Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis Journal Article

  

Authors:	Shah, N. P.; Kasap, C.; Weier, C.; Balbas, M.; Nicoll, J. M.; Bleickardt, E.; Nicaise, C.; Sawyers, C. L.
Article Title:	Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis
Abstract:	The BCR-ABL inhibitor dasatinib achieves clinical remissions in chronic myeloid leukemia (CML) patients using a dosing schedule that achieves potent but transient BCR-ABL inhibition. In vitro, transient potent BCR-ABL inhibition with either dasatinib or imatinib is cytotoxic to CML cell lines, as is transient potent EGFR inhibition with erlotinib in a lung cancer cell line. Cytotoxicity correlates with the magnitude as well as the duration of kinase inhibition. Moreover, cytotoxicity with transient potent target inhibition is equivalent to prolonged target inhibition and in both cases is associated with BIM activation and rescued by BCL-2 overexpression. In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy. © 2008 Elsevier Inc. All rights reserved.
Keywords:	controlled study; treatment response; human cell; erlotinib; antineoplastic agents; drug targeting; drug megadose; cell survival; imatinib; gene overexpression; protein bcl 2; low drug dose; apoptosis; enzyme inhibition; bim protein; receptor, epidermal growth factor; drug potency; cell line, tumor; dasatinib; chronic myeloid leukemia; pyrimidines; protein kinase inhibitors; cancer regression; correlation analysis; kinetics; drug mechanism; leukemia cell; cellcycle; bcr abl protein; piperazines; drug cytotoxicity; drug half life; thiazoles; leukemia, myelogenous, chronic, bcr-abl positive; fusion proteins, bcr-abl; k562 cells; drug intermittent therapy
Journal Title:	Cancer Cell
Volume:	14
Issue:	6
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2008-12-09
Start Page:	485
End Page:	493
Language:	English
DOI:	10.1016/j.ccr.2008.11.001
PUBMED:	19061839
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-56849117387&partnerID=40&md5=3cde13defba3c80cf6f1467c05b57806
Notes:	--- - "Cited By (since 1996): 82" - "Export Date: 17 November 2011" - "CODEN: CCAEC" - "Source: Scopus"

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