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Research Articles: Therapeutics, Targets, and Development

Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia

Departments of ¹ Pharmaceutical Sciences and ² Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee; and ³ Department of Pediatric Hematology Oncology, Stanford University School of Medicine, Palo Alto, California

Requests for reprints: Sharyn D. Baker, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale Street, DTRC Room D1034, Mail Stop 314, Memphis, TN 38105. Phone: 901-495-3089; Fax: 901-495-3125. E-mail: sharyn.baker{at}stjude.org

Abstract

We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC₅₀, 0.27 to >40, 0.002-9.1, and 0.007-13 µmol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC₅₀, 2 and 7 nmol/L) and c-KIT N822K mutations (IC₅₀, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 µmol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by 50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML. [Mol Cancer Ther 2008;7(5):1110–20]

Grant support: American Lebanese Syrian Associated Charities and USPHS Cancer Center Support Grant 3P30CA021765.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 10/22/07; revised 3/11/08; accepted 3/15/08.

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