The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure-most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.
"The human organic cationic transporter-1 (OCT-1) is the main transporter protein responsible for imatinib influx, and polymorphisms can potentially have affect expression of OCT-1.82 Patients with CML and a low level of OCT-1 have inferior levels of MMR, CMR, EFS, and OS at 5 years.82 Increasing the dose of imatinib can overcome the negative effect of a low level of OCT-1, but this strategy needs to be confirmed by further studies. "
[Show abstract][Hide abstract] ABSTRACT: Chronic myeloid leukemia (CML) is a malignant disease that originates in the bone marrow and is designated by the presence of the Philadelphia (Ph+) chromosome, a translocation between chromosomes 9 and 22. Targeted therapy against CML commenced with the development of small-molecule tyrosine kinase inhibitors (TKIs) exerting their effect against the oncogenic breakpoint cluster region (BCR)-ABL fusion protein. Imatinib emerged as the first successful example of a TKI used for the treatment of chronic-phase CML patients and resulted in significant improvements in response rate and overall survival compared with previous treatments. However, a significant portion of patients failed to respond to the therapy and developed resistance against imatinib. Second-generation TKIs nilotinib and dasatinib were to have higher efficiency in clinical trials in imatinib- resistant or intolerant CML patients compared with imatinib. Identification of novel strategies such as dose escalation, drug combination therapy, and use of novel BCR-ABL inhibitors may eventually overcome resistance against BCR-ABL TKIs. This article reviews the history of CML, including the treatment strategies used prediscovery of TKIs and the preclinical and clinical data obtained after the use of imatinib, and the second-generation TKIs developed for the treatment of CML.
Hematology Research and Reviews 11/2012; 3:139-50. DOI:10.2147/JBM.S29132
"The clinical use of tyrosine kinase inhibitors for the treatment of a variety of cancers has markedly increased treatment options available to patients. Inhibition of specific kinase signaling pathways can result in decreased tumor size and time to disease progression (recent reviews of the clinical aspects of tyrosine kinase inhibition on the treatment of cancer can be found in Natoli et al., 2010; Agrawal et al., 2010; Liegl-Atzwanger et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: The inhibition of protein kinases has gained general acceptance as an effective approach to treat a wide range of cancers. However, in many cases, prolonged administration of kinase inhibitors often leads to acquired resistance, and the therapeutic effect is subsequently diminished. The wealth of recent studies using biochemical, kinetic, and structural approaches have revealed the molecular basis for the clinically observed resistance. In this review, we highlight several of the most common molecular mechanisms that lead to acquired resistance to kinase inhibitors observed with the cAbl (cellular form of the Abelson leukemia virus tyrosine kinase) and the type III receptor tyrosine kinase cKit, including a newly identified mechanism resulting from accelerated kinase activation caused by mutations in the activation loop. Strategies to overcome the loss of drug sensitivity that represents a challenge currently facing the field and the emerging approaches to circumvent resistance are discussed.
Critical Reviews in Biochemistry and Molecular Biology 05/2011; 46(4):295-309. DOI:10.3109/10409238.2011.578612 · 7.71 Impact Factor
"Despite the responses observed with imatinib, a proportion of patients develops resistance to imatinib or cannot tolerate its side effects. This led to the development of newer tyrosine kinase inhibitors (TKIs) of BCR-ABL, including dasatinib, nilotinib, and bosutinib, that were initially tested in clinical studies of patients with prior imatinib therapy [2-5]. Dasatinib, nilotinib and bosutinib, respectively, have 325-fold, 20-30-fold, and 30-fold increased potency over imatinib against BCR-ABL kinase in vitro [6-9]. "
[Show abstract][Hide abstract] ABSTRACT: Imatinib, a tyrosine kinase inhibitor (TKI) of BCR-ABL, was the standard first-line therapy for chronic myeloid leukemia (CML) for almost 10 years. Dasatinib and nilotinib, two newer drugs with higher potency than imatinib against BCR-ABL and activity against most imatinib-resistant BCR-ABL mutations, have each shown superior efficacy compared with imatinib for first-line treatment of chronic-phase CML in randomized phase 3 trials. With 14 months follow-up time, available data suggest no obvious differences in efficacy between dasatinib and nilotinib. Compared with imatinib, dasatinib is associated with higher rates of pleural effusion and thrombocytopenia, but lower rates of edema, gastrointestinal AEs, musculoskeletal AEs, and rash. Nilotinib is associated with higher rates of dermatologic toxicity, headache, and biochemical abnormalities associated with hepatic and pancreatic toxicity compared with imatinib, but lower rates of edema, gastrointestinal AEs, muscle spasm, and neutropenia. Several studies have shown that poor adherence to imatinib detrimentally affects responses and should be considered in patients with a suboptimal response. The different dosing requirements of dasatinib (once daily with or without food) and nilotinib (twice daily with fasting) may be an additional factor in selecting frontline agents. This review compares and contrasts the three FDA approved first line TKI agents.
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