This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakajima, A. Articles by Ohyashiki, K. Search for Related Content PubMed PubMed Citation Articles by Nakajima, A. Articles by Ohyashiki, K.

First Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan [A. N., T. T., M. S., K. O.], and Department of Tumor Biology, the Schering-Plough Research Institute, Kenilworth, New Jersey 07033 [W. R. B.]

² To whom requests for reprints should be addressed, at First Department of Internal Medicine, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan. Phone: 81-3-3342-6111; Fax: 81-3-5381-6651; E-mail: tauchi{at}tokyo-med.ac.jp

BCR-ABL fusion proteins exhibit elevated tyrosine kinase activity and transforming properties. Genetic and biochemical data suggest that Ras activation plays a central role in leukemogenic transformation by BCR-ABL. Imatinib (Novartis, Basel, Switzerland) is a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL. Although imatinib has shown promise against Ph-positive leukemia in human clinical trials, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for combination chemotherapy to eradicate this disease. In the present study, combined use of a farnesyl transferase inhibitor, SCH66336 (lonafarnib), with the antileukemic agents imatinib, daunorubicin, cytosine arabinoside, or etoposide was investigated by cell proliferation assays. The effects of the combination of SCH66336 and imatinib were also investigated by apoptosis assay and colony-forming assay. In proliferation assays with BCR-ABL-expressing cells, combination of SCH66336 with imatinib or cytosine arabinoside showed enhanced antiproliferative activity, whereas combination of SCH66336 with daunorubicin or etoposide demonstrated an antagonistic effect. The combination of imatinib plus SCH66336 more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. SCH66336 combined with imatinib was shown to induce apoptosis in imatinib-resistant BCR-ABL cells by flow cytometric analysis with an APO2.7 monoclonal antibody. These results indicate that SCH66336 is a promising candidate for use in the treatment of patients with imatinib-resistant, Ph-positive leukemia and that the combination of SCH66336 plus imatinib may be useful to circumvent resistance.

This article has been cited by other articles:

				S.-Y. Sun, X. Liu, W. Zou, P. Yue, A. I. Marcus, and F. R. Khuri The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells J. Biol. Chem., June 29, 2007; 282(26): 18800 - 18809. [Abstract] [Full Text] [PDF]

				T. K. Nguyen, M. Rahmani, H. Harada, P. Dent, and S. Grant MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825 Blood, May 1, 2007; 109(9): 4006 - 4015. [Abstract] [Full Text] [PDF]

				A. D. Basso, P. Kirschmeier, and W. R. Bishop Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors J. Lipid Res., January 1, 2006; 47(1): 15 - 31. [Abstract] [Full Text] [PDF]

				E. David, S.-Y. Sun, E. K. Waller, J. Chen, F. R. Khuri, and S. Lonial The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT Blood, December 15, 2005; 106(13): 4322 - 4329. [Abstract] [Full Text] [PDF]

				J. Cortes and H. Kantarjian New Targeted Approaches in Chronic Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6316 - 6324. [Abstract] [Full Text] [PDF]

				B. Zhang, J. Groffen, and N. Heisterkamp Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a Blood, August 15, 2005; 106(4): 1355 - 1361. [Abstract] [Full Text] [PDF]

				L. J. Elrick, H. G. Jorgensen, J. C. Mountford, and T. L. Holyoake Punish the parent not the progeny Blood, March 1, 2005; 105(5): 1862 - 1866. [Abstract] [Full Text] [PDF]

				Y. Takada, F. R. Khuri, and B. B. Aggarwal Protein Farnesyltransferase Inhibitor (SCH 66336) Abolishes NF-{kappa}B Activation Induced by Various Carcinogens and Inflammatory Stimuli Leading to Suppression of NF-{kappa}B-regulated Gene Expression and Up-regulation of Apoptosis J. Biol. Chem., June 18, 2004; 279(25): 26287 - 26299. [Abstract] [Full Text] [PDF]

				K. J. Smith, E. Jacobson, S. Hamza, and H. Skelton Unexplained Hypereosinophilia and the Need for Cytogenetic and Molecular Genetic Analyses Arch Dermatol, May 1, 2004; 140(5): 584 - 588. [Abstract] [Full Text] [PDF]

				B. J. Druker Overcoming Resistance to Imatinib by Combining Targeted Agents Mol. Cancer Ther., March 1, 2003; 2(3): 225 - 226. [Full Text] [PDF]