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)

The therapy of chronic myeloid leukemia, characterized by the presence of the Philadelphia chromosome in the clonal hematopoietic stem cells, has changed dramatically in the last years with the development of a specific inhibitor of the BCR-ABL tyrosine kinase: tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Glivec]). Glivec selectively blocks cellular proliferation and induces apoptosis in Philadelphia chromosome-positive (Ph+) cells harbouring the Bcr-Abl tyrosine kinase. Clinical development of imatinib mesylate began with 3 large, multicenter, phase II trials. The majority (88%) of interferon-alpha-resistant or intolerant patients in chronic-phase CML, achieved a complete hematologic response to imatinib mesylate. More importantly, approximately half of the patients achieved a major cytogenetic response, a result historically associated with improved survival. Furthermore, 21% of patients in accelerated-phase CML and 13.5% of patients in blastic-phase CML (patient populations with typically poor prognosis before the advent of imatinib mesylate) achieved major cytogenetic responses.
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PMID:[A new drug in the therapy of chronic myeloid leukemia: ST1571]. 1285 55

Atypical nevi are the precursors and risk markers of melanoma. Apart from persistently monitoring these nevocytic lesions and resecting them at the earliest signs of clinical changes, there is as yet no systemic clinical treatment available to interfere with their progression to melanoma. To explore clinical treatments that might interfere with and possibly prevent atypical nevus progression, a previous study documented that 3 months systemic low-dose interferon-alpha (IFN-alpha) treatment of patients with a clinical history of melanoma and numerous atypical nevi, led to inactivation of the STAT1 and STAT3 transcription factors in atypical nevi. Based upon this finding, we initiated a second study to determine whether systemic low-dose IFN-alpha treatment also impairs the expression of upstream regulators and downstream targets of STAT1 and STAT3 in atypical nevi. Using cyanine dye-conjugated antibodies, fluorescence imaging analysis revealed expression of JAK2, JNK1, AKT1, NF-kappa B, and IFN-alpha/beta receptor in benign and atypical nevi, and early- and advanced-stage melanomas. To determine possible changes in the level of expression of these molecules in atypical nevi, excised before and after 3 months of systemic low-dose IFN-alpha treatment, newly designed optical imaging software was used to quantitate the captured fluorescent hybridization signals on a cell-by-cell basis and across an entire nevus section. The results of this analysis did not provide evidence that systemic low-dose IFN-alpha treatment alters the level of expression of upstream regulators or downstream targets of STAT1 and STAT3.
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PMID:Fluorescence imaging analysis of upstream regulators and downstream targets of STAT3 in melanoma precursor lesions obtained from patients before and after systemic low-dose interferon-alpha treatment. 1292 38

Interphase fluorescence in situ hybridization (I-FISH) for the BCR-ABL translocation performed on peripheral blood (PB) white cells has been suggested as a surrogate for conventional bone marrow (BM) cytogenetics for monitoring patients with chronic myeloid leukemia (CML). I-FISH is faster, less costly, and does not require BM aspiration. For patients treated with interferon-alpha (IFN), a good correlation between the two methods has been demonstrated in several though not all studies. However, imatinib mesylate (STI571) has largely replaced IFN as the standard drug treatment for CML, raising the question if the results obtained in IFN-treated patients are applicable to patients on imatinib. We therefore compared the two methods in patients on imatinib and patients on other therapies, mainly IFN (collectively referred to as nonimatinib therapies). Our results demonstrate that the correlation between I-FISH and cytogenetics is much weaker in patients on imatinib than in patients on nonimatinib therapies. Correction of the I-FISH values for the proportion of lymphocytes barely improved the correlation, probably as a result of unpredictable proportions of Philadelphia-positive B cells. By contrast, I-FISH of PB neutrophils was much better correlated with BM cytogenetics. We conclude that I-FISH on unselected PB white cells is not suitable for monitoring patients on imatinib.
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PMID:FISH for BCR-ABL on interphases of peripheral blood neutrophils but not of unselected white cells correlates with bone marrow cytogenetics in CML patients treated with imatinib. 1451 39

Chronic myeloproliferative disorders (CMPD) are neoplastic disorders of the hematopoietic stem cell. Four different entities are defined: chronic myeloid leukemia (CML), polycythemia vers, essential thrombocythaemia, and idiopathic myelofibrosis. In addition, overlapping entities within the CMPDs and between CMPDs and myelodysplastic syndrome have been described. Diagnostic measures are performed to classify the subtype exactly and to assess risk factors and prognosis. Cytogenetic and molecular analyses are mandatory for the characterization of the malignant clone. Hydroxyurea and interferon-alpha have proven effective in all CMPE. In CML, specific inhibition of the elevated ABL tyrosine kinase activity with imatinib is associated with high response rates. Allogeneic stem cell transplantation is the only curative treatment option for all entities. In CML, the decision-making analysis should be based on established scores. In BCR-ABL negative CMPDs an allogeneic stem cell transplantation should only be performed in patients with unfavorable prognosis.
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PMID:[Chronic myeloproliferative diseases. Diagnosis and therapy]. 1467 16

We examined the effects of interferon-alpha (IFN-alpha) treatment on the growth, cell cycle, proliferation, and apoptotic parameters as well as adhesive properties and proteome of chronic myelogenous leukemia (CML)-derived K562 cells. IFN-alpha treatment (200 to 600 U/ml, 24 to 72 h) suppressed growth and caused accumulation of K562 cells in the S-phase of cell cycle (increase in S-phase cells by up to 52% in comparison with the untreated controls) at the expenses of cells in G1-phase. No transition of cells to G0-phase occurred as followed from Ki-67 protein determination. Although the level of chimeric gene product, BCR-ABL mRNA coding for BCR-ABL protein with anti-apoptotic properties, decreased by 30%, apoptosis was not triggered as judged from Annexin-V, APO2.7, and TUNEL assays. Adhesion of K562 cells to fibronectin-coated surfaces increased by up to 52% as determined by calcein assay. The proteomic analysis (2-D electrophoresis in combination with mass spectrometry, MALDI-MS) revealed a single protein, ubiquitine cross-reactive protein (UBCR), whose level markedly increased due to IFN-alpha treatment. The ubiquitination-like directed degradation processes may thus play a role in the mechanism of IFN-alpha antiproliferative effects.
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PMID:Interferon-alpha suppresses proliferation of chronic myelogenous leukemia cells K562 by extending cell cycle S-phase without inducing apoptosis. 1475 43

We reviewed 261 patients with chronicphase chronic myelogenous leukemia (CML) after interferon-alpha (IFN-alpha) failure treated with imatinib mesylate 400 mg daily. With a median follow-up time of 45 months, the major cytogenetic response rate was 73% and the complete cytogenetic response rate 63%. The estimated 4-year survival rate was 86%. Multivariate analysis for survival identified hematologic resistance to IFN-alpha (P =.01), splenomegaly (P =.03), and lack of any cytogenetic response after 3 months of therapy (P =.01) to have independent poor prognostic significance. Patients could be divided into good (no adverse factors), intermediate (1 adverse factor), and poor-risk groups (2 or 3 adverse factors; 12% of patients) with estimated 4-year survival rates of 96%, 86%, and 49%, respectively (P <.00001). The 4-year cumulative major molecular response (quantitative reverse transcriptase-polymerase chain reaction [Q-PCR] = BCR-ABL/ABL less than 0.05%) rate was 43% and complete molecular response rate (BCR-ABL undetectable) 26%. Compared with a historical group of 251 similar patients treated with nonimatinib therapies, imatinib mesylate was associated with a better 4-year survival rate (86% versus 43%; P <.0001); the survival advantage was confirmed by multivariate analysis (hazard ratio, 0.19; P <.0001).
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PMID:Long-term survival benefit and improved complete cytogenetic and molecular response rates with imatinib mesylate in Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia after failure of interferon-alpha. 1519 56

We have previously reported that interferon-alpha (IFNalpha) induces apoptosis and EGF can antagonize this effect in human epidermoid cancer KB cells. Since apoptosis occurs together with cytoskeleton reorganization we have evaluated if IFNalpha and EGF could modulate cell remodeling in our experimental conditions. We have found that 48 h 1,000 IU/ml IFNalpha induced structural reorganization of stress fibers and membrane delocalization and partial capping of the actin severing protein gelsolin. The transfection of KB cells with both a wild type (WT) or a C-terminal truncated form of gelsolin caused overexpression of the protein and an increase of both the spontaneous and IFNalpha-induced apoptosis and cell cytoskeletal modifications. In fact, after 48 h of treatment IFNalpha induced 45% of apoptotic cell death in parental cells while an approximately 80% of cell population was apoptotic in transfected cells. These effects occurred together with an increase of the expression and consequent degradation of gelsolin. Again the addition of EGF to IFNalpha-treated transfected cells caused a recovery of the apoptosis. Notably, IFNalpha and EGF did not modify the expression of other molecules associated to cytoskeleton such as focal adhesion kinase and vinculin. In the same experimental conditions IFNalpha induced also gelsolin cleavage that occurred together with caspase-3 activation and release of cytochrome c. All these effects were antagonized by the exposure of IFNalpha-treated KB to 10 nM EGF for the last 12 h. Moreover, the specific inhibition of caspase-3 with 20 microM DEVD completely abrogated apoptosis and gelsolin cleavage induced by IFNalpha. In conclusion, our data are the first demonstration that IFNalpha can induce morphological cell changes that are peculiar of apoptosis onset through the caspase-3-mediated cleavage of gelsolin. Furthermore, we have demonstrated that EGF is able to antagonize these effects through the inhibition of caspase-3 activation.
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PMID:Apoptosis induced by interferon-alpha and antagonized by EGF is regulated by caspase-3-mediated cleavage of gelsolin in human epidermoid cancer cells. 1528 Oct 90

Imatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-alpha (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription-polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.
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PMID:The development of imatinib as a therapeutic agent for chronic myeloid leukemia. 1561 70

T-cell receptor (TCR) stimulation results in the recruitment and activation of the proteins ZAP70 and Lck. These two proteins have been implicated in signalling derived from interferon receptors, although their precise role in this independent pathway has not been determined fully. These observations raise a fundamental question of how a given protein in a cell can be involved in more than one signalling pathway, yet each pathway is able to produce a highly specific downstream response to its own stimulant. To maintain exclusivity of response, each pathway must isolate its component molecules chemically, spatially or dynamically from other prevailing pathways. To address this question, the proteins ZAP70 and Lck were investigated following stimulation of the interferon-alpha receptor and the TCR in T cells by two different extracellular stimulants: interferon-alpha and the anti-CD3 antibody, OKT3, respectively. We first demonstrate that ZAP70 plays a pivotal role in interferon-stimulated MAPK activation, and that the tyrosine residue at position 319 of ZAP70 is important for interferon-stimulated ERK activation. Translocation of both ZAP70 and Lck to the nucleus following interferon receptor stimulation is demonstrated for the first time. Fluorescence resonance energy transfer microscopy revealed a high degree of spatial localization of the ZAP70/Lck complex within the cell following IFNalpha stimulation, in contrast to a diffuse presence following the application of OKT3. The difference in the spatio-temporal localization of these proteins following stimulation may eliminate signal crosstalk, and could explain the differentiation of the specific downstream responses of these pathways.
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PMID:Distinct spatial and temporal distribution of ZAP70 and Lck following stimulation of interferon and T-cell receptors. 1621 25

More than 80% of newly diagnosed patients with chronic myeloid leukemia in chronic phase will achieve a complete cytogenetic response (CCR) with the standard dose of 400 mg imatinib daily. The probability of progression free survival is tightly correlated with the level of response, approaching 100% in those patients who achieve a reduction of BCR-ABL mRNA by at least 3-log at 12 months. High Sokal risk predicts poorer outcome, but on-treatment response parameters generally override pretherapeutic prognostic variables. Standard disease monitoring includes full blood counts, cytogenetics and quantitative RT-PCR for BCR-ABL mRNA but must be tailored to the level of response attained by a given patient. Conservative therapeutic milestones include a complete hematologic response at 3 months, a minor cytogenetic response at 6, a major cytogenetic response at 12 and CCR at 18, but a more aggressive approach may be justified in specific circumstances. Failure to achieve any of these milestones should trigger a re-assessment of the therapeutic strategy. Most patients with CCR remain positive by RT-PCR, and discontinuation of drug is usually followed by relapse, suggesting that imatinib fails to eradicate leukemic stem cells. The mechanisms underlying disease persistence are not well understood. Evidence is accumulating that early therapy intensification using high doses of imatinib (800 mg daily) or imatinib in combination with cytarabine or interferon-alpha may induce higher rates of RT-PCR negativity. Large studies will be required to determine whether this translates into improved progression free and overall survival.
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PMID:Management of early stage disease. 1630 77


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