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)

To prevent the resistance to Glivec in patients with chronic myelogenous leukaemia (CML), it is necessary to get a good understanding of its potential mechanisms. The present hypothesis accents on the mechanisms whereby Bcr-Abl tyrosine kinase remains inhibited by Glivec, but alternative signalling pathways become activated-the potential reason associates with activation of telomerase after long-term treatment with Glivec and recovery of cell proliferation and immortality. The hypothesis is based on the observations about differences in telomere dynamics and telomerase activity between chronic and blast phases of CML patients, as well as about the potential effect of Glivec on the cross-talk between telomerase, Bcr-Abl tyrosine kinase and protein kinase C family-key enzymes in CML. It proceeds from recently published data, demonstrating that protein kinase C activates and c-Abl tyrosine kinase inhibits telomerase. During optimization of chemical structure, Glivec loose its effect on protein kinase C and enhances the effect on Bcr-Abl tyrosine kinase, resulting in a high potential to activate telomerase indirectly through its effect on both kinases. Experimental preclinical data are given in confirmation of this hypothesis.
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PMID:Cross-talk between Bcr-Abl tyrosine kinase, protein kinase C and telomerase-a potential reason for resistance to Glivec in chronic myelogenous leukaemia. 1459 45

Imatinib mesylate (IM, STI 571, Glivec) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT-PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [rHu-G-CSF; 10 micro g/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11.5/ microl (range 0-108/ microl), and 43/58 (74%) patients underwent a median of two (range 1-3) apheresis procedures. A median dose of 2.1 x 10(6)/kg CD34+ cells (range 0.1-6.5 x 10(6)/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR-ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 x 10(6)/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph- CD34+ cells from IM-treated patients in CCR is possible using rHu-G-CSF alone.
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PMID:Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission. 1461 10

Chronic myeloid leukemia is characterized by the Philadelphia chromosome translocation that causes expression of Bcr-Abl, a deregulated tyrosine kinase. Imatinib mesylate (STI571, Gleevec), a therapeutically used inhibitor of Bcr-Abl, causes apoptosis of Bcr-Abl-positive cells. In the leukemia cell line K562, we observed spontaneous resistance to imatinib at very low frequencies when cells were exposed to the drug (1 micro M) for more than 4 weeks. Surprisingly, in the presence of erythropoietin (Epo), K562 cells were temporarily able to sustain proliferation in the presence of imatinib, and imatinib-resistant clones could be isolated with high frequencies. From such imatinib-resistant, Epo-dependent clones, sublines could be established that were resistant to imatinib in the absence of Epo. Mitogen-activated protein (MAP) kinase activity was inhibited by imatinib treatment but could be partially restored by Epo. Inhibition of MAP kinase or phosphatidylinositol 3-kinase blocked the protective effect of Epo. The data suggest that K562 cells acquire factor dependency under imatinib/Epo treatment, allowing them to escape from imatinib-induced, immediate cell death. This pool of cells provides the basis for the outgrowth of imatinib-resistant clones of unlimited proliferative capacity. Thus, Epo, an endogenous regulator of hematopoiesis, promotes the development of resistance to imatinib.
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PMID:Erythropoietin promotes resistance against the Abl tyrosine kinase inhibitor imatinib (STI571) in K562 human leukemia cells. 1463 69

Imatinib (Glivec), STI571) is an intracellular acting drug that demonstrates high activity against BCR-ABL-positive chronic myelogenous leukemia (CML) or acute lymphoblastic leukemia (ALL). However, many patients, especially with advanced disease, develop drug resistance. Here, we show by a novel high-performance liquid chromatography-based method that intracellular levels of imatinib decrease in P-glycoprotein (Pgp)-positive leukemic cells. In a model of K562 cells with gradually increasing Pgp expression, a Pgp-dependent decline of intracellular imatinib levels was observed. Decreased imatinib levels were associated with a retained phosphorylation pattern of the Bcr-Abl target Crkl and loss of effect of imatinib on cellular proliferation and apoptosis. The modulation of Pgp by cyclosporin A (CSA) readily restored imatinib cytotoxicity in these cells. Finally, we provide first data showing a biological effect of Pgp modulation in the imatinib treatment of a patient with BCR-ABL-positive ALL. MDR1 overexpression must therefore be considered as an important clinical mechanism in the diversity of resistance development to imatinib treatment.
Leukemia 2004 Mar
PMID:P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. 1472 52

Chronic myelogenous leukemia represents 7-20% of all leukemia cases, with a worldwide incidence projected at less than one to two per 100,000 people. Approximately 85% of patients are diagnosed with chronic-phase chronic myelogenous leukemia and up to 40% are asymptomatic. Treatment strategies include chemotherapy, interferon-alpha therapy, transplantation (bone marrow/stem cell transplant) and imatinib mesylate (Gleevec), with the impact of treatment best realized during the chronic phase of the disease. Only transplantation has been clinically demonstrated to eradicate the Philadelphia chromosome, alter the natural course of the disease and cure patients diagnosed with chronic myelogenous leukemia. Interferon-alpha is currently considered for first-line treatment, however, the recent introduction of targeted therapy may change clinical practice. Ongoing research focused on new drug combinations and target therapies may eventually expand the armamentarium available to cure this disease.
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PMID:Clinical and epidemiologic burden of chronic myelogenous leukemia. 1474 60

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.
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PMID:Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. 1530 31

Targeted protein-tyrosine kinase inhibitors (PTKIs) comprise a new, rapidly evolving class of low molecular weight anticancer drugs. Two members of this class, imatinib (Gleevec) and gefitinib (Iressa), are currently approved for market use in the United States. This review discusses the scientific history behind these two PTKI drugs, including the role of the targeted kinase in cancer etiology, the biochemistry of selective inhibition, the evaluation of clinical efficacy, and the mechanisms whereby drug resistance has emerged. Other PTKIs undergoing clinical evaluation are also described, including epidermal growth factor receptor kinase inhibitors (erlotinib, PKI166, and CI-1033) and PTKIs designed to disrupt tumor vascularization (SU5416, SU6668, SU11248, PTK787, and ZD6474). How might one apply current knowledge to the efficient development of new agents that would target as-yet-unexploited oncogenic PTKs such as chimeric anaplastic leukemia kinases or Janus kinases? Ideally, the targets should contain structurally distinct drug interaction epitopes, although it is not necessary that these epitopes be unique to a single target, because effective drugs may inhibit multiple kinases involved in an oncogenic process. Oral availability is a highly desirable feature because daily oral administration can maintain a sustained efficacious plasma concentration, whereas intermittent parenteral administration may not. Perhaps most importantly, one must verify the presence of an appropriate molecular target on a case-by-case basis before selecting a patient for PTKI therapy. Thus, the development of molecularly targeted diagnostic tools will be crucial to the ultimate success of molecularly targeted PTKI therapy.
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PMID:Emerging roles of targeted small molecule protein-tyrosine kinase inhibitors in cancer therapy. 1497 53

Sweet's syndrome (acute febrile neutrophilic dermatosis) is characterized by an acute onset of erythematous plaques, fever, and leukocytosis. This syndrome has been reported to be associated with leukemia including chronic myelogenous leukemia (CML). Sweet's syndrome seen in patients with leukemia is usually associated with active and/or refractory disease. Imatinib Mesylate (STI-571, Gleevec) is widely used for therapy of CML. In this case report, CML cell infiltration of the skin was documented by fluorescence in situ hybridization (FISH) analysis in a patient with chronic-phase CML on Imatinib Mesylate (STI-571, Gleevec), who was at the time in molecular remission.
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PMID:Sweet's syndrome with CML cell infiltration of the skin in a patient with chronic-phase CML while taking Imatinib Mesylate. 1560 74

Imatinib mesylate (STI571), a specific inhibitor of the BCR-ABL tyrosine kinase, exhibits potent antileukemic effects in vitro and in vivo. Despite the well established role of STI571 in the treatment of chronic myelogenous leukemia, the precise mechanisms by which inhibition of BCR-ABL tyrosine kinase activity results in generation of antileukemic responses remain unknown. In the present study we provide evidence that treatment of CML-derived BCR-ABL-expressing leukemia cells with STI571 results in activation of the p38 mitogen-activated protein (MAP) kinase signaling pathway. Our data indicate that STI571 induces phosphorylation of the p38 and activation of its kinase domain, in KT-1 cells and other BCR-ABL-expressing cell lines. We also identify the kinases MAP kinase-activated protein kinase-2 and Msk1 as two downstream effectors of p38, activated during inhibition of BCR-ABL activity by STI571. Importantly, pharmacological inhibition of p38 reverses the growth inhibitory effects of STI571 on primary leukemic colony-forming unit granulocyte/macrophage progenitors from patients with CML. Altogether, our data establish that activation of the p38 MAP kinase signaling cascade plays an important role in the generation of the effects of STI571 on BCR-ABL-expressing cells. They also suggest that, in addition to activation of mitogenic pathways, BCR-ABL promotes leukemogenesis by suppressing the function of growth inhibitory signaling cascades.
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PMID:Role of the p38 mitogen-activated protein kinase pathway in the generation of the effects of imatinib mesylate (STI571) in BCR-ABL-expressing cells. 1505 60

Imatinib mesylate has become an effective agent for the treatment of chronic myeloid leukemia (CML). However, the development of drug resistance has led to examination of combination therapies. In this study, we investigated the effects of combining imatinib with immunotherapy against a murine bcr-abl(+) leukemia, 12B1. We have previously shown that multiple chaperone proteins may be enriched into a vaccine form from tumor cell lysates by a free-solution isoelectric focusing method. We refer to these vaccines as chaperone-rich cell lysates (CRCLs) and have found that they are potent immunologic agents against a variety of murine tumors, including 12B1. We now demonstrate that the combination of imatinib with dendritic cells loaded with 12B1-derived CRCL yields high activation of anti-12B1-specific T cells and potent antitumor activity, resulting in tumor-free survival in up to 63% of mice with bcr-abl(+) 12B1 tumors. Our data suggest that immunotherapy can be effectively combined with imatinib for the treatment of CML.
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PMID:Imatinib mesylate effectively combines with chaperone-rich cell lysate-loaded dendritic cells to treat bcr-abl+ murine leukemia. 1506 90


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