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

We report here an unusual case of a 30-year old male patient with essential thrombocythemia (ET) and dilated cardiomyopathy, who on further investigation was found to have Philadelphia chromosome positive (Ph+) cells in the bone marrow. The reverse transcriptase-polymerase chain reaction (RT-PCR) test on his peripheral blood leucocytes revealed b2a2 transcript of the bcr-abl fusion gene. Literature shows that the boundary line between Ph+ essential thrombocythemia and chronic myeloid leukemia (CML) is getting blurred day by day. Each one may be a part of the spectrum of a single clonal proliferative disease. Association of dilated cardiomyopathy with ET has not been reported.
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PMID:Philadelphia chromosome positive essential thrombocythemia with dilated cardiomyopathy. 1612 16

Imatinib mesylate (Gleevec) was developed as the first molecularly targeted therapy that specifically inhibits the BCR-ABL tyrosine kinase activity in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). Due to its excellent hematologic and cytogenetic responses, particularly in patients with chronic phase CML, imatinib has moved towards first-line treatment for newly diagnosed CML. Nevertheless, resistance to the drug has been frequently reported and is attributed to the fact that transformation of hematopoietic stem cells by BCR-ABL is associated with genomic instability. Point mutations within the ABL tyrosine kinase of the BCR-ABL oncoprotein are the major cause of resistance, though overexpression of the BCR-ABL protein and novel acquired cytogenetic aberrations have also been reported. A variety of strategies derived from structural studies of the ABL-imatinib complex have been developed, resulting in the design of novel ABL inhibitors, including AMN107, BMS-354825, ON012380 and others. The major goal of these efforts is to create new drugs that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. Some of these drugs have already been successfully tested in preclinical studies where they show promising results. Additional approaches are geared towards targeting the expression or stability of the BCR-ABL kinase itself or targeting signaling pathways that are chronically activated and required for transformation. In this review, we will discuss the underlying mechanisms of resistance to imatinib and novel targeted approaches to overcome imatinib resistance in CML.
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PMID:Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). 1621 51

Patients presenting with thrombocytosis require thorough clinical and laboratory evaluation to determine whether they suffer from essential thrombocythemia or another myeloproliferative disorder. This distinction becomes increasingly relevant as targeted agents become available to treat specific myeloproliferative diseases. Cytogenetic testing plays a major role in this analysis. This study presents a patient with Philadelphia chromosome positive (Ph + ) thrombocytosis and a cryptic der(9q)t(5;9)t(9;22) not found by conventional cytogenetics, whose disease progressed within 2 years to typical myeloblastic crisis of CML. It discusses the entity of Ph + ET, the utility of molecular cytogenetic testing in the diagnosis of this unusual disease entity and the importance of cytogenetic testing in the prognosis of ET.
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PMID:Variant translocation with a deletion of derivative (9q) in a case of Philadelphia chromosome positive (Ph +) essential thrombocythemia (ET), a variant of chronic myelogenous leukemia (CML) with a poor prognosis. 1626 84

Imatinib mesylate is a major advance in the therapy of patients with chronic myelogenous leukemia (CML). Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. Clinical studies have yielded impressive results in all phases of CML. With higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease is now advisable in assessing response and determining prognosis. Emergence of resistance to imatinib may be manifest at the hematologic, cytogenetic, or molecular levels in patients who remain in chronic phase, or may be evidenced by the development of more advanced CML phases. Resistance and eventual clinical failure of imatinib occurs in most patients with blastic phase disease. Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. The various mechanisms underlying these differing, non-mutually exclusive, mechanisms of resistance must be understood to develop corresponding therapeutic remedies. We review the current data on imatinib in CML, the criteria for diagnosis of imatinib resistance, and the mechanisms that underlie such resistance in CML.
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PMID:Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid leukemia. 1630 88

Imatinib mesylate, STI571, is a novel anticancer drug used to treat Philadelphia chromosome positive (Ph+) chronic myeloid leukemia. Studies have demonstrated the efficacy of imatinib mesylate in human cancers; however, its effects in murine cancer cell lines are not well documented. This study investigated the cytogenetic and cytotoxic effects of imatinib mesylate in vitro on virus-induced mouse erythroleukemia GM-86 cells. Cytogenetic studies revealed a noticeable increase in chromosomal abnormalities and multinucleation, as well as micro and macronuclei formation in treated cells. An increase in abnormalities such as condensed nuclei and nuclear and cytoplasmic degradations were also detected in cells treated with imatinib mesylate. It is suggested that the reduction in cell proliferation, mitotic index, and increase in cell damaging effects observed in imatinib mesylate-treated GM-86 cells were a result of the induced chromosomal and nuclear abnormalities.
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PMID:An in vitro study of the cytogenetic and cytotoxic effects of imatinib mesylate, STI571 on murine erythroleukemia GM-86 cells. 1657 94

Around 20% of patients with acute lymphoblastic leukemia are Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia) and express the Bcr/Abl tyrosine kinase. Treatment with the tyrosine kinase inhibitor Imatinib is currently standard for chronic myelogenous leukemia, which is also caused by Bcr/Abl. However, Imatinib has shown limited efficacy for treating Ph-positive acute lymphoblastic leukemia. In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells. Three of four cultures were very sensitive to treatment with 5 mumol/L Imatinib. Significant cell death also initially occurred when the same cultures were treated in the presence of stromal support. However, after 6 days, remaining cells started to proliferate vigorously. The Bcr/Abl tyrosine kinase present in the cells that were now able to multiply in the presence of 5 mumol/L Imatinib was still inhibited by the drug. In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant. The effect of stroma in selecting Imatinib-resistant lymphoblasts did not require direct cell-cell contact. SDF-1alpha could substitute for the presence of stromal cells. Our results show that stroma selects Imatinib-resistant Bcr/Abl P190 lymphoblasts that are less dependent on Bcr/Abl tyrosine kinase activity. Therefore, therapy for Ph-positive acute lymphoblastic leukemia, aimed at interfering with the protective effect of stroma in combination with Imatinib, could be of benefit for the eradication of the leukemic cells.
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PMID:Resistance to imatinib of bcr/abl p190 lymphoblastic leukemia cells. 1670 66

Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50< 30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed.
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PMID:AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. 3121 80

Molecularly targeted therapy is a novel approach in cancer treatment. Imatinib, a specific tyrosine kinase inhibitor, since its inception in 1990s, has become the first-line drug in management of chronic myelogenous leukemia (CML) chronic phase. It has also shown promising results in treatment of gastro-intestinal stromal tumors, clonal eosinophilic disorders and Philadelphia chromosome positive acute lymphatic leukemia. The efficacy of imatinib has geared up further research into development of designer drugs with molecular targets. This review gives a comprehensive description of the development, biology, utility, dosing, and limitations of imatinib mesylate.
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PMID:Imatinib mesylate: A designer drug. 1680 Mar 47

Renal dysfunction as a sequel to extended interferon alfa (IFNalpha) treatment in chronic myeloid leukaemia (CML) has been reported previously in six patients. An additional patient is presented with Philadelphia chromosome positive (Ph+) CML and nephrotic syndrome in whom initial renal insufficiency developed after only one month of low dose IFNalpha therapy. The renal biopsy showed a focal segmental mononuclear cell infiltration, basal membrane thickening, and deposits of immunoglobulins (IgG; IgAGM IC3). In spite of discontinuation of IFNalpha, renal function deteriorated and the patient died six months later. This case represents an instance of fatal kidney insufficiency as an untoward effect of sensitisation to the IFNalpha, confirmed by modified Coombs assay.
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PMID:Interferon alpha sensitisation induced fatal renal insufficiency in a patient with chronic myeloid leukaemia: case report and review of literature. 1687 66

Patients with blast crisis (BC) CML frequently become resistant to Imatinib, a Bcr-Abl tyrosine kinase-targeting agent. Eg5, a microtubule-associated motor protein has been described to be highly expressed in BC CML by microarray analysis (Nowicki et al., Oncogene 2003; 22:3952-63). We investigated the regulation of Eg5 by Bcr-Abl tyrosine kinase and its potential as a therapeutic target in BC CML. Eg5 was highly expressed in all Philadelphia chromosome positive (Ph(+)) cell lines and BC CML patient samples. Inhibition of Bcr-Abl by Imatinib downregulated Eg5 expression in Imatinib-sensitive KBM5 and HL-60p185 cells, but not in Imatinib-resistant KBM5-STI571, harboring a T315I mutation, and Bcr-Abl-negative HL-60 cells. Blocking Eg5 expression with antisense oligonucleotide (Eg5-ASO) or inhibiting its activity with the small-molecule Eg5 inhibitor, S-trityl-L-cysteine induced G(2)/M cell cycle block and subsequent cell death in both Imatinib-sensitive and -resistant cells. Further, Eg5-ASO treatment of SCID mice harboring KBM5 cell xenografts significantly prolonged the median survival of the animals (p = 0.03). Our findings suggest that Eg5 is downstream of and regulated by Bcr-Abl tyrosine kinase in Philadelphia chromosome positive cells. Inhibition of Eg5 expression or its activity blocks cell cycle progression and induces cell death independent of the cellular response to Imatinib. Therefore, Eg5 could be a potential therapeutic target for the treatment of BC CML, in particular Imatinib-resistant BC CML.
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PMID:Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. 1696 80


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