Transient Potent BCR-ABL Inhibition Is Sufficient to Commit Chronic Myeloid Leukemia Cells Irreversibly to Apoptosis
| Autor: | Claude Nicaise, Charles L. Sawyers, Eric Bleickardt, Neil P. Shah, Minna D. Balbas, Christopher Weier, John Nicoll, Corynn Kasap |
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| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Cell Survival Dasatinib Fusion Proteins bcr-abl Antineoplastic Agents Apoptosis CELLCYCLE Pharmacology Piperazines Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Humans Protein Kinase Inhibitors neoplasms Kinase Chemistry Myeloid leukemia Imatinib Cell Biology medicine.disease ErbB Receptors Leukemia Kinetics Thiazoles Imatinib mesylate Pyrimidines Oncology Benzamides Imatinib Mesylate Erlotinib K562 Cells medicine.drug K562 cells |
| Zdroj: | Cancer Cell. 14(6):485-493 |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccr.2008.11.001 |
| Popis: | SummaryThe 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. |
| Databáze: | OpenAIRE |
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