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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2112-2120. Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-06-026377. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-06-026377v1 109/5/2112    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Weisberg, E. L. Articles by Griffin, J. D. Search for Related Content PubMed PubMed Citation Articles by Weisberg, E. L. Articles by Griffin, J. D. Related Collections Related Article in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 2, 2006 Accepted October 15, 2006 Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR/ABL+ leukemias Ellen L. Weisberg, Laurie Catley, Renee D. Wright, Daisy Moreno, Lolita Banerji, Arghya Ray, Paul W. Manley, Juergen Mestan, Doriano Fabbro, Jingrui Jiang, Elizabeth Hall-Meyers, Linda Callahan, Jamie L. DellaGatta, Andrew L. Kung, and James D. Griffin* Dana Farber Cancer Institute, Boston, MA Novartis Institutes of Biomedical Research, Basel, Switzerland * Corresponding author; email: james_griffin{at}dfci.harvard.edu. Drug resistance resulting from emergence of imatinib-resistant Bcr-Abl point mutations is a significant problem in advanced stage chronic myelogenous leukemia (CML). The Bcr-Abl inhibitor, nilotinib (AMN107), is significantly more potent against Bcr-Abl than imatinib, and is active against many imatinib-resistant Bcr-Abl mutants. Phase I/II clinical trials show that nilotinib can induce remissions in patients who have previously failed imatinib, indicating that sequential therapy with these two agents has clinical value. However, simultaneous, rather than sequential, administration of two BCR/ABL kinase inhibitors is attractive for many reasons, including the theoretical possibility that this could reduce emergence of drug-resistant clones. Here we show that exposure of a variety of BCR/ABL+ cell lines to imatinib and nilotinib results in additive or synergistic cytotoxicity, including testing of a large panel of cells expressing BCR/ABL point mutations causing resistance to imatinib in patients. Further, using a highly quantifiable bioluminescent in vivo model, drug combinations were at least additive in anti-leukemic activity, compared to each drug alone. These results suggest that despite binding to the same site in the same target kinase, the combination of imatinib and nilotinib is highly efficacious in these models, indicating that clinical testing of combinations of BCR/ABL kinase inhibitors is warranted. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations Heather A. Bradeen, Christopher A. Eide, Thomas O'Hare, Kara J. Johnson, Stephanie G. Willis, Francis Y. Lee, Brian J. Druker, and Michael W. Deininger Blood 2006 108: 2332-2338. [Abstract] [Full Text] [PDF] Related Letter in Blood Online: Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs Deborah L. White, Verity A. Saunders, Steven R. Quinn, Paul W. Manley, and Timothy P. Hughes Blood 2007 109: 3609-3610. [Full Text] [PDF] This article has been cited by other articles: G. D. Demetri, P. G. Casali, J.-Y. Blay, M. von Mehren, J. A. Morgan, R. Bertulli, I. Ray-Coquard, P. Cassier, M. Davey, H. Borghaei, et al. A Phase I Study of Single-Agent Nilotinib or in Combination with Imatinib in Patients with Imatinib-Resistant Gastrointestinal Stromal Tumors Clin. Cancer Res., September 15, 2009; 15(18): 5910 - 5916. [Abstract] [Full Text] [PDF] E. Weisberg, R. D. Wright, D. W. McMillin, C. Mitsiades, A. Ray, R. Barrett, S. Adamia, R. Stone, I. Galinsky, A. L. Kung, et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1121 - 1129. [Abstract] [Full Text] [PDF] T. O'Hare, C. A. Eide, J. W. Tyner, A. S. Corbin, M. J. Wong, S. Buchanan, K. Holme, K. A. Jessen, C. Tang, H. A. Lewis, et al. SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib PNAS, April 8, 2008; 105(14): 5507 - 5512. [Abstract] [Full Text] [PDF] N. Carayol, E. Katsoulidis, A. Sassano, J. K. Altman, B. J. Druker, and L. C. Platanias Suppression of Programmed Cell Death 4 (PDCD4) Protein Expression by BCR-ABL-regulated Engagement of the mTOR/p70 S6 Kinase Pathway J. Biol. Chem., March 28, 2008; 283(13): 8601 - 8610. [Abstract] [Full Text] [PDF] T. Fojo Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better Oncologist, March 1, 2008; 13(3): 277 - 283. [Full Text] [PDF] D. L. White, V. A. Saunders, S. R. Quinn, P. W. Manley, and T. P. Hughes Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs Blood, April 15, 2007; 109(8): 3609 - 3610. [Full Text] [PDF]

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