constitutive activation of FLT3 with internal tandem duplication in the juxtamembrane domain. Oncogene (2002) 21:2555-2563.
   PubMed Web of Science ®Google Scholar
• MARCHETTO S, FOURNIER E, BESLU N et al.: SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia (1999) 13:1374-1382.
   PubMed Web of Science ®Google Scholar
• ROTTAPEL R, TURCK CW, CASTERAN N et al.: Substrate specificities and identification of a putative binding site for PI3K in the carboxy tail of the murine Flt3 receptor tyrosine kinase. Oncogene (1994) 9:1755-1765.
   PubMed Web of Science ®Google Scholar
• ZHANG S, BROXMEYER HE: p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells. Biochem. Biophys. Res. Commun. (1999) 254:440-445.
   PubMed Web of Science ®Google Scholar
• JONSSON M, ENGSTROM M, JONSSON JI: FLT3 ligand regulates apoptosis through AKT-dependent inactivation of transcription factor FoxO3. Biochem. Biophys. Res. Commun. (2004) 318:899-903.
   PubMed Web of Science ®Google Scholar
• SCHEIJEN B, NGO HT, KANG H, GRIFFIN JD: FLT3 receptors with internal tandem duplications promote cell viability and proliferation by signaling through Foxo proteins. Oncogene (2004) 23:3338-3349.
   PubMed Web of Science ®Google Scholar
• MOHI MG, BOULTON C, GU TL et al.: Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl. Acad. Sci. USA (2004) 101:3130-3135.
   PubMed Web of Science ®Google Scholar
• BENEKLI M, BAER MR, BAUMANN H, WETZLER M: Signal transducer and activator of transcription proteins in leukemias. Blood (2003) 101:2940-2954.
   PubMed Web of Science ®Google Scholar
• GOUILLEUX-GRUART V, GOUILLEUX F, DESAINT C et al.: STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood (1996) 87:1692-1697.
   PubMed Web of Science ®Google Scholar
• MIZUKI M, SCHWABLE J, STEUR C et al.: Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood (2003) 101:3164-3173.
   PubMed Web of Science ®Google Scholar
• SPIEKERMANN K, BAGRINTSEVA K, SCHWAB R, SCHMIEJA K, HIDDEMANN W: Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. Clin. Cancer Res. (2003) 9:2140-2150.
   PubMed Web of Science ®Google Scholar
• MORIGGL R, SEXL V, KENNER L et al.: Stat5 tetramer formation is associated with leukemogenesis. Cancer Cell (2005) 7:87-99.
   PubMed Web of Science ®Google Scholar
• DOSIL M, WANG S, LEMISCHKA IR: Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Mol. Cell. Biol. (1993) 13:6572-6585.
   PubMed Web of Science ®Google Scholar
• ROBINSON LJ, XUE J, COREY SJ: Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations. Exp. Hematol. (2005) 33:469-479.
   PubMed Web of Science ®Google Scholar
• PABST T, MUELLER BU, ZHANG P et al.: Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat. Genet. (2001) 27:263-270.
   PubMed Web of Science ®Google Scholar
• MUELLER BU, PABST T, OSATO M et al.: Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood (2002) 100:998-1007.
   PubMed Web of Science ®Google Scholar
• DAHL R, SIMON MC: The importance of PU.1 concentration in hematopoietic lineage commitment and maturation. Blood Cells Mol. Dis. (2003) 31:229-233.
   PubMed Web of Science ®Google Scholar
• ROSENBAUER F, WAGNER K, KUTOK JL et al.: Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat. Genet. (2004) 36:624-630.
   PubMed Web of Science ®Google Scholar
• ZHENG R, FRIEDMAN AD, LEVIS M et al.: Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression. Blood (2004) 103:1883-1890.
   PubMed Web of Science ®Google Scholar
• ZHENG R, FRIEDMAN AD, SMALL D: Targeted inhibition of FLT3 overcomes the block to myeloid differentiation in 32Dcl3 cells caused by expression of FLT3/ITD mutations. Blood (2002) 100:4154-4161.
   PubMed Web of Science ®Google Scholar
• SCHWABLE J, CHOUDHARY C, THIEDE C et al.: RGS2 is an important target gene of Flt3-ITD mutations in AML and functions in myeloid differentiation and leukemic transformation. Blood (2005) 105:2107-2114.
   PubMed Web of Science ®Google Scholar
• JAMIESON CH, AILLES LE, DYLLA SJ et al.: Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. (2004) 351:657-667.
   PubMed Web of Science ®Google Scholar
• REYA T, DUNCAN AW, AILLES L et al.: A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature (2003) 423:409-414.
   PubMed Web of Science ®Google Scholar
• MULLER-TIDOW C, STEFFEN B, CAUVET T et al.: Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol. Cell. Biol. (2004) 24:2890-2904.
   PubMed Web of Science ®Google Scholar
• TICKENBROCK L, SCHWABLE J, WIEDEHAGE M et al.: Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction. Blood (2005) 105(9):3699-3706.
   PubMed Web of Science ®Google Scholar
• MURAKAMI Y, FUKAZAWA H, MIZUNO S, UEHARA Y: Effect of herbimycin A on tyrosine kinase receptors and platelet derived growth factor (PDGF)-induced signal transduction. Biol. Pharm. Bull. (1998) 21:1030-1035.
   PubMed Web of Science ®Google Scholar
• ZHAO M, KIYOI H, YAMAMOTO Y et al.: In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor. Leukemia (2000) 14:374-378.
   PubMed Web of Science ®Google Scholar
• MINAMI Y, KIYOI H, YAMAMOTO Y et al.: Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia (2002) 16:1535-1540.
   PubMed Web of Science ®Google Scholar
• TSE KF, NOVELLI E, CIVIN CI, BOHMER FD, SMALL D: Inhibition of FLT3-mediated transformation by use of a tyrosine kinase inhibitor. Leukemia (2001) 15:1001-1010.
   PubMed Web of Science ®Google Scholar
• LEVIS M, TSE KF, SMITH BD, GARRETT E, SMALL D: A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internal tandem duplication mutations. Blood (2001) 98:885-887.
   PubMed Web of Science ®Google Scholar
• WEISBERG E, BOULTON C, KELLY LM et al.: Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell (2002) 1:433-443.
   PubMed Web of Science ®Google Scholar
• FONG TA, SHAWVER LK, SUN L et al.: SU-5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. (1999) 59:99-106.
   PubMed Web of Science ®Google Scholar
• MENDEL DB, SCHRECK RE, WEST DC et al.: The angiogenesis inhibitor SU-5416 has long-lasting effects on vascular endothelial growth factor receptor phosphorylation and function. Clin. Cancer Res. (2000) 6:4848-4858.
   PubMed Web of Science ®Google Scholar
• YEE KW, O’FARRELL AM, SMOLICH BD et al.: SU-5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood (2002) 100:2941-2949.
   PubMed Web of Science ®Google Scholar
• MENDEL DB, LAIRD AD, XIN X et al.: In vivo antitumor activity of SU-11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. (2003) 9:327-337.
   PubMed Web of Science ®Google Scholar
• O’FARRELL AM, FORAN JM, FIEDLER W et al.: An innovative Phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU-11248 in acute myeloid leukemia patients. Clin. Cancer Res. (2003) 9:5465-5476.
   Google Scholar
• O’FARRELL AM, ABRAMS TJ, YUEN HA et al.: SU-11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood (2003) 101:3597-3605.
   PubMed Web of Science ®Google Scholar
• KELLY LM, YU JC, BOULTON CL et al.: CT-53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer Cell (2002) 1:421-432.
   PubMed Web of Science ®Google Scholar
• CORBIN AS, GRISWOLD IJ, LA ROSEE P et al.: Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN-518 and PD-180970. Blood (2004) 104:3754-3757.
   PubMed Web of Science ®Google Scholar
• GRISWOLD IJ, SHEN LJ, LA ROSEE P et al.: Effects of MLN-518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Blood (2004) 104:2912-2918.
   PubMed Web of Science ®Google Scholar
• LEVIS M, ALLEBACH J, TSE KF et al.: A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood (2002) 99:3885-3891.
   PubMed Web of Science ®Google Scholar
• GEORGE DJ, DIONNE CA, JANI J et al.: Sustained in vivo regression of Dunning H rat prostate cancers treated with combinations of androgen ablation and Trk tyrosine kinase inhibitors, CEP-751 (KT-6587) or CEP-701 (KT-5555). Cancer Res. (1999) 59:2395-2401.
   PubMed Web of Science ®Google Scholar
• BROWN P, LEVIS M, SHURTLEFF S et al.: FLT3 inhibition selectively kills childhood acute lymphoblastic leukemia cells with high levels of FLT3 expression. Blood (2005) 105:812-820.
   PubMed Web of Science ®Google Scholar
• WILHELM SM, CARTER C, TANG L et al.: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. (2004) 64:7099-7109.
   PubMed Web of Science ®Google Scholar
• PROPPER DJ, MCDONALD AC, MAN A et al.: Phase I and pharmacokinetic study of PKC-412, an inhibitor of protein kinase C. J. Clin. Oncol. (2001) 19:1485-1492.
   PubMed Web of Science ®Google Scholar
• STONE RM, DEANGELO DJ, KLIMEK V et al.: Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC-412. Blood (2005) 105:54-60.
   PubMed Web of Science ®Google Scholar
• MESTERS RM, PADRO T, BIEKER R et al.: Stable remission after administration of the receptor tyrosine kinase inhibitor SU-5416 in a patient with refractory acute myeloid leukemia. Blood (2001) 98:241-243.
   PubMed Web of Science ®Google Scholar
• FIEDLER W, MESTERS R, TINNEFELD H et al.: A Phase II clinical study of SU-5416 in patients with refractory acute myeloid leukemia. Blood (2003) 102:2763-2767.
   PubMed Web of Science ®Google Scholar
• GILES FJ, STOPECK AT, SILVERMAN LR et al.: SU-5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood (2003) 102:795-801.
   PubMed Web of Science ®Google Scholar
• O’FARRELL AM, YUEN HA, SMOLICH B et al.: Effects of SU-5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk. Res. (2004) 28:679-689.
   PubMed Web of Science ®Google Scholar
• FIEDLER W, SERVE H, DOHNER H et al.: A Phase I study of SU-11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood (2005) 105:986-993.
   PubMed Web of Science ®Google Scholar
• SMITH BD, LEVIS M, BERAN M et al.: Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood (2004) 103:3669-3676.
   PubMed Web of Science ®Google Scholar
• HEINRICH MC: A ‘first in man’ study of the safety and PK/PD of an oral FLT3 inhibitor (MLN-518) in patients with AML or high risk myelodysplasia [abstract]. Blood (2002) 100:336a-337a.
   Google Scholar
• DEANGELO D Sr, BRUNNER RJ et al.: Phase I clinical results with MLN-518, a novel FLT3 antagonist: tolerability. Pharmacokinetics and pharmacodynamics [abstract]. Blood (2003) 102:65a.
   Google Scholar
• DE ANGELO J: Phase II evaluation of the tyrosine kinase inhibitor MLN-518 in patients with acute myeloid leukemia (AML) bearing a FLT3 internal tandem duplication (ITD) mutation. [abstract]. Blood (2004) 104:496a.
   Google Scholar
• LEVIS M, PHAM R, SMITH BD, SMALL D: In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects. Blood (2004) 104(4):1145-1150.
   PubMed Web of Science ®Google Scholar
• YEE KW, SCHITTENHELM M, O’FARRELL AM et al.: Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells. Blood (2004) 104:4202-4209.
   PubMed Web of Science ®Google Scholar
• AZAM M, LATEK RR, DALEY GQ: Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell (2003) 112:831-843.
   PubMed Web of Science ®Google Scholar
• SHAH NP, NICOLL JM, NAGAR B et al.: Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI-571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell (2002) 2:117-125.
   PubMed Web of Science ®Google Scholar
• COOLS J, MENTENS N, FURET P et al.: Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res. (2004) 64:6385-6389.
   PubMed Web of Science ®Google Scholar
• BAGRINTSEVA K, SCHWAB R, KOHL TM et al.: Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD-transformed hematopoietic cells. Blood (2004) 103:2266-2275.
   PubMed Web of Science ®Google Scholar