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

Imatinib mesylate (Gleevec, Glivec, STI571) is a targeted, small molecule inhibitor of the oncogenes, BCR/ABL and c-KIT, and has striking antitumor activity in patients with chronic myelogenous leukemia or gastrointestinal stromal tumors. We have developed a liquid chromatographic-electrospray ionization mass spectrometric (LC-MS) method for quantifying imatinib and its main metabolite (CGP 74588) in plasma. The assay uses deuterated imatinib as the internal standard; acetonitrile deproteination; a Phenomenex Luna C(18)(2) (5 microm, 50 x 4.6 mm) reversed-phase analytical column; a gradient mobile phase of 0.1% formic acid in methanol and water; and mass spectrometric detection using electrospray positive mode electron ionization. The assay has a lower limit of quantitation (LLOQ) of 30 ng/ml and is linear between 30 and 10000 ng/ml for both imatinib and CGP 74588. We demonstrated the suitability of this assay for imatinib using it to quantify the concentrations of imatinib and CGP 74588 in plasma of a patient given a 200-mg dose of imatinib orally. We believe that this LC-MS assay should be an important tool for future pharmacokinetic studies of imatinib.
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PMID:Liquid chromatographic-mass spectrometric assay for quantitation of imatinib and its main metabolite (CGP 74588) in plasma. 1279 63

Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breakpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt's lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBP alpha, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia.
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PMID:[Oncogenes and leukemia: history and perspectives]. 1283 14

Elevated expression of multidrug efflux pumps such as P-glycoprotein (Pgp) have been associated with resistance to cytotoxic drugs used in the treatment of leukemias and other cancers. Imatinib mesylate (STI-571 or Gleevec) is a potent inhibitor of the BCR/ABL and c-KIT tyrosine kinases. It has displayed considerable efficacy in treatment of patients with Philadelphia-positive acute lymphoblastic leukemia and chronic myelogenous leukemia and those with gastrointestinal stromal tumors (GISTs). However, recently imatinib-resistant relapse has emerged as a significant problem. Although a major cause of resistance appears to be point mutation in the kinase domain of the target enzyme, the potential contribution of elevated multidrug efflux activity has not been systematically evaluated. The imatinib-sensitive human leukemic cell line K562, which is dependent on the activity of BCR/ABL for survival and growth, provides a convenient system for evaluating modulation of drug activity. By expressing Pgp at high levels in these cells, we have demonstrated that this pump provides minimal protection against cell growth inhibition and apoptosis induced by imatinib. In contrast, overexpression of Bcl-xL, which blocks apoptosis, resulted in partial protection against the drug. We conclude that Pgp up-regulation is not likely to be a significant contributor to imatinib resistance.
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PMID:Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro. 1288 21

Two cases of atypical chronic myeloid leukaemia (CML) carrying the t(4;22)(q12;q11) translocation involving the breakpoint cluster region (BCR) and platelet-derived growth factor alpha receptor (PDGFRA) genes have been recently characterized. We report a third case of atypical CML with the same translocation but with a distinct breakpoint fusing BCR exon 1 with PDGFRA exon 13. The patient had a clinical presentation of CML with progressive transformation in B-cell acute lymphoblastic leukaemia. The involvement of PDGFRA led us to treat the patient with the small organic compound imatinib mesylate/STI571 (Glivec) that blocks the ATP binding site of tyrosine kinases such as Abelson, KIT and platelet-derived growth factor receptors. The patient subsequently achieved a rapid clinical and molecular response clearly demonstrating, for the first time, that Glivec is active against PDGFRA in vivo. Therefore, our study expands the list of Glivec targets and has direct biological and also clinical implications.
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PMID:Chronic myeloproliferative disorders with rearrangement of the platelet-derived growth factor alpha receptor: a new clinical target for STI571/Glivec. 1294 19

Over the past few years, a number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The leading drug in this area is imatinib mesylate, which targets ABL, KIT and PDGFR. It has been remarkably effective in the treatment of chronic myeloid leukaemia, although resistance remains a significant problem. From the imatinib experience in this setting, we present some principles of kinase inhibition that may have more general applicability in targeted anticancer therapy. It is clear that the identification of appropriate targets (activated kinases) and monitoring levels of response (to recognise emerging resistance) are essential to optimise clinical management.
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PMID:Cancer treatment with kinase inhibitors: what have we learnt from imatinib? 1471 Jan 99

Imatinib, a specific inhibitor of the Abl, Kit and platelet-derived growth factor receptor (PDGFR) tyrosine kinases, is effective in all phases of chronic myelogenous leukemia. While responses in chronic phase are usually durable, resistance frequently develops in patients with advanced disease after an initial response. Several mechanisms of resistance have been demonstrated in vivo, including mutations in the BCR-ABL kinase domain and amplification of the BCR-ABL gene. We analyzed cytogenetics and screened for mutations of the BCR-ABL kinase domain as well as the activation loops of KIT and PDGFRA and B in 49 patients with CML or Ph-positive acute lymphoblastic leukemia with resistance to imatinib. Mutations in the kinase domain of BCR-ABL were detected in 51.6% of patients with secondary resistance but not in patients with primary resistance. Three of these mutations have not been described before (T315D, F359D and D276G). By contrast, KIT and PDGFRA and B were consistently wildtype. Clonal evolution prior to imatinib was present in 68.8% of patients with primary resistance and in 45.5% with secondary resistance. Additional cytogenetic aberrations developed in 18.2% of patients at the time of relapse. Our results confirm the high frequency of BCR-ABL kinase domain mutations in patients with secondary resistance to imatinib and exclude mutations of the activation loops of KIT, PDGFRA and PDGFRB as possible causes of resistance in patients without ABL mutations.
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PMID:High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. 1474 31

The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases. Analysis of CML patients resistant to BCR-ABL suppression by Imatinib mesylate coupled with the crystallographic structure of ABL complexed to this inhibitor have shown how structural mutations in ABL can circumvent an otherwise potent anticancer drug. The successes and limitations of Imatinib mesylate hold general lessons for the development of alternative molecular targeted therapies in oncology.
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PMID:The BCR-ABL story: bench to bedside and back. 1503 71

We report a case of BCR-ABL-negative atypical chronic myeloid leukemia (CML) with translocation t(4;22) (q12;q11.2) juxtaposing the breakpoint cluster region (BCR) and platelet-derived growth factor receptor-alpha (PDGFRA) genes. The patient was a 57-year-old man with a history of stage IV diffuse large B-cell lymphoma, status post-6 cycles of combination chemotherapy in 1999, who presented in August 2002 with enlarged lymph nodes, anemia, and marked leukocytosis (50 x 10(9) g/dL) consistent with a myeloproliferative disorder (MPD). A bone marrow biopsy showed granulocytic hyperplasia, neutrophilia, and mild eosinophilia. Initial cytogenetic evaluation by interphase FISH for BCR-ABL, to rule out a translocation 9;22, showed a variant signal pattern consistent with rearrangement of BCR at 22q11.2, but not ABL at 9q34. Analysis of the patient's cDNA by polymerase chain reaction (PCR) for BCR-ABL was negative. Cytogenetic analysis showed an abnormal karyotype with rearrangement of chromosomes 4 and 22. PCR amplification and subsequent sequence analysis demonstrated an in-frame 5'-BCR/3'-PDGFRA fusion in the patient's cDNA. PDGFRA encodes a receptor tyrosine kinase and shares structural and organizational homology with the KIT and CSf1R receptor genes. However, although the incidence of MPD involving translocations of PDGFRB has been well established, to our knowledge there are only two previous reports describing a BCR-PDGFRA fusion gene, in 3 patients diagnosed with atypical CML. Here, we report the molecular and cytogenetic characterization of a patient with BCR-PDGFRA-positive MPD who had a complete hematologic response after treatment with imatinib mesylate.
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PMID:Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia. 1503 67

Imatinib mesylate is remarkably effective in treating chronic myeloid leukemia and metastatic gastrointestinal stromal tumors. Meanwhile, anaplastic thyroid carcinoma (ATC) remains a fatal malignancy for which there are currently no effective curative interventions. In chronic myeloid leukemia and gastrointestinal stromal tumors, imatinib inhibits the constitutive tyrosine kinase activity of BCR-ABL and c-KIT, respectively. Reports suggest that imatinib may also be effective against ABL and platelet-derived growth factor receptor kinase-dependent pathological conditions. These mechanisms provide a wide scope of possible clinical applications for the drug. Potentially, diseases instigated by constitutive kinase activity that can be inhibited with imatinib should be treatable with this drug. We evaluated the effects of imatinib on the viability, cycling, and tyrosine phosphorylation of ATC cells in vitro. Our data indicate that imatinib has negligible antineoplastic activity against ATC cell lines within established therapeutically useful concentrations. No constitutive kinase activity was detected in these cell lines that could be exploited as a therapeutic target by imatinib. We conclude that imatinib mesylate monotherapy would not be effective in ATC patients. Current preclinical data do not warrant future clinical studies of imatinib monotherapy for ATC.
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PMID:Imatinib mesylate (gleevec; STI571) monotherapy is ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro. 1512 30

Imatinib (Gleevec) exemplifies the successful development of a rationally designed, molecularly targeted therapy for the treatment of a specific cancer. This article reviews the identification of the BCR-ABL tyrosine kinase as a therapeutic target in chronic myeloid leukemia and the steps in the development of an agent to specifically inactivate this abnormality. The clinical trials results are reviewed along with a description of resistance mechanisms. As imatinib also inhibits the tyrosine kinase activity of KIT and the platelet-derived growth factor receptors, the extension of imatinib to malignancies driven by these kinases will be described. Issues related to clinical trials of molecularly targeted agents are discussed, including patient and dose selection. Last, the translation of this paradigm to other malignancies is explored.
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PMID:Imatinib as a paradigm of targeted therapies. 1532 87


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