Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n = 33), lymphoid blast crisis (n = 2), accelerated phase (n = 16), chronic phase (n = 13), and BCR-ABL-positive acute lymphoblastic leukemia (n = 2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.
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PMID:Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. 1239 61

A 73-year-old woman with chronic myeloid leukemia was treated with interferon-alpha, hydroxyurea, and busulfan before imatinib mesylate treatment. The leukocyte count was 8,400/; hemoglobin concentration, 12.0 g/; and platelet count, 19.7 x 10(4)/. She received 400 mg of imatinib mesylate for 17 days before the agent was discontinued because of pancytopenia. A bone marrow biopsy on the 87th day after the last imatinib mesylate administration demonstrated severe hypocellularity. She needed many RBC and Plt transfusions and filgrastim administration. Grade 4 neutropenia continued for 35 days and Grade 3 thrombocytopenia continued for over 122 days. Imatinib mesylate, an agent targeting BCR-ABL, is expected to be useful as an effective therapeutic agent for chronic myeloid leukemia. However the present case suggests that its appropriate dose is individually variable and we should carefully consider the former treatment, and the clinical stage of the disease before initiating imatinib treatment.
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PMID:[Chronic myeloid leukemia associated with sustained severe pancytopenia after imatinib mesylate therapy]. 1241 95

Significant advances have been made in the development of targeted interventions for hematologic malignancies. Progress has been made in defining the molecular pathogenesis of human leukemias. Data indicate that nonrandom, somatically acquired translocations, inversions, and other abnormalities occur in many acute leukemias. In the treatment of acute promyelocytic leukemia (APL), targeted therapy with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy leads to dramatic improvements in disease-free survival. Imatinib mesylate, a signal transduction inhibitor that inhibits tyrosine kinase activity, the protein product of the ABL proto-oncogene, has remarkable activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL). Farnesyltransferase inhibitors (FTIs), a promising class of agents that target multiple pathways including Ras proteins, are potential anticancer therapy for a wide range of malignancies, including leukemias and myelodysplastic syndromes (MDS). There also is evidence that recombinant human erythropoietin therapy (r-HuEPO) can benefit patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. This supplement will discuss advances in our understanding of human leukemias, including the use of unconjugated monoclonal antibodies such as Campath-1H (Wellcome, Beckenham, UK, and Ilex Oncology, San Antonio, TX) and rituximab and immunoconjugates such as gemtuzumab ozogamicin and BL-22. Although these novel therapies are beginning to fulfill their promise, continued research efforts are needed to determine the optimal role of targeted therapy in acute and chronic leukemias.
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PMID:Advancing the treatment of hematologic malignancies through the development of targeted interventions. 1244 45

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ; Glivec, Novartis Pharma AG, Basel, Switzerland), a signal transduction inhibitor with preferential effects against the tyrosine kinase activity of the protein product of the ABL proto-oncogene, induced hematologic responses in >or=90% of patients with chronic-phase chronic myeloid leukemia (CML). In Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event, making it another hematologic malignancy targeted by this ABL-tyrosine kinase inhibitor. In an international multicenter phase II trial, imatinib-induced hematologic responses (typically brief) were achieved in 60% of patients with relapsed or refractory Ph(+) ALL. Subsequently, the German Multicenter Study Group for Adult ALL (GMALL) analyzed 59 patients treated in two successive nonrandomized phase II trials of imatinib in patients with relapsed or refractory Ph(+) ALL. Peripheral blood blasts cell clearance occurred within 8 to 14 days in most patients. However, in a significant proportion, blast counts subsequently increased 16 to 50 days after treatment onset. Imatinib mesylate was particularly effective in patients with relapse after stem cell transplantation (SCT); 75% of patients achieved complete leukemic response. Rapid development of resistance during treatment with imatinib mesylate remains a major problem. Further research efforts should explore the mechanisms of resistance to imatinib mesylate; effectiveness of other targeted therapies (eg, farnesyl transferase inhibitors [FTIs]); combination therapies; and inclusion of strategies for immune response modification (eg, donor lymphocyte infusions, interferon-alpha) for Ph/BCR-ABL-positive leukemias.
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PMID:Targeted therapies in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. 1244 50

We present a patient with a Philadelphia chromosome positive (Ph+) acute lymphocytic leukaemia (ALL) refractory to standard induction chemotherapy. Treatment with the ABL-specific tyrosine kinase inhibitor STI571 (Glivec, Gleevec, imatinib mesylate) resulted in a complete haematologic and cytogenetic remission. Allogeneic stem cell transplantation from an unrelated donor could be undertaken while the patient was in STI571-induced complete remission from the leukaemia. At present, the patient has a 15-month post-transplantation follow-up and is in stable molecular remission as evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for the BCR/ABL fusion gene transcript. Our case demonstrates that STI571 can act as a bridge to potentially curative allogeneic stem cell transplant in otherwise poor prognosis Ph+ ALL.
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PMID:Favorable outcome with STI571 (imatinib mesylate) and allogeneic stem cell transplantation in a case of Ph+ chemorefractory acute lymphocytic leukaemia. 1247 93

Modern molecular technology helped identify more than 10 protein tyrosine kinases related to myeloid malignancies, which allowed the development of small molecule inhibitors targeting deregulated protein tyrosine kinase activity. Protein tyrosine kinase deregulation can occur as a consequence of fusion gene formation because of chromosomal translocations, or as distinct gain-of-function point mutations. Although the tyrosine kinase inhibitor imatinib mesylate (Gleevec) targeting the ABL protein tyrosine kinase has revolutionized current chronic myeloid leukemia therapy, it became rapidly evident that overcoming the multiple cellular resistance mechanisms will be very challenging. To develop efficient therapeutic alternatives, one must understand the complex signal transduction mechanisms involved in transformation by deregulated protein tyrosine kinases. This article reviews the most recently identified molecular mechanisms involved in cell transformation by the BCR/ABL protein tyrosine kinase fusion and presents new members of the increasing family of deregulated protein tyrosine kinases involved in myeloproliferative disorders. In addition, the article discusses new, promising small molecule protein tyrosine kinase inhibitors and the molecular mechanism that may lead to resistance to these drugs. Finally, the article highlights putative alternative strategies that could be used to block signal transduction pathways of deregulated protein tyrosine kinase activity.
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PMID:Role of constitutively activated protein tyrosine kinases in malignant myeloproliferative disorders: an update. 1248 10

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL genetic translocation and constitutive activation of the Abl tyrosine kinase. Among members of the Signal Transducers and Activators of Transcription (STAT) family of transcription factors, Stat5 is activated by the Bcr-Abl kinase and is implicated in the pathogenesis of CML. We recently identified PD180970 as a new and highly potent inhibitor of Bcr-Abl kinase. In this study, we show that blocking Bcr-Abl kinase activity using PD180970 in the human K562 CML cell line resulted in inhibition of Stat5 DNA-binding activity with an IC(50) of 5 nM. Furthermore, abrogation of Abl kinase-mediated Stat5 activation suppressed cell proliferation and induced apoptosis in K562 cells, but not in the Bcr-Abl-negative myeloid cell lines, HEL 92.1.7 and HL-60. Dominant-negative Stat5 protein expressed from a vaccinia virus vector also induced apoptosis of K562 cells, consistent with earlier studies that demonstrated an essential role of Stat5 signaling in growth and survival of CML cells. RNA and protein analyses revealed several candidate target genes of Stat5, including Bcl-x, Mcl-1, c-Myc and cyclin D2, which were down-regulated after treatment with PD180970. In addition, PD180970 inhibited Stat5 DNA-binding activity in cultured primary leukemic cells derived from CML patients. To detect activated Stat5 in CML patient specimens, we developed an immunocytochemical assay that can be used as a molecular end-point assay to monitor inhibition of Bcr-Abl signaling. Moreover, PD180970 blocked Stat5 signaling and induced apoptosis of STI-571 (Gleevec, Imatinib)-resistant Bcr-Abl-positive cells. Together, these results suggest that the mechanism of action of PD180970 involves inhibition of Bcr-Abl-mediated Stat5 signaling and provide further evidence that compounds in this structural class may represent potential therapeutic agents for CML.
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PMID:Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. 1248 33

Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, most patients will either die of relapse or die from the complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed. Recently, a small molecular inhibitor (STI571 or Gleevec) that targets the BCR-ABL gene was found to have a dramatic clinical effect in patients with chronic myelogenous leukemia (CML). These results have encouraged investigators to search for additional small molecular inhibitors and other targeted therapies that may be applicable to other forms of leukemia. In this review, we examine some of the signaling pathways that are aberrantly regulated in AML, focusing on the tyrosine kinase/RAS/MAP kinase and JAK/STAT pathways. After reviewing these two pathways, we explore some of the targeted therapies directed at these pathways that are under development for AML, many of which are already in clinical trials.
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PMID:Molecular targets in acute myelogenous leukemia. 1249 Feb 7

Cytoreductive therapy can ameliorate symptoms in chronic myeloid leukemia (CML) but only treatment beyond hematologic remission aiming to affect the leukemic clone can improve prognosis. Up to now bone marrow transplantation is the only established therapy with the potential to completely eliminate the BCR-ABL positive cell population. Interferon-alpha (IFN-alpha) as well as cytosine arabinoside (ARA-C), particularly in combination, have been shown to be effective in achieving cytogenetic remission in some patients. With Glivec (STI-571) there is now a drug available which can induce major cytogenetic response in more than half of the patients who have failed IFN-alpha treatment and thus possibly delay or prevent blast crisis. Recent reports, however, have shown that primitive, quiescent, Philadelphia-positive stem cells are insensitive to STI-571 in vitro. Such cells could be the basis of relapse after termination of Glivec-therapy.
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PMID:[Treatment of residual disease in chronic myeloid leukemia with STI-571 (Glivec)]. 1250 64

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic myelogenous leukemias and non-Hodgkin's lymphoma. Murine hematopoietic growth factor dependent BaF3 cells and cells transformed by FTK (BaF3-FTK) were used to investigate the role of FTKs in response to DNA damage. FTK-transformed cells displayed resistance to genotoxic treatment including gamma-radiation and cytostatic agents such as idarubicin and MNNG. More FTK-transformed cells survived genotoxic treatment and were able to proliferate in comparison to parental non-transformed cells. Similar or higher levels of DNA damage was detected in gamma-irradiated in BaF3-FTK cells in comparison to BaF3 parental cells. Idarubicin induced different amounts of DNA damage in various BaF3-FTK cells. All BaF3-FTK cells treated with MNNG displayed significantly more DNA damage in comparison to BaF3 cells. Despite the extent of genotoxic effect BaF3-FTK cells were often able to repair damaged DNA more efficiently that the non-transformed counterparts. Inhibition of BCR/ABL kinase activity by STI571 (Gleevec, inatinib mesylate) abrogated the resistance to genotoxic treatment and inhibited DNA repair mechanisms. We hypothesize that facilitation of the DNA repair in FTK-positive cells may contribute to their resistance to genotoxic treatment.
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PMID:Fusion oncogenic tyrosine kinases alter DNA damage and repair after genotoxic treatment: role in drug resistance? 1253 80


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