1. Second-generation tyrosine kinase inhibitors as therapy for chronic myeloid leukemia.
- Author
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Swords R, Alvarado Y, Cortes J, and Giles FJ
- Subjects
- Animals, Benzamides, Clinical Trials as Topic, Dasatinib, Drug Delivery Systems, Drug Design, Drug Resistance, Neoplasm genetics, Drug Screening Assays, Antitumor, Drugs, Investigational pharmacology, Fusion Proteins, bcr-abl genetics, Genes, abl, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myeloid, Chronic-Phase drug therapy, Leukemia, Myeloid, Chronic-Phase enzymology, Leukemia, Myeloid, Chronic-Phase genetics, Mice, Multicenter Studies as Topic, Mutation, Piperazines pharmacology, Piperazines therapeutic use, Protein Isoforms antagonists & inhibitors, Protein Isoforms genetics, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Pyrimidines therapeutic use, Signal Transduction drug effects, Signal Transduction genetics, Thiazoles pharmacology, Thiazoles therapeutic use, Fusion Proteins, bcr-abl antagonists & inhibitors, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Protein Kinase Inhibitors therapeutic use
- Abstract
Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a single genetic abnormality, characterized by a reciprocal translocation involving chromosomes 9 and 22 (the Philadelphia chromosome). The fusion gene that results (BCR-ABL) produces a constitutively activated tyrosine kinase that exists in different isoforms depending on BCR break-points. Imatinib mesylate is a highly selective inhibitor of this kinase, producing normal blood-counts in 98% of patients in chronic phase CML and disappearance of the Philadelphia chromosome in 86%. However, 17% of patients in the chronic phase will either relapse or develop resistance resulting mainly from one or more point mutations affecting at least 30 amino acids within the Abl kinase protein. This review focuses on the relevant biology of CML, imatinib mesylate resistance mechanisms, and the current status of the next generation of Bcr-Abl inhibitors.
- Published
- 2007
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