Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by Philadelphia chromosome and resultant production of the constitutively activated BCR-ABL tyrosine kinase. Imatinib (STI571), selective inhibitor of the ABL-tyrosine kinase, inhibits the activity of BCR-ABL tyrosine kinase. A phase I and II study of STI571 showed remarkable cytogenetic effect in patients with interferon-refractory CML, offering new hope for therapy for CML. It will, however, require long-term follow-up data from phase II and III clinical studies to validate the effect of STI571 on survival. As therapy for CML improves, monitoring minimal residual disease will be important.
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PMID:[Antileukemic drug--a selective inhibitor of BCR-ABL tyrosine kynase, imatinib(STI571)]. 1180 44

Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Abl-expressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P <.05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-x(L). Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34(+) leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (BC) of chronic myelocytic leukemia (CML) while receiving therapy with imatinib. Taken together, these findings indicate that cotreatment with SAHA enhances the cytotoxic effects of imatinib and may have activity against imatinib-refractory CML-BC.
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PMID:Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. 1244 42

Chronic myelogenous leukaemia (CML) is a clonal malignancy of the pluripotent haematopoietic stem cell, characterised by an uncontrolled proliferation and expansion of myeloid progenitors expressing a fusion oncogene, BCR-ABL, the molecular counterpart of the Ph1 chromosome. The tyrosine kinase (TK) activity of BCR-ABL is known to activate several major signalling pathways in malignant cells, including Ras, JAK/STAT and PI3K/Akt with evidence of proteasome-mediated degradation of other targets such as the DNA repair protein DNA-PKcs and cyclin-dependent kinases inhibitor p27. Targeting these abnormalities by blocking TK of BCR-ABL with STI571 provided a promising approach for the therapy of CML. The recent development of resistance to STI571 illustrates, however, that the use of other TK inhibitors could be of major interest for therapeutic purposes. To this end, the TK inhibitor Tyrphostin AG1024 was used to evaluate effect on regulation of BCR-ABL expression, inhibition of cell proliferation and tumour formation in vivo in human and murine BCR-ABL expressing cell lines. Tyrphostin AG1024 was shown to downregulate expression of BCR-ABL and P-Akt, and to upregulate DNA-PKcs expression. In addition, Tyrphostin AG1024 was able to inhibit cell proliferation, and delay tumour growth in vivo. Thus, AG1024 is able to interfere with three major targets of BCR-ABL in leukaemic cells. Interestingly, Tyrphostin AG1024 was also effective against cells resistant to STI571 by distinct mechanisms including Bcr-Abl mutation. Therefore, these data suggest that Tyrphostin AG1024 could represent the basis of a novel therapy for STI571 refractory CML.
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PMID:Tyrosine kinase inhibitor AG1024 exerts antileukaemic effects on STI571-resistant Bcr-Abl expressing cells and decreases AKT phosphorylation. 1549 18

Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.
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PMID:In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. 1593 Feb 65

Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34(+) CML cells using a strategy that combines a brief exposure to imatinib (0.5-1.0 microM for 72 h) and then mafosfamide (30-90 microg/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 microM imatinib, 60 microg/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL(+) cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.
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PMID:A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts. 1643 11

MK-0457 (VX-680) is a small-molecule aurora kinase (AK) inhibitor with preclinical antileukemia activity. The T315I BCR-ABL mutation mediates resistance to imatinib, nilotinib, and dasatinib. MK-0457 has in vitro activity against cells expressing wild-type or mutated BCR-ABL, including the T315I BCR-ABL mutation. Three patients with T315I abl-mutated chronic myeloid leukemia (CML) or Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) have achieved clinical responses to doses of MK-04547 that are not associated with adverse events. Higher MK-0457 dose levels were associated with clinical responses and down-regulation of CrkL phosphorylation in leukemia cells. The possible role of AK inhibition in these clinical responses requires further investigation. The currently reported cases are the first observed clinical activity of a kinase inhibitor against the T315I phenotype. The observation of responses in 3 patients with T315I phenotype-refractory CML or Ph-positive ALL, at doses of MK-0457 associated with no significant extramedullary toxicity, is very encouraging.
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PMID:MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. 1699 Jun 3

In 2006, most newly diagnosed patients with chronic myeloid leukemia (CML) underwent first-line, molecular-targeted therapy with the Bcr-Abl tyrosine kinase inhibitor, imatinib. The expectation was that the vast majority of these patients would exhibit a complete cytogenetic response on imatinib alone. Studies of patients with acquired imatinib resistance revealed that Bcr-Abl signaling is reactivated at the time of resistance, predominantly because of mutations that interfere with drug binding in the kinase domain of Bcr-Abl. The knowledge that Bcr-Abl remains the optimal target for treating imatinib-refractory CML has driven an already highly successful search for alternative approaches to restore target inhibition. Here, we review the current state of affairs in the realm of controlling drug resistance in CML, including cutting-edge strategies to reign in Bcr-AblT315I, which is cross resistant to imatinib, as well as the "next generation" Bcr-Abl inhibitors, nilotinib and dasatinib. We also critically assess the role of combined Abl kinase inhibitor therapy in overcoming resistance and provide recommendations for monitoring patients for kinase domain mutations.
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PMID:Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia. 1738 21

Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukaemia (CML) is the consummate success story for targeted therapy, yet relapse is a nearly inevitable consequence of cessation or interruption of therapy. Primitive TKI-refractory CML stem cells are the likely source of these relapses, as they provide sanctuary for the Philadelphia chromosome. In advanced disease, their progressively anaplastic progeny ultimately maintain CML independently of the CML haematopoietic stem cell (HSC). Interestingly, there are at least two distinct cell types capable of self-renewal in different phases of CML: first, a primitive HSC with BCR-ABL mutation, which maintains the more indolent chronic-phase disease and, second, a coexisting mutated progenitor cell which acquires stem cell characteristics responsible for rapid cell expansion in advanced disease.
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PMID:Getting to the stem of chronic myeloid leukaemia. 1857 66

The introduction of imatinib mesylate (Gleevec) has dramatically changed the management and prognostic outlook of patients with chronic myeloid leukemia (CML). Despite the outstanding results achieved with imatinib, approximately 20% to 30% of patients may either not respond to therapy or eventually develop resistance or intolerance to the drug. Resistance to imatinib is mediated to a great extent by the emergence of mutations within the tyrosine kinase domain of the BCR-ABL oncogene. A growing number of tyrosine kinase inhibitors (TKIs) with different pharmacokinetic and pharmacodynamic profiles are currently being investigated in clinical trials to determine their efficacy against CML resistant to imatinib therapy. The leading examples of this group of second-generation TKIs are nilotinib (Tasigna) and dasatinib (Sprycel). This review addresses the causes and consequences of imatinib resistance and current management of refractory CML with the second-generation TKIs.
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PMID:Management of patients with resistant or refractory chronic myelogenous leukemia. 1847 16

Recent work indicates that an Aurora kinase inhibitor MK-0457 (VX-680), a small-molecule inhibitor of Aurora kinases A, B, C and BCR-ABL, FLT-3, JAK-2, can block the progression of cell growth cycle, causing apoptosis in a range of human tumors. MK-0457 has the activity against expressions of wild-type and mutated bcr-abl gene, including the T315I mutant, and can inhibit the activity of FLT-3, JAK-2 and their mutated types as well. Clinical applications suggest that the MK-0457 has therapeutic effect on the highly refractory CML and CML with poor prognosis, Ph(+) ALL with T315I mutant, relapse refractory AML and JAK-2 positive myeloproliferative diseases (MPD). The intensive preclinical studies and the on-going phase II clinical trials will open up a new vista of therapy for some hematological malignancies. This review focuses on the pharmacologic action of MK-0457 and its clinical trial as well as combined application.
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PMID:[Research progress on aurora kinase inhibitor MK-0457 in therapy for some hematological malignancies -- review]. 1954 14


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