Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gleevec, which is an inhibitor of the bcr/abl tyrosine kinase, has been a remarkable success for the treatment of chronic myelogenous leukemia (CML). However, a significant proportion of patients chronically treated with Gleevec develop resistance. Here we describe the activity of a natural small molecular compound, berbamine from plant Berberis amurensis that can selectively induce cell death of both Gleevec-sensitive and -resistant Ph+ CML cells. The IC50 values of berbamine were 8.80 microg/ml in Gleevec-sensitive Ph+ CML cells, 11.34 microg/ml in Gleevec-resistant Ph+ CML cells, and 54.40 microg/ml in Ph- KG-1 cells, respectively. Similarly, berbamine was also found to display a selective anti-proliferative activity of primary leukemia cells from CML patients, and its IC50 values were 4.20-10.50 microg/ml in primary CML cells, and 185.20 microg/ml in normal bone marrow cells, respectively. More importantly, our studies demonstrate that berbamine down-regulates p210bcr/abl oncoprotein level, and induces apoptosis of bcr/abl+ cells through caspase-3-dependent pathway. These data suggest that berbamine might be a novel bcr/abl inhibitor with potent anti-leukemia activity.
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PMID:Berbamine: a novel inhibitor of bcr/abl fusion gene with potent anti-leukemia activity. 1602 22

Hungary is among the leading countries in Europe regarding the mortality and incidence of different types of tumours. Therefore, developing effective therapies is especially important in this country. Investigation of tumour formation and progression on the molecular level is required to develop possible therapeutical targets. Such targets can be proteins with tumour suppressor function, which inhibit intracellular signalling processes that under pathophysiological conditions can lead to uncontrolled cell proliferation and tumour formation. Protein e3B1/Abi-1, which belongs to the family of Abl-interactors, was isolated recently as a possible tumour suppressor. As a partner of Abl kinase, its role has been investigated in the development and progression of some types of leukemias, however, more and more experimental data suggest that it is a general suppressor protein. According to the latest results, e3B1/Abi-1 via the Ras small G-protein has an essential role in the regulation of cell proliferation, and via Rac activation it can affect actin remodelling, cell adhesion and migration. Cell proliferation is important in tumour development, while cell adhesion and migration has a role in metastasis formation. The latest results showed deletion of the gene encoding protein e3B1/Abi-1 in prostate cancer, loss of its expression during the progression of some types of leukemias, and there are data on the effect of imatinib mesylate (Gleevec or outside USA Glivec, Novartis), one of the newest drugs in leukemia treatment, on the phosphorylation of e3B1/Abi-1 as well. This report summarizes the data published on protein e3B1/Abi-1, with special interest in practical implications.
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PMID:[The role of EGF receptor-dependent e3B1/Abi1 protein as a tumor suppressor protein in malignant tumors]. 1602 98

BCR/ABL-kinase mutations frequently mediate clinical resistance to the selective tyrosine kinase inhibitor Imatinib mesylate (IM, Gleevec). However, mechanisms that promote survival of BCR/ABL-positive cells before clinically overt IM resistance occurs have poorly been defined so far. Here, we demonstrate that IM-treatment activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTor)-pathway in BCR/ABL-positive LAMA-cells and primary leukemia cells in vitro, as well as in a chronic phase CML patient in vivo. In fact, PI3K/Akt-activation critically mediated survival during the early phase of IM resistance development before manifestation of BCR/ABL-dependent strong IM resistance such as through a kinase mutation. Accordingly, inhibition of IM-induced Akt activation using mTor inhibitors and Akt-specific siRNA effectively antagonized development of incipient IM-resistance in vitro. In contrast, IM-resistant chronic myeloid leukemia (CML) patients with BCR/ABL kinase mutations (n=15), and IM-refractory BCR/ABL-positive acute lymphatic leukemia patients (n=2) displayed inconsistent and kinase mutation-independent autonomous patterns of Akt-pathway activation, and mTor-inhibition overcame IM resistance only if Akt was strongly activated. Together, an IM-induced compensatory Akt/mTor activation may represent a novel mechanism for the persistence of BCR/ABL-positive cells in IM-treated patients. Treatment with mTor inhibitors may thus be particularly effective in IM-sensitive patients, whereas Akt-pathway activation variably contributes to clinically overt IM resistance.
Leukemia 2005 Oct
PMID:Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. 1613 69

The selective tyrosine kinase inhibitor imatinib (Glivec; Novartis International, Basel, Switzerland, http://www.glivec.com/content/home.jsp) is increasingly used for the treatment of Philadelphia chromosome-positive leukemias and other malignancies. In principle, the drug is well tolerated and clinical side effects are mostly moderate. However, it was shown that imatinib can affect the function of normal, nonmalignant cells, resulting in myelosuppression in treated patients. Recently, it has been demonstrated that imatinib might affect mobilization, proliferation, and differentiation of hematopoietic progenitor cells while leaving hematopoietic stem cells unaffected. Furthermore, in several in vitro studies and animal models, it was demonstrated that imatinib can affect the function and differentiation of antigen-presenting cells and inhibit the effector functions of T lymphocytes. Moreover, the induction of specific cytotoxic T cells seems to be impaired in chronic myeloid leukemia (CML) patients treated with imatinib compared with patients receiving interferon-alpha. This is of importance because some of the therapeutic effects in the treatment of patients with CML are mediated by the induction of leukemia-specific T-cell responses. Further studies investigating the effects of imatinib on normal hematopoiesis are of interest as they might lead to a better understanding of the clinically observed side effects and also might help identify new therapeutic applications of the drug, possibly in Bcr-Abl-negative myeloproliferative disorders and potentially as an immunomodulatory agent.
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PMID:Effects of imatinib on normal hematopoiesis and immune activation. 1614 Aug 70

Donor lymphocyte infusions (DLI) have been the mainstay of treatment for chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (allo-SCT). Imatinib mesylate (IM) is also effective in these patients. However, advanced phase relapse (APRel) responds poorly with either treatment. To test the possibility that combinations of DLI and IM might be more effective, 37 patients with CML relapsing after allo-SCT between August 1994 and May 2004 were studied. Ten had molecular relapse (MRel), 14 hematological relapse (HRel) and 13 APRel. Thirteen received DLI, 9 IM and 11 DLI+IM. Four patients received DLI+IM but not concurrently. Thirty (81%) patients responded (actuarial survival and current leukemia-free survival of 80.6 +/- 6.7% and 69.1 +/- 7.7%). Of 30 patients, 26 are in molecular remission (MR), median follow-up of 1,226 days (range 249-3257) since relapse. Ten of 11 patients (including four with APRel) treated with DLI+IM achieved MR in 3 months and all are alive in MR. In contrast, only two of 22 treated with either modality (1/13 DLI and 1/9 IM) achieved MR at 3 months, 15 are alive, 11 in MR. Four patients receiving nonconcurrent DLI+IM are also alive in MR. In conclusion, DLI appears to synergize with IM to induce rapid and durable MR.
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PMID:Imatinib synergizes with donor lymphocyte infusions to achieve rapid molecular remission of CML relapsing after allogeneic stem cell transplantation. 1620 32

The Wnt signalling pathway can activate transcription of genes such as c-myc through beta-catenin. Here, we describe the protein breakpoint cluster region, Bcr, as a negative regulator of this pathway. Bcr can form a complex with beta-catenin and negatively regulate expression of c-Myc. Knockdown of Bcr by short interfering RNA relieves the block and activates expression of c-Myc. Expression of Bcr in the human colon carcinoma cell line HCT116, which has a high level of endogenous beta-catenin, leads to reduced c-Myc expression. The negative effect is exerted by the amino terminus of Bcr, which does not harbour the kinase domain. Bcr-Abl, the oncogene protein expressed in chronic myelogenous leukaemia (CML), does not bind to beta-catenin. It phosphorylates Bcr in the first exon sequence on tyrosines, which abrogates the binding of Bcr to beta-catenin. The inhibitor of the Bcr-Abl tyrosine kinase, STI-571 or Gleevec, a drug against CML, reverses this effect. Our data contribute to the understanding of Bcr as a tumour suppressor in the Wnt signalling pathway, as well as in CML.
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PMID:Bcr is a negative regulator of the Wnt signalling pathway. 1621 Oct 85

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

Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.
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PMID:Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells. 1633 89

A multicentric phase 2 study was conducted to determine the efficiency and the tolerance of imatinib mesylate in children with chronic myelogenous leukemia (CML) in advanced phase of the disease, in relapse after stem cell transplantation, or in case of failure to an interferon alpha-based regimen. In all, 30 children from eight European countries were enrolled. In 18 children assessable for hematologic response, imatinib mesylate induced complete hematologic response in eight (80%) of the 10 patients included in chronic phase and in six (75%) of eight enrolled in advanced phase of the disease with acceptable toxicity. In 27 patients assessable for cytogenetic response, imatinib mesylate induced disappearance of Philadelphia chromosome-positive bone marrow cells in 12 (60%) of 20 children included in chronic phase and in two (29%) of seven included in advanced phase. A reduction of the bcr-abl/abl ratio to less than 10(-4) was achieved in 11 (50%) of the children included in chronic phase. Estimated 12-month overall survival rate was 95% (95% CI, 87-100%) for the patients included in chronic phase and 75% (95%CI, 45-100%) for those enrolled in advanced phase. Imatinib mesylate is well tolerated and molecular remission can be achieved in children with CML.
Leukemia 2006 Feb
PMID:Imatinib mesylate is effective in children with chronic myelogenous leukemia in late chronic and advanced phase and in relapse after stem cell transplantation. 1634 Oct 42

Imatinib mesylate (STI571), a specific inhibitor of BCR/ABL tyrosine kinase, exhibits potent antileukemic effects in the treatment of chronic myelogenous leukemia (CML). However, the precise mechanism by which inhibition of BCR/ABL activity results in pharmacological responses remains unknown. BCR/ABL-positive human K562 CML cells resistant to doxorubicin (K562DoxR) and their sensitive counterparts (K562DoxS) were used to determine the mechanism by which the STI571 inhibitor may overcome drug resistance. K562 wild type cells and CCRF-CEM lymphoblastic leukemia cells without BCR/ABL were used as controls. The STI571 specificity was examined by use of murine pro-B lymphoid Baf3 cells with or without BCR/ABL kinase expression. We examined kinetics of DNA repair after cell treatment with doxorubicin in the presence or absence of STI571 by the alkaline comet assay. The MTT assay was used to estimate resistance against doxorubicin and Western blot analysis with Crk-L antibody was performed to evaluate BCR/ABL kinase inhibition by STI571. We provide evidence that treatment of CML-derived BCR/ABL-expressing leukemia K562 cells with STI571 results in the inhibition of DNA repair and abrogation of the resistance of these cells to doxorubicin. We found that doxorubicin-resistant K562DoxR cells exhibited accelerated kinetics of DNA repair compared with doxorubicin-sensitive K562DoxS cells. Inhibition of BCR/ABL kinase in K562DoxR cells with 1 microM STI571 decreased the kinetics of DNA repair and abrogated drug resistance. The results suggest that STI571-mediated inhibition of BCR/ABL kinase activity can affect the effectiveness of the DNA-repair pathways, which in turn may enhance drug sensitivity of leukemia cells.
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PMID:Imatinib mesylate (STI571) abrogates the resistance to doxorubicin in human K562 chronic myeloid leukemia cells by inhibition of BCR/ABL kinase-mediated DNA repair. 1638 76


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