期刊
ONCOLOGIST
卷 16, 期 6, 页码 868-876出版社
WILEY
DOI: 10.1634/theoncologist.2010-0388
关键词
Chronic myeloid leukemia; Imatinib; Nilotinib; Dasatinib; Bcr-Abl mutations
类别
资金
- Novartis
- Actinium Pharmaceuticals
- Chroma Therapeutics
- European LeukemiaNet
- AIL
- AIRC
- PRIN
- Fondazione del Monte di Bologna e Ravenna
Development of drug resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients is often accompanied by selection of point mutations in the kinase domain (KD) of the Bcr-Abl oncoprotein, where imatinib binds. Several second-generation tyrosine kinase inhibitors (TKIs) have been designed rationally so as to enhance potency and retain the ability to bind mutated forms of Bcr-Abl. Since the preclinical phase of their development, most of these inhibitors have been tested in in vitro studies to assess their half maximal inhibitory concentration (IC50) for unmutated and mutated Bcr-Abl-that is, the drug concentration required to inhibit the cell proliferation or the phosphorylation processes driven by either the unmutated or the mutated forms of the kinase. A number of such studies have been published, and now that two inhibitors-dasatinib and nilotinib-are available for the treatment of imatinib-resistant cases, it is tempting for clinicians to reason on the IC50 values to guess, case by case, which one will work best in patients harboring specific Bcr-Abl KD mutations. Here, we discuss the pros and cons of using this approach in TKI selection. The Oncologist 2011;16:868-876
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