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Research Articles: Therapeutics, Targets, and Development

The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling

¹ Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan; ² Department of Internal Medicine, Kagawa University, Kita-gun, Kagawa, Japan; and ³ Department of Hematology and Oncology, Cedars-Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, California

Requests for reprints: Takayuki Ikezoe, Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi 783-8505, Japan. Phone: 81-88-880-2345; Fax: 81-88-880-2348. E-mail: ikezoet{at}med.kochi-u.ac.jp

Abstract

We studied antitumor effects of receptor tyrosine kinase inhibitor sunitinib (formerly SU11248) against a variety of hematologic malignancies including the following leukemias: eosinophilic (EOL-1), acute myeloid (THP-1, U937, Kasumi-1), biphenotypic (MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, PALL-2), blast crisis of chronic myeloid (KU812, Kcl-22, K562), and adult T-cell (MT-1, MT-2, MT-4), as well as non-Hodgkin's lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine uptake studies showed that sunitinib was active against EOL-1, MV4-11, and Kasumi-1 cells, which possessed activating mutations of the PDGFR, FLT-3, and c-KIT genes, respectively, with IC₅₀s of <30 nmol/L. In addition, sunitinib inhibited the proliferation of freshly isolated leukemia cells from patients possessing mutations in FLT3 gene. Annexin V staining showed that sunitinib induced apoptosis of these cells. Sunitinib inhibited phosphorylation of FLT3 and PDGFR in conjunction with blockade of mammalian target of rapamycin signaling in MV4-11 and EOL-1 cells, respectively. Interestingly, rapamycin analogue RAD001 enhanced the ability of sunitinib to inhibit the proliferation of leukemia cells and down-regulate levels of mammalian target of rapamycin effectors p70 S6 kinase and eukaryotic initiation factor 4E–binding protein 1 in these cells. Taken together, sunitinib may be useful for treatment of individuals with leukemias possessing activation mutation of tyrosine kinase, and the combination of sunitinib and RAD001 represents a promising novel treatment strategy. [Mol Cancer Ther 2006;5(10):2522–30]

Grant support: Ministry of Education, Culture Sports, Science, and Technology of Japan (T. Ikezoe), Uehara Memorial Foundation (T. Ikezoe), and NIH grants and the Inger Fund (H.P. Koeffler).

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.

Received 2/ 7/06; revised 7/16/06; accepted 8/16/06.