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)

The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI-571 resistance, we performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all of the major mutations previously identified in patients and numerous others that illuminate novel mechanisms of acquired drug resistance. Structural modeling implies that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase to which STI-571 preferentially binds. This screening strategy is a paradigm applicable to a growing list of target-directed anti-cancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.
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PMID:Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. 1265 40

c-Abl is normally regulated by an autoinhibitory mechanism, the disruption of which leads to chronic myelogenous leukemia. The details of this mechanism have been elusive because c-Abl lacks a phosphotyrosine residue that triggers the assembly of the autoinhibited form of the closely related Src kinases by internally engaging the SH2 domain. Crystal structures of c-Abl show that the N-terminal myristoyl modification of c-Abl 1b binds to the kinase domain and induces conformational changes that allow the SH2 and SH3 domains to dock onto it. Autoinhibited c-Abl forms an assembly that is strikingly similar to that of inactive Src kinases but with specific differences that explain the differential ability of the drug STI-571/Gleevec/imatinib (STI-571) to inhibit the catalytic activity of Abl, but not that of c-Src.
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PMID:Structural basis for the autoinhibition of c-Abl tyrosine kinase. 1265 40

Imatinib (glivec), formerly known as STI571) effectively blocks the ATP-binding site of the bcr/abl fusion protein thereby inactivating selectively the tyrosine kinase activity of bcr/abl. Therefore, it is a promising drug in Philadelphia chromosome positive chronic myeloid leukemia showing high hematologic and cytogenetic response rates combined with a mild toxicity profile. Here we report two cases of squamous cell carcinoma of the skin, which appeared in the photo-exposed areas in two elderly patients treated for advanced chronic myeloid leukemia with imatinib. The role of chemotherapy, chronic sun exposure and of possible additional risk factors such as human papillomavirus infection is discussed.
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PMID:Squamous cutaneous epithelial cell carcinoma in two CML patients with progressive disease under imatinib treatment. 1265 46

BCR-ABL fusion proteins exhibit elevated tyrosine kinase activity and transforming properties. Genetic and biochemical data suggest that Ras activation plays a central role in leukemogenic transformation by BCR-ABL. Imatinib (Novartis, Basel, Switzerland) is a potent and selective inhibitor of the tyrosine kinase activity of BCR-ABL. Although imatinib has shown promise against Ph-positive leukemia in human clinical trials, the emergence of imatinib resistance in patients with acute forms of Ph-positive leukemia has highlighted the need for combination chemotherapy to eradicate this disease. In the present study, combined use of a farnesyl transferase inhibitor, SCH66336 (lonafarnib), with the antileukemic agents imatinib, daunorubicin, cytosine arabinoside, or etoposide was investigated by cell proliferation assays. The effects of the combination of SCH66336 and imatinib were also investigated by apoptosis assay and colony-forming assay. In proliferation assays with BCR-ABL-expressing cells, combination of SCH66336 with imatinib or cytosine arabinoside showed enhanced antiproliferative activity, whereas combination of SCH66336 with daunorubicin or etoposide demonstrated an antagonistic effect. The combination of imatinib plus SCH66336 more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. SCH66336 combined with imatinib was shown to induce apoptosis in imatinib-resistant BCR-ABL cells by flow cytometric analysis with an APO2.7 monoclonal antibody. These results indicate that SCH66336 is a promising candidate for use in the treatment of patients with imatinib-resistant, Ph-positive leukemia and that the combination of SCH66336 plus imatinib may be useful to circumvent resistance.
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PMID:Efficacy of SCH66336, a farnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells. 1265 16

(1) Chronic myeloid leukaemia goes through three clinical phases: a chronic phase, an acceleration phase, and a terminal blast crisis. In the chronic phase, interferon alfa-2 is more effective than cytotoxic chemotherapies but it also has more adverse effects. (2) Imatinib inhibits tyrosine kinase, an enzyme encoded by the pathological gene BCR-ABL, which is created during a reverse translocation between chromosomes 9 and 22 (characteristic of chronic myeloid leukaemia). This translocation almost always creates the pathological chromosome Philadelphia in blood cell lines. (3) 1 027 patients were recruited to three non comparative trials of imatinib, each focusing on a different phase of chronic myeloid leukaemia. Efficacy was evaluated largely on the basis of blood cell count and clearance of cells harbouring the Philadelphia chromosome. (4) During the chronic phase, in patients in whom interferon alfa-2 had failed or been poorly tolerated, a major cytogenetic response, lasting at least one month, occurred in 35% of patients on imatinib, compared to 20% of patients on interferon alfa-2 + cytarabine (historical comparison). It is not known whether this translated into longer survival. (5) Preliminary results from a randomised but unblinded trial comparing imatinib with interferon + cytarabine seem to favour imatinib. Some patients developed relapses resistant to imatinib, owing to mutations in the BCR-ABL gene. (6) In patients going through the acceleration phase or blast crisis, imatinib did not improve survival compared with standard treatments. (7) The main adverse effects so far described with imatinib are gastrointestinal problems, oedema and fluid retention, and muscle and joint pain, which prompted patients to stop treatment in no more than 5% of cases. (8) Imatinib has a strong potential to interact with other drugs, including paracetamol, but few specific studies have been done. (9) In practice imatinib may be a useful option during the chronic phase, after interferon alfa-2 has failed or been stopped because of adverse effects, provided that its benefits, so far shown only in surrogate endpoints, translate into longer survival. During the acceleration phase and blast crisis imatinib may cause fewer side effects than existing treatments.
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PMID:Imatinib: new preparation. For Chronic myeloid leukaemia: further assessment required. 1266 27

Imatinib mesylate (Gleevec) or Glivec), a small molecule tyrosine kinase inhibitor for the treatment of chronic myeloid leukaemia, has been said to herald the dawn of a new era of rationally designed, molecularly targeted oncotherapy. Lurking on the same new horizon, however, is the age-old spectre of drug resistance. This review sets the intoxicating clinical perspective against the more sobering laboratory evidence of such divergent mechanisms of imatinib resistance as gene amplification and stem cell quiescence. Polychemotherapy has already been considered to combat resistance, but a more innovative, as yet unformulated, approach may be advocated.
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PMID:Is there a cloud in the silver lining for imatinib? 1267 92

Chronic myeloid leukaemia (CML) is a malignant disease of the bone marrow characterised by the presence of the Philadelphia (Ph) chromosome. About 20% of acute lymphoblastic leukaemia (ALL) patients also show this genetic abnormality. A new drug, imatinib (Glivec, Novartis Pharma AG, Basel, Switzerland, and formerly STI571) is having a profound effect on the treatment and management of all stages of CML and Philadelphia chromosome positive (Ph+) ALL. New treatment algorithms are being developed. Should imatinib replace or be combined with existing therapies? To address this question, we review the pros and cons of therapy with interferon-alpha (IFN-alpha), allogeneic transplantation, autologous transplantation, imatinib, and in the case of Ph+ ALL, chemotherapy and experimental approaches. Conservative and aggressive treatments will be discussed and new molecular methods of monitoring cytogenetic response and their significance will also be reviewed.
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PMID:Perspectives on the treatment of chronic phase and advanced phase CML and Philadelphia chromosome positive ALL(1). 1268 26

The purine nucleoside analogues (PNA), fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and 2'-deoxycoformycin (DCF), represent a novel group of cytotoxic agents with high activity in low-grade lymphoid malignancies. However, several investigations have revealed that these agents are active also in acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). Synergistic interaction between FA or 2-CdA with cytarabine (Ara-C) have been demonstrated in both preclinical and clinical studies. PNA enhance the cell concentration of Ara-CTP, which is active metabolite of Ara-C. It is likely that the addition of granulocyte colony stimulating factor (G-CSF) may further improve the effects of FA (FLAG) or 2-CdA (CLAG). The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. An alternative approach to increase FLAG activity might be the addition of investigational drugs with novel mechanism of action, such as topoiromerase I inhibitors. The addition of anthracyclines to induction therapy does not appear to result in a substantial advantage in terms of CR achievement and duration. Clinical studies have confirmed the efficacy of PNA alone or in combination protocols in the treatment of AML. These regimens seem to produce superior results with acceptable toxicities in previously treated and relapsed, poor risk AML. However, early relapses remain a significant problem in a majority of refractory or relapsed patients in CR after treatment with PNA based regimens. To prolong remission duration or even cure AML, auto--or allo stem cell transplantation should be considered. However, FAMP or 2-CdA containing regimens may impair mobilization and collection of stem cells from peripheral blood for autotransplantation. Few studies have analyzed the role of PNA in CML. 2-CdA, FAMP and DCF can induce hematologic response in chronic phase of CML but cytogenetic responses have not been observed. Preliminary results suggest, that PNA used alone or in combination may be used as palliation in blast phase of the disease. However, currently, the role of these agents in CML is insignificant because of the high activity of Glivec in this disease. Finally, PNA, especially FA play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients, possibly also with myeloid malignancies.
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PMID:Purine nucleoside analogues in the treatment of myleoid leukemias. 1268 9

Chronic myelogenous leukaemia (CML) is one of the most intensively studied human malignancies. It has been the focus of major efforts to develop potent drugs for several decades, but until recently cure rates remained low. A breakthrough in CML therapy was very likely accomplished with the clinical introduction of STI-571 [imatinib mesylate; Gleevec (USA); Glivec (other countries)] in 2000/2001. Despite the hope that STI-571 has generated for many CML patients, development of resistance to this drug is already apparent in some cases, especially if the CML is diagnosed in its later stages. Therefore, novel drugs which can be used alone or in combination with STI-571 are highly desirable. This review briefly summarises the current understanding and therapy of CML and then discusses in more detail basic laboratory research that attempts to target Grb2, an adaptor protein known to directly interact with the Bcr portion of the Bcr-Abl fusion protein. Blocking the binding of Grb2 to the GDP-releasing protein SoS is well known to abrogate the activation of the GTPase Ras, a major driving force of the central mitogenic (MAP kinase) pathway. Additional Grb2 effector proteins may also contribute to the proliferation-inhibiting effects observed upon uncoupling Grb2 from its downstream signalling system. Since Grb2 is a known signal transducer for several major human oncogenes, this approach may have applications for a wider range of human cancers.
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PMID:High affinity molecules disrupting GRB2 protein complexes as a therapeutic strategy for chronic myelogenous leukaemia. 1268 10

Imatinib is a new promising therapeutic option for chronic myeloid leukemia (CML) with efficacy even in the blast phase of the disease. However, most patients treated with imatinib in the blast phase develop progressive disease rapidly. Thus, treatment with imatinib has to be followed by other treatment strategies. The normally mild to moderate side effects of imatinib including skin rashes might therefore be aggravated. Here, we describe a patient with severe epidermal necrolysis after treatment with imatinib and consecutive allogeneic hematopoietic stem cell transplantation. Prolonged inhibition of platelet-derived growth factor by imatinib may be an explanation for this observed skin toxicity.
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PMID:Severe epidermal necrolysis after treatment with imatinib and consecutive allogeneic hematopoietic stem cell transplantation. 1270 20


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