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

Chronic myeloid leukemia cells contain a constitutively active Bcr-Abl tyrosine kinase, the target protein of Gleevec (STI571) phenylaminopyrimidine class protein kinase inhibitor. Here we provide evidence for metabolic phenotypic changes in cultured K562 human myeloid blast cells after treatment with increasing doses of STI571 using [1,2-13C2]glucose as the single tracer and biological mass spectrometry. In response to 0.68 and 6.8 microm STI571, proliferation of Bcr-Abl-positive K562 cells showed a 57% and 74% decrease, respectively, whereas glucose label incorporation into RNA decreased by 13.4% and 30.1%, respectively, through direct glucose oxidation, as indicated by the decrease in the m1/Sigma(m)n ratio in RNA. Based on the in vitro proliferation data, the IC50 of STI571 in K562 cultures is 0.56 microm. The decrease in 13C label incorporation into RNA ribose was accompanied by a significant fall in hexokinase and glucose-6-phosphate 1-dehydrogenase activities. The activity of transketolase, the enzyme responsible for nonoxidative ribose synthesis in the pentose cycle, was less affected, and there was a relative increase in glucose carbon incorporation into RNA through nonoxidative synthesis as indicated by the increase in the m2/Sigma(m)n ratio in RNA. The restricted use of glucose carbons for de novo nucleic acid and fatty acid synthesis by altering metabolic enzyme activities and pathway carbon flux of the pentose cycle constitutes the underlying mechanism by which STI571 inhibits leukemia cell glucose substrate utilization and growth. The administration of specific hexokinase/glucose-6-phosphate 1-dehydrogenase inhibitor anti-metabolite substrates or competitive enzyme inhibitor compounds, alone or in combination, should be explored for the treatment of STI571-resistant advanced leukemias as well as that of Bcr-Abl-negative human malignancies.
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PMID:Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells. 1148 2

Imatinib (STI571, Glivec) is a small molecule drug selected for its ability to inhibit the Bcr-Abl kinase, the pathogenic molecular abnormality in chronic myelogenous leukemia (CML). It also is an efficient inhibitor of the Kit and platelet-derived growth factor receptor tyrosine kinases. In vitro studies have demonstrated that this drug potently inhibits proliferation and induces apoptosis of cells that depend on activation of these kinases. Phase I clinical studies have demonstrated remarkable activity against CML. However, these studies, as well as a variety of experimental models, have suggested that clinical resistance to STI571 could develop. The mechanisms for the development of this resistance will be discussed along with the potential for circumventing STI571 resistance by combining it with traditional anti-neoplastic agents.
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PMID:Mechanisms of resistance to imatinib (STI571) and prospects for combination with conventional chemotherapeutic agents. 1151 48

The tyrosine kinase inhibitor imatinib (STI571, Glivec) blocks the activity of the BCR/ABL oncogene and induces hematologic remissions in the majority of patients with chronic myeloid leukemia (CML). Glivec is an aminopyrimidine derivative that interacts with the ATP-binding site within the kinase domain of ABL and several other tyrosine kinases, including c-KIT, PDGF beta receptor, and ARG. The compound is currently in phase III clinical trials. Although patients with chronic phase CML have been found to develop drug resistance only rarely so far, patients in more advanced phases of the leukemia develop resistance frequently. The available information on Glivec resistance will be reviewed.
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PMID:Mechanisms of resistance imatinib (STI571) in preclinical models and in leukemia patients. 1151 49

ASCO 2001 was a banner year for innovative systemic therapy for sarcomas. Imatinib mesylate (STI571, Gleevec) shows clear activity not only in chronic myelogenous leukemia, for which the drug received Food and Drug Administration approval, but also in gastrointestinal stromal tumors as well, by virtue of imatinib mesylate binding to the abl, kit, and platelet-derived growth factor receptor tyrosine kinases. Ecteinascidin-743 (ET-743) demonstrates activity against a fraction of other soft-tissue sarcomas. Gemcitabine-based regimens show at least some activity against a subset of soft-tissue sarcomas. Given the lack of new agents for sarcoma therapy since the development of ifosfamide, these studies give hope that the term "effective systemic therapy for sarcoma" might become a reality.
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PMID:Sarcoma. 1152 51

The tyrosine kinase inhibitor, imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) showed significant antileukemic activity with minimal toxicity in preclinical studies. Based on these data, a phase I clinical trial was conducted in patients with chronic myeloid leukemia (CML) who failed other treatment options. Once therapeutic doses were attained, 53 of 54 patients (98%) in the chronic phase achieved hematologic remissions. With prolonged therapy of 2 to 5 months duration, a growing percentage of patients achieved cytogenetic responses. Imatinib mesylate also has activity as a single agent in CML blast crisis and in patients with Ph(+) acute lymphocytic leukemia (ALL). Although responses tend not to be durable, 20% of patients with myeloid blast crisis are in continuous remission for periods up to 1 year. Ongoing clinical studies are directed at optimizing the use of imatinib mesylate.
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PMID:Signal transduction inhibition: results from phase I clinical trials in chronic myeloid leukemia. 1152 96

The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) blocks the constitutively activated Bcr-Abl tyrosine kinase that is characteristic of chronic myeloid leukemia (CML). Molecular analysis for the presence of residual Bcr-Abl-positive cells in patients with a cytogenetic response following treatment with imatinib mesylate reveals that some patients have undetectable disease using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assays capable of detecting 1 in 10(5) Philadelphia chromosome-positive (Ph(+)) cells. To examine whether the leukemia is still Bcr-Abl-dependent in patients who have responded to imatinib mesylate but have relapsed, a quantitative assay that directly measures enzymatic activity of Bcr-Abl toward one of its major signaling substrates has been developed. This assay allows monitoring both of the imatinib mesylate sensitivity of patient cells in vitro, and of the endogenous inhibition of Bcr-Abl kinase activity during imatinib mesylate treatment and relapse. Studies show that imatinib mesylate resistance is associated with restored activation of the Bcr-Abl signal transduction pathway in the majority of cases, indicating that Bcr-Abl remains a valid target for therapeutic intervention. Understanding resistance mechanisms of Ph(+) leukemia to imatinib mesylate will allow design of therapies to overcome such barriers to efficacy.
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PMID:Molecular studies in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. 1152 97

The cytokine interferon-alfa (IFN-alpha) has substantial activity in chronic myeloid leukemia (CML) and is the nontransplant standard of care for chronic-phase disease. When used as front-line therapy, IFN-alpha induces a state of tumor dormancy and delays progression to advanced phase. Unfortunately, IFN-alpha is associated with substantial toxicity at therapeutic doses. The introduction of pegylated IFN-alpha (PEG-IFN-alpha), a modified form of the protein that permits weekly administration, may alleviate some of the problems observed with IFN-alpha. Combination regimens of IFN-alpha with other drugs such as cytarabine (Ara-C) appear to enhance efficacy and are currently under investigation. The tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) also is efficacious in chronic-phase CML, with a low toxicity profile. However, its potential to cure CML remains unknown even though it achieves frequent cytogenetic responses. To enhance treatment outcome, a combination of IFN-alpha and imatinib mesylate therapies is proposed. Low-dose IFN-alpha may be given after imatinib mesylate-induced remission as a specific immune stimulant to consolidate the remission. Recent data showing a possible additive effect of imatinib mesylate and IFN-alpha suggest that concurrent use of these agents may also be more effective than single use, particularly in advanced stages of CML where imatinib mesylate has activity but resistance develops.
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PMID:Interferon-alfa-based treatment of chronic myeloid leukemia and implications of signal transduction inhibition. 1152 98

The ability of allogeneic bone marrow or blood stem cell transplantation (SCT) to induce long-term remission or cure of chronic myeloid leukemia (CML) is well established. However, the use of this treatment is limited by the availability of suitable human leukocyte antigen (HLA) identical siblings or matched unrelated donors (MUD). As a consequence only a relatively small proportion of CML patients are eligible for a transplant, and of these not all are cured. The preliminary results of trials using the new Bcr-Abl kinase inhibitor imatinib mesylate (formerly CGP57-148B, STI571, Gleevec) to treat CML are very encouraging. However, a number of important questions cannot yet be answered: Can imatinib mesylate induce durable molecular remissions? Can the drug prolong survival in comparison with other nontransplant treatments? and, can it actually cure CML patients? Until answers to these questions are available, SCT and use of interferon-alfa (IFN-alpha) alone or in combination (perhaps with imatinib mesylate) must remain major therapeutic options. I summarize here the advantages and disadvantages associated with currently available therapy. I review three different approaches to initial treatment of the CML patient diagnosed in chronic phase, and make a tentative recommendation for one of these options. It is likely that the situation will alter considerably in the foreseeable future.
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PMID:Implications of imatinib mesylate for hematopoietic stem cell transplantation. 1152 99

Chronic myeloid leukemia (CML) is probably the best understood human malignancy at the molecular level, but among the hardest to explain to patients concerning appropriate treatment options. At present, we do not know the long-term outcome of promising new therapies such as the tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) (formerly STI571) and nonmyeloablative transplants. There is also no reliable way to predict which patients will respond to a particular therapy. The development of methods to predict therapeutic response will be of major benefit to patients, and the newly emerging science of gene array analysis may provide such a tool. In this context, given the proven likelihood of cure with allogeneic transplantation and the negative effects of delay, in Seattle we continue to suggest transplantation as the initial form of therapy for patients below age 55 years with matched sibling donors. For patients without matched donors below the age of 40, we would suggest an unrelated donor search and only proceed directly to transplant for those with allele-level matches. For younger patients without matches and those aged 40 to 55, an initial trial of imatinib mesylate might be preferred. For patients over age 55 with CML, initial therapy with imatinib mesylate, possibly an interferon-containing regimen or nonmyeloablative allogeneic transplantation may be considered.
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PMID:Perspectives on the future of chronic myeloid leukemia treatment. 1152

Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.
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PMID:Tyrosine kinase inhibitors: from rational design to clinical trials. 1160 31


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