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Oregon Health and Science University Cancer Institute, Portland, Oregon
Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9. The chimerical Bcr-Abl protein expressed by CML cells has constitutive tyrosine kinase activity, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl, has unprecedented efficacy for the treatment of CML. Most patients with early stage disease achieve durable complete hematological and complete cytogenetic remissions, with minimal toxicity. In contrast, responses are less stable in patients with advanced CML. This review highlights the pathogenesis of CML, its clinical features, and the development of imatinib as a specific molecularly targeted therapy. Aspects of disease monitoring and side effects are covered as well as resistance to imatinib and strategies to overcome resistance, such as alternative signal transduction inhibitors and drug combinations. Perspectives for further development are also discussed.
Abstract I. Introduction A. Historical Remarks B. Epidemiology C. Clinical Features II. Pathogenesis of Chronic Myelogenous Leukemia A. The Philadelphia Translocation and the BCR-ABL Fusion Gene B. Bcr and Abl Proteins C. Essential Features of Bcr-Abl D. Consequences of Deregulated Tyrosine Kinase Activity 1. Increased Proliferation. 2. Reduced Apoptosis. 3. Disturbed Interaction with the Extracellular Matrix. III. Conventional Treatment Options for Chronic Myelogenous Leukemia A. Assessment of Response to Therapy B. Conventional Cytotoxic Drugs C. Interferon-{alpha} D. Allogeneic Stem Cell Transplantation IV. Imatinib A. Development of Abl-Specific Tyrosine Kinase Inhibitors B. Preclinical Evaluation of Imatinib 1. In Vitro Studies a. Kinase Assays. b. Studies in Cell Lines. c. Studies in Primary Cells. 2. Animal Studies. C. Clinical Trials 1. Phase I. 2. Phase II. 3. Phase III. D. Side Effects 1. Nonhematological Toxicity a. Edema and Fluid Retention. b. Gastrointestinal Side Effects. c. Skin Reactions. d. Arthralgia, Myalgia, and Bone Pain. e. Liver Toxicity. 2. Hematological Toxicity. V. Pharmakokinetics VI. Monitoring Patients on Imatinib VII. Imatinib in Drug Combinations VIII. Mechanism of Action A. Binding of Imatinib to the Abl Kinase Domain IX. Resistance to Imatinib A. In Vitro Models B. Resistance in Patients X. Other Novel Agents for the Treatment of Chronic Myelogenous Leukemia A. Agents That Target Pathways Downstream of Bcr-Abl 1. Farnesyl Transferase Inhibitors. 2. Mitogen-Activated Protein Kinase Inhibitors. 3. Phosphatidylinositol-3 Kinase Inhibitors. B. Agents That Affect the Bcr-Abl Protein C. Alternative Abl Inhibitors D. Partially Selective Inhibitors XI. Imatinib for the Treatment of Malignancies Other Than Philadelphia-Positive Leukemia XII. Future Perspectives
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