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)

Imatinib induces remissions in approximately 30% of patients with chronic myeloid leukemia (CML) in myeloid blast crisis (M-BC). Because most patients eventually relapse, allogeneic stem cell transplantation (SCT) in remission offers the best chance for cure. Remission induction with imatinib alone would seem ideal because it is less toxic than conventional chemotherapy. Conversely, patients unlikely to respond may benefit from combination therapy up front. To identify prognostic factors, we studied the mRNA expression of genes related to drug resistance and apoptosis in leukemic cells from patients with M-BC and their in vitro sensitivity to imatinib, and analyzed the results with other baseline factors for their impact on response. We show that high levels of BAX, low levels of MRP-1, and a high platelet count are independently predictive of response to imatinib. Combined into a score, these parameters may be clinically useful for risk-adapted patient stratification.
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PMID:High levels of BAX, low levels of MRP-1, and high platelets are independent predictors of response to imatinib in myeloid blast crisis of CML. 1240 6

The constitutive activity of the Bcr-Abl tyrosine kinase plays a critical role in the molecular pathogenesis of not only the chronic but also the accelerated and blastic phases of chronic myelogenous leukemia. Therefore, Bcr-Abl tyrosine kinase is a rational therapeutic target in all phases of chronic myelogenous leukemia. Although imatinib mesylate (STI571, Gleevec, Novartis, Basal, Switzerland) produces high rates of complete clinical and cytogenetic responses in the chronic phase, resistance is universal and clinical relapse develops rapidly in the advanced phases of chronic myelogenous leukemia. This resistance has been shown to be caused by specific ATP binding site mutations or amplification of Bcr-Abl gene, resulting in a Bcr-Abl tyrosine kinase that is resistant to further inhibition by imatinib. Alternative (Bcr-Abl-independent) mechanisms driving the growth and survival of the malignant clone may also be responsible for imatinib resistance. Novel tyrosine kinase inhibitors that also target Bcr-Abl tyrosine kinase, or agents that downregulate Bcr-Abl levels regardless of its wild-type or mutant status, may need to be developed clinically for the future therapy of imatinib-resistant chronic myelogenous leukemia.
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PMID:Mechanisms of resistance to imatinib mesylate in Bcr-Abl-positive leukemias. 1240 51

Chronic myelogenous leukemia (CML) is characterized by the presence of a Bcr-Abl fusion protein with deregulated tyrosine kinase activity that is required for maintaining the malignant phenotype. Imatinib, a selective inhibitor of Bcr-Abl, induces major cytogenetic remission (MCR) or complete cytogenetic remission (CCR) in the majority of patients with CML in first chronic phase. However, thorough re-evaluation of cytogenetics in a cohort of patients in MCR or CCR demonstrated clonal karyotypic abnormalities in more than 10% of cases, some of which were clinically associated with a myelodysplastic syndrome (MDS). Further analysis identified previous exposure to cytarabine and idarubicin as significant risk factors for the subsequent occurrence of abnormalities in Philadelphia chromosome-negative (Ph-) cells. To investigate if cytogenetically normal but clonal hematopoiesis might be present in other patients in cytogenetic remission, we studied X-chromosome inactivation as a marker of clonality by polymerase chain reaction analysis of the human androgen receptor (HUMARA). We find that imatinib restores a polyclonal pattern in most patients in CCR and MCR. Nonetheless, our results are consistent with the notion that targeted therapy of CML with imatinib favors the manifestation of Ph- clonal disorders in some patients. They indicate that patients on imatinib should be followed with conventional cytogenetics, even after induction of CCR.
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PMID:Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. 1450 73

The choice of primary treatment for patients with chronic myeloid leukaemia diagnosed in chronic phase has become exceedingly difficult. There is little doubt that allogeneic stem cell transplantation (allo-SCT) can eradicate the leukaemia and that a 'graft-versus-leukaemia' effect makes a major contribution to this result; conversely only a minority of patients are eligible for transplant, which still carries an appreciable risk of mortality or protracted morbidity. For the majority of patients interferon-alpha prolongs life to some degree in comparison with hydroxyurea but is associated with considerable toxicity. The newly introduced tyrosine kinase inhibitor imatinib mesylate (imatinib, Glivec) induces complete haematologic remission in almost all cases and is associated with a very high incidence of cytogenetic response; its capacity to prolong life in comparison with interferon-alpha is not yet established. Here we review some factors that predict survival after non-transplant therapy and after allografting for CML in chronic phase. We consider two contrasting options for managing the newly diagnosed patient and conclude that for the present allogeneic stem cell transplantation soon after diagnosis should continue to be offered as an option for selected patients. Further experience with the use of imatinib as a single agent or in combination with other anti-leukemic agents may alter the picture in the near future.
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PMID:Treatment of chronic myeloid leukaemia: lessons and challenges. 1243 Sep 24

The treatment options for chronic myelogenous leukemia (CML) continue to evolve rapidly. Imatinib mesylate (Gleevec, Glivec, formerly STI571) has continued to show remarkable clinical benefits and the updated results with this agent are reviewed. As relapses using single agent imatinib have occurred, particularly in advanced phase patients, the issue of whether combinations of other antileukemic agents with imatinib may yield improved results is addressed. In addition, data on new agents that have potential in the treatment of CML are reviewed. These agents are presented in the context of their molecular mechanism of action. The most recent data for stem cell transplantation, along with advances in nonmyeloablative transplants, are also reviewed. In Section I, Drs. Stephen O'Brien and Brian Druker update the current status of clinical trials with imatinib and review ongoing investigations into mechanisms of resistance and combinations of imatinib with other agents. They also present their views on integration of imatinib with other therapies. In Section II, Dr. Jorge Cortes describes the most recent data on novel therapies for CML, including farnesyl transferase inhibitors, arsenic trioxide, decitabine, and troxatyl, among others. These agents are discussed in the context of their molecular mechanism of action and rationale for use. In Section III, Dr. Jerald Radich updates the results of stem cell transplants for CML, including emerging data on nonmyeloablative transplants. He also presents data on using microarrays to stratify patients into molecularly defined risk groups.
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PMID:Chronic myelogenous leukemia. 1244 21

Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Abl-expressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P <.05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-x(L). Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34(+) leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (BC) of chronic myelocytic leukemia (CML) while receiving therapy with imatinib. Taken together, these findings indicate that cotreatment with SAHA enhances the cytotoxic effects of imatinib and may have activity against imatinib-refractory CML-BC.
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PMID:Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. 1244 42

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ; Glivec, Novartis Pharma AG, Basel, Switzerland), a signal transduction inhibitor with preferential effects against the tyrosine kinase activity of the protein product of the ABL proto-oncogene, induced hematologic responses in >or=90% of patients with chronic-phase chronic myeloid leukemia (CML). In Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL), the BCR-ABL translocation is the main transforming event, making it another hematologic malignancy targeted by this ABL-tyrosine kinase inhibitor. In an international multicenter phase II trial, imatinib-induced hematologic responses (typically brief) were achieved in 60% of patients with relapsed or refractory Ph(+) ALL. Subsequently, the German Multicenter Study Group for Adult ALL (GMALL) analyzed 59 patients treated in two successive nonrandomized phase II trials of imatinib in patients with relapsed or refractory Ph(+) ALL. Peripheral blood blasts cell clearance occurred within 8 to 14 days in most patients. However, in a significant proportion, blast counts subsequently increased 16 to 50 days after treatment onset. Imatinib mesylate was particularly effective in patients with relapse after stem cell transplantation (SCT); 75% of patients achieved complete leukemic response. Rapid development of resistance during treatment with imatinib mesylate remains a major problem. Further research efforts should explore the mechanisms of resistance to imatinib mesylate; effectiveness of other targeted therapies (eg, farnesyl transferase inhibitors [FTIs]); combination therapies; and inclusion of strategies for immune response modification (eg, donor lymphocyte infusions, interferon-alpha) for Ph/BCR-ABL-positive leukemias.
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PMID:Targeted therapies in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. 1244 50

Imatinib mesylate (STI571, Glivec, Gleevec) is a powerful inhibitor of the tyrosine kinase activity of Bcr-Abl, the oncoprotein responsible for chronic myeloid leukemia (CML). The drug shows great efficacy in chronic phase, but is less effective in maintaining hematologic remissions in blast crisis patients. Our group has previously described several cell lines made resistant to imatinib. We now examine the question of cross-resistance to other chemotherapeutic drugs used in CML. Four paired imatinib-sensitive/resistant CML cell lines were assessed by caspase-3 and MTS assays for their proliferative response to cytosine arabinoside (Ara-C), daunorubicin (DNR), homoharringtonine (HHT) and hydroxyurea (HU), either alone or in combination with imatinib. Primary blasts from advanced-stage CML patients refractory to imatinib therapy were studied by semi-solid media clonogenic assays. We found that these drugs are generally capable of major inhibition of proliferation of the CML cell lines, although differential responses to DNR and HHT were noted between some sensitive and resistant cell line pairs, implying that resistance to imatinib may confer a growth advantage under such conditions. The four drugs were also effective in preventing the formation of progenitor cell colonies from CML patients both before treatment with imatinib, and after relapse on the drug. Isobolographic analysis implied that these drugs will generally combine well with imatinib, and in some cases will be synergistic. We conclude that Ara-C, DNR or HHT, either alone or in combination with imatinib, are likely to be the best therapeutic alternatives in the management of patients who become resistant to imatinib monotherapy.
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PMID:Drug responses of imatinib mesylate-resistant cells: synergism of imatinib with other chemotherapeutic drugs. 1245 39

Modern molecular technology helped identify more than 10 protein tyrosine kinases related to myeloid malignancies, which allowed the development of small molecule inhibitors targeting deregulated protein tyrosine kinase activity. Protein tyrosine kinase deregulation can occur as a consequence of fusion gene formation because of chromosomal translocations, or as distinct gain-of-function point mutations. Although the tyrosine kinase inhibitor imatinib mesylate (Gleevec) targeting the ABL protein tyrosine kinase has revolutionized current chronic myeloid leukemia therapy, it became rapidly evident that overcoming the multiple cellular resistance mechanisms will be very challenging. To develop efficient therapeutic alternatives, one must understand the complex signal transduction mechanisms involved in transformation by deregulated protein tyrosine kinases. This article reviews the most recently identified molecular mechanisms involved in cell transformation by the BCR/ABL protein tyrosine kinase fusion and presents new members of the increasing family of deregulated protein tyrosine kinases involved in myeloproliferative disorders. In addition, the article discusses new, promising small molecule protein tyrosine kinase inhibitors and the molecular mechanism that may lead to resistance to these drugs. Finally, the article highlights putative alternative strategies that could be used to block signal transduction pathways of deregulated protein tyrosine kinase activity.
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PMID:Role of constitutively activated protein tyrosine kinases in malignant myeloproliferative disorders: an update. 1248 10

Chronic myelogenous leukemia (CML) is a myeloproliferative disease characterized by the BCR-ABL genetic translocation and constitutive activation of the Abl tyrosine kinase. Among members of the Signal Transducers and Activators of Transcription (STAT) family of transcription factors, Stat5 is activated by the Bcr-Abl kinase and is implicated in the pathogenesis of CML. We recently identified PD180970 as a new and highly potent inhibitor of Bcr-Abl kinase. In this study, we show that blocking Bcr-Abl kinase activity using PD180970 in the human K562 CML cell line resulted in inhibition of Stat5 DNA-binding activity with an IC(50) of 5 nM. Furthermore, abrogation of Abl kinase-mediated Stat5 activation suppressed cell proliferation and induced apoptosis in K562 cells, but not in the Bcr-Abl-negative myeloid cell lines, HEL 92.1.7 and HL-60. Dominant-negative Stat5 protein expressed from a vaccinia virus vector also induced apoptosis of K562 cells, consistent with earlier studies that demonstrated an essential role of Stat5 signaling in growth and survival of CML cells. RNA and protein analyses revealed several candidate target genes of Stat5, including Bcl-x, Mcl-1, c-Myc and cyclin D2, which were down-regulated after treatment with PD180970. In addition, PD180970 inhibited Stat5 DNA-binding activity in cultured primary leukemic cells derived from CML patients. To detect activated Stat5 in CML patient specimens, we developed an immunocytochemical assay that can be used as a molecular end-point assay to monitor inhibition of Bcr-Abl signaling. Moreover, PD180970 blocked Stat5 signaling and induced apoptosis of STI-571 (Gleevec, Imatinib)-resistant Bcr-Abl-positive cells. Together, these results suggest that the mechanism of action of PD180970 involves inhibition of Bcr-Abl-mediated Stat5 signaling and provide further evidence that compounds in this structural class may represent potential therapeutic agents for CML.
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PMID:Inhibition of Bcr-Abl kinase activity by PD180970 blocks constitutive activation of Stat5 and growth of CML cells. 1248 33


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