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Related Collections Neoplasia Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 96 No. 3 (August 1), 2000: pp. 1070-1079 Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance François Xavier Mahon, Michael W. N. Deininger, Beate Schultheis, Jérome Chabrol, Josy Reiffers, John M. Goldman, and Junia V. Melo From the Department of Haematology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London, UK; and the Laboratoire Greffe de Moelle, Université Victor Segalen, Bordeaux, France. Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML). A few CML cell lines and primary progenitors are, however, resistant to this compound. We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 µmol/L) than in the sensitive (0.2-0.25 µmol/L) clones. The mechanism of resistance to STI571 varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene. In K562-r, there was no Bcr-Abl overexpression, but the IC50 for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571. We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Another possible mechanism of resistance to STI571 Zachary A. Knight;, Carlo Gambacorti-Passerini, Philipp le Coutre, Elena Tassi, and Holger Ruchatz Blood 2000 96: 4003-4005. [Full Text] [PDF] This article has been cited by other articles: D. J. Kominsky, J. Klawitter, J. L. Brown, L. G. Boros, J. V. 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Talpaz BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571 Blood, January 15, 2003; 101(2): 690 - 698. [Abstract] [Full Text] [PDF] H. M. Kantarjian, M. Talpaz, S. O'Brien, F. Giles, G. Garcia-Manero, S. Faderl, D. Thomas, J. Shan, M. B. Rios, and J. Cortes Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia Blood, January 15, 2003; 101(2): 473 - 475. [Abstract] [Full Text] [PDF] J. V. Melo, T. P. Hughes, and J. F. Apperley Chronic Myeloid Leukemia Hematology, January 1, 2003; 2003(1): 132 - 152. [Abstract] [Full Text] [PDF] J. M.L. Ebos, J. Tran, Z. Master, D. Dumont, J. V. Melo, E. Buchdunger, and R. S. Kerbel Imatinib Mesylate (STI-571) Reduces Bcr-Abl-Mediated Vascular Endothelial Growth Factor Secretion in Chronic Myelogenous Leukemia Mol. Cancer Res., December 1, 2002; 1(2): 89 - 95. [Abstract] [Full Text] [PDF] R. P. DeMatteo The GIST of Targeted Cancer Therapy: A Tumor (Gastrointestinal Stromal Tumor), a Mutated Gene (c-kit), and a Molecular Inhibitor (STI571) Ann. Surg. Oncol., November 1, 2002; 9(9): 831 - 839. [Abstract] [Full Text] [PDF] C. Ricci, B. Scappini, V. Divoky, S. Gatto, F. Onida, S. Verstovsek, H. M. Kantarjian, and M. Beran Mutation in the ATP-binding Pocket of the ABL Kinase Domain in an STI571-resistant BCR/ABL-positive Cell Line Cancer Res., November 1, 2002; 62(21): 5995 - 5998. [Abstract] [Full Text] [PDF] R. Nimmanapalli, E. O'Bryan, M. Huang, P. Bali, P. K. Burnette, T. Loughran, J. Tepperberg, R. Jove, and K. Bhalla Molecular Characterization and Sensitivity of STI-571 (Imatinib Mesylate, Gleevec)-resistant, Bcr-Abl-positive, Human Acute Leukemia Cells to SRC Kinase Inhibitor PD180970 and 17-Allylamino-17-demethoxygeldanamycin Cancer Res., October 15, 2002; 62(20): 5761 - 5769. [Abstract] [Full Text] [PDF] C. Yu, G. Krystal, P. Dent, and S. Grant Flavopiridol Potentiates STI571-induced Mitochondrial Damage and Apoptosis in BCR-ABL-positive Human Leukemia Cells Clin. Cancer Res., September 1, 2002; 8(9): 2976 - 2984. [Abstract] [Full Text] [PDF] O. G. Ottmann, B. J. Druker, C. L. Sawyers, J. M. Goldman, J. Reiffers, R. T. Silver, S. Tura, T. Fischer, M. W. Deininger, C. A. Schiffer, et al. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias Blood, August 28, 2002; 100(6): 1965 - 1971. [Abstract] [Full Text] [PDF] A. F. List, K. J. Kopecky, C. L. Willman, D. R. Head, M. L. Slovak, D. Douer, S. R. Dakhil, and F. R. Appelbaum Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase Blood, August 13, 2002; 100(5): 1910 - 1912. [Abstract] [Full Text] [PDF] D. Wisniewski, C. L. Lambek, C. Liu, A. Strife, D. R. Veach, B. Nagar, M. A. Young, T. Schindler, W. G. Bornmann, J. R. Bertino, et al. 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Ivanovic Hypoxia Modifies Proliferation and Differentiation of CD34+ CML Cells Stem Cells, July 1, 2002; 20(4): 347 - 354. [Abstract] [Full Text] [PDF] C. L. Sawyers, A. Hochhaus, E. Feldman, J. M. Goldman, C. B. Miller, O. G. Ottmann, C. A. Schiffer, M. Talpaz, F. Guilhot, M. W. N. Deininger, et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study Blood, May 15, 2002; 99(10): 3530 - 3539. [Abstract] [Full Text] [PDF] M. Levis, J. Allebach, K.-F. Tse, R. Zheng, B. R. Baldwin, B. D. Smith, S. Jones-Bolin, B. Ruggeri, C. Dionne, and D. Small A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo Blood, May 13, 2002; 99(11): 3885 - 3891. [Abstract] [Full Text] [PDF] S. G. O'Brien, S. A. D. Vieira, S. Connors, N. Bown, J. Chang, R. Capdeville, and J. V. Melo Transient response to imatinib mesylate (STI571) in a patient with the ETV6-ABL t(9;12) translocation Blood, May 1, 2002; 99(9): 3465 - 3467. [Abstract] [Full Text] [PDF] S. Branford, Z. Rudzki, S. Walsh, A. Grigg, C. Arthur, K. Taylor, R. Herrmann, K. P. Lynch, and T. P. Hughes High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance Blood, May 1, 2002; 99(9): 3472 - 3475. [Abstract] [Full Text] [PDF] M. O'Dwyer Multifaceted Approach to the Treatment of Bcr-Abl-Positive Leukemias Oncologist, April 1, 2002; 7(90001): 30 - 38. [Abstract] [Full Text] [PDF] M. Talpaz, R. T. Silver, B. J. Druker, J. M. Goldman, C. Gambacorti-Passerini, F. Guilhot, C. A. Schiffer, T. Fischer, M. W. N. Deininger, A. L. Lennard, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study Blood, March 15, 2002; 99(6): 1928 - 1937. [Abstract] [Full Text] [PDF] B. Schultheis, M. Carapeti-Marootian, A. Hochhaus, A. Weibeta er, J. M. Goldman, and J. V. Melo Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism Blood, March 1, 2002; 99(5): 1766 - 1775. [Abstract] [Full Text] [PDF] W.-K. Hofmann, L. C. Jones, N. A. Lemp, S. de Vos, H. Gschaidmeier, D. Hoelzer, O. G. Ottmann, and H. P. Koeffler Ph+ acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCR-ABL gene mutation Blood, March 1, 2002; 99(5): 1860 - 1862. [Abstract] [Full Text] [PDF] D. G. Savage and K. H. Antman Imatinib Mesylate -- A New Oral Targeted Therapy N. Engl. J. Med., February 28, 2002; 346(9): 683 - 693. [Full Text] [PDF] B. M. F. Mow, J. Chandra, P. A. Svingen, C. G. Hallgren, E. Weisberg, T. J. Kottke, V. L. Narayanan, M. R. Litzow, J. D. Griffin, E. A. Sausville, et al. Effects of the Bcr/abl kinase inhibitors STI571 and adaphostin (NSC 680410) on chronic myelogenous leukemia cells in vitro Blood, January 15, 2002; 99(2): 664 - 671. [Abstract] [Full Text] [PDF] H. G. Jorgensen, M. A. Elliott, E. K. Allan, C. E. Carr, T. L. Holyoake, and K. D. Smith alpha 1-Acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571 Blood, January 15, 2002; 99(2): 713 - 715. [Abstract] [Full Text] [PDF] M. J. Mauro, M. O'Dwyer, M. C. Heinrich, and B. J. Druker STI571: A Paradigm of New Agents for Cancer Therapeutics J. Clin. Oncol., January 1, 2002; 20(1): 325 - 334. [Abstract] [Full Text] [PDF] C. Yu, G. Krystal, L. Varticovksi, R. McKinstry, M. Rahmani, P. Dent, and S. Grant Pharmacologic Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase/Mitogen-activated Protein Kinase Inhibitors Interact Synergistically with STI571 to Induce Apoptosis in Bcr/Abl-expressing Human Leukemia Cells Cancer Res., January 1, 2002; 62(1): 188 - 199. [Abstract] [Full Text] [PDF]

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