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)

Angiogenesis is defined as the formation of new capillaries from prexisting blood vessels and plays an important role in the progression of solid tumors and hematologic malignancies. Markers of angiogenesis correlate with clinical characteristics in leukemia and non-Hodgkin's-lymphoma, serving as predictors of poor prognosis. Antiangiogenic effects of chemotherapeutics as well as of novel drugs such as farnesyltransferase inhibitors and tyrosine kinase inhibitors such as Gleevec might contribute to their therapeutic potential. Thalidomide which has antiangiogenic effects and direct cytotoxic effects was found to be effective in multiple myeloma and is considered as an established treatment modality for patients with refractory or relapsed multiple myeloma. Thalidomide has a significant therapeutic effect in myelodysplastic syndrome (MDS) by improving cytopenia and achieving independence of transfusion therapy in a subset of patients. Preliminary data indicate activity of specific VEGF receptor tyrosine kinase (RTK) inhibitors in multiple myeloma (MM) and acute myeloid leukemia (AML). The positive correlation between increased levels of angiogenic cytokines and clinical response to VEGF-RTK inhibitors and thalidomide indicates the relevance of detecting angiogenesis markers to identify best candidate patients for specific approaches. Including antiangiogenic drugs into treatment protocols for hematologic malignancies is an important task for future clinical studies.
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PMID:Antiangiogenic therapy in hematologic malignancies. 1507 37

STI-571 (Imatinib/Glivec) has been shown to have synergism with various chemotherapeutic agents including cytosine arabinoside (Ara-C) in BCR/ABL positive leukemia cells. The antiproliferative and proapopotic effects of STI-571 in these experiments are mainly explained by its ability to specifically block the fusion-protein BCR/ABL which has a constitutively active tyrosine kinase activity. We investigated the effects of STI-571 in combination with Ara-C on BCR/ABL negative leukemia cell lines and CD34+ hematopoietic progenitor cells in-vitro. Raji, HL-60, K562, Kasumi and KG1a leukemia cells and CD34+ cells from healthy donors were incubated with 5-20 microg/ml Ara-C for 5 h alone or in combination with 10 microg/ml STI-571. Intracellular levels of Ara-CTP measured by HPLC were increased 1.5-3 fold in leukemia cells with most promiment effects in HL-60, Kasumi and Raji cells. In HL-60 cells a linear correlation between the concentration of STI-571 (1-10 microg/ml) and the subsequent levels of Ara-CTP was observed. A linear increase of Ara-CTP could be induced by increasing the incubation time with STI-571 from 2-6 h with a ceiling effect after 8 h. In contrast coincubation of mononuclear cells or purified CD34+ cells with STI-571 at therapeutic concentrations lead to decreased intracellular levels of Ara-CTP. The synergism between Ara-C and STI-571 was even more pronounced in Raji and HL-60 cells when 300 ng/ml G-CSF were added at the beginning of the culture period. Intracellular measurements of STI-571 revealed no decreased or increased levels of the compound when increasing Ara-C concentrations were used. Our findings indicate that STI-571 can have significant impact on nucleoside metabolism in malignant and non-malignant hematopoietic cells. Further investigations will have to show whether theses effects can lead to increased cytotoxicity in primary blasts of patients with acute leukemia.
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PMID:Imatinib mesylate selectively influences the cellular metabolism of cytarabine in BCR/ABL negative leukemia cell lines and normal CD34+ progenitor cells. 1512 75

Imatinib mesylate (Gleevec), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.
Leukemia 2004 Aug
PMID:Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. 1562 54

Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters--hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.
Leukemia 2004 Aug
PMID:Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. 1521 76

Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20+ acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20(-) leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatinib and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia.
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PMID:Existence of leukemic clones resistant to both imatinib mesylate and rituximab before drug therapies in a patient with Philadelphia chromosome-positive acute lymphocytic leukemia. 1529 70

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. 1475 33

We described here four patients diagnosed with Philadelphia chromosome positive (Ph+) leukemia, consisting of chronic myeloid leukemia (CML) (n=2) and Ph+ acute lymphoblastic leukemia (ALL) (n=2). All patients were treated with imatinib mesylate (300-400 mg/day) for the treatment of relapsed CML after allogeneic hematopoietic stem cell transplantation (SCT) (n=2), relapsed Ph+ ALL after SCT (n=1), and Ph+ ALL preceding SCT (n=1). Significant clinical and molecular responses were observed in all patients and three of them achieved sustained molecular remission. Imatinib was well tolerated and did not induce noticeable graft versus host disease although one patient presented severe skin rash (Grade III). Notably, serum cyclosporine A concentration increased after the initiation of imatinib treatment, probably through competitive inhibition of P450 3A4 isoenzyme. Our data suggest that imatinib in conjunction with SCT for the Ph+ leukemia may be a promising treatment strategy.
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PMID:Imatinib mesylate in conjunction with allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome positive leukemias: report of 4 cases. 1532 66

Recent data suggest that STI571 (Imatinib) induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT). However, little is known about molecular responses to STI571 and the duration of leukemia-free survival in these patients. We report on a 43 year old female patient who presented with a relapse from Ph+ CML in December 2000. Five years earlier she had received an SCT from an unrelated male donor in accelerated phase. At the time of relapse, she presented with marked leukocytosis (89,000 microl) and 10% blasts. In December 2000, therapy with Imatinib was started. After 3 months, the karyotype showed an XY, with trisomy 8 in about 50% of all metaphases, but without evidence of residual Ph+ cells. Moreover, in response to Imatinib, BCR/ABL transcripts decreased and were no longer detectable after 6 months. After a total observation period of 36 months, the patient is still in complete cytogenetic and molecular remission without signs of occurrence of a donor-type hematopoietic neoplasm or CML relapse. These data suggest that Imatinib is a useful agent for long term treatment of relapsed CML after allogeneic SCT.
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PMID:Detection of trisomy 8 in donor-derived Ph- cells in a patient with Ph+ chronic myeloid leukemia successfully treated with Imatinib (STI571) in relapse after allogeneic transplantation. 1535 47

We report the cloning of a novel PDGFRB fusion gene partner in a patient with a chronic myeloproliferative disorder characterized by t(5;14)(q33;q32), who responded to treatment with imatinib mesylate. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in the translocation. Long distance inversion PCR identified KIAA1509 as the PDGFRB fusion partner. KIAA1509 is an uncharacterized gene with a predicted coiled-coil oligomerization domain with homology to the HOOK family of proteins. The predicted KIAA1509-PDGFRbeta fusion protein contains the KIAA1509 coiled-coil domain fused to the cytoplasmic domain of PDGFRbeta that includes the tyrosine kinase domain. Imatinib therapy resulted in rapid normalization of the patient's blood counts, and subsequent bone marrow biopsies and karyotypic analysis were consistent with sustained complete remission.
Leukemia 2005 Jan
PMID:KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). 1549 75

NVP-LAQ824 is a novel potent hydroxamic acid-derived histone deacetylase inhibitor that induces apoptosis in nanomolar concentrations in myeloid leukemia cell lines and patient samples. Here we show the activity of NVP-LAQ824 in acute myeloid leukemia cells and BCR/ABL-expressing cells of mouse and human origin, both sensitive and resistant to imatinib mesylate (Gleevec, STI-571). Whereas imatinib inhibited overall cellular tyrosine phosphorylation in Ba/F3.p210 cells, NVP-LAQ824 did not inhibit tyrosine phosphorylation, and did not affect BCR/ABL or ABL protein expression. Neither compound was able to inhibit cellular tyrosine phosphorylation in the imatinib-resistant Ba/F3.p210-T315I cell line. These data taken together suggest that BCR/ABL kinase activity is not a direct target of NVP-LAQ824. Synergy between NVP-LAQ824 and imatinib was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. In addition, we show that NVP-LAQ824 was well tolerated in vivo in a pre-clinical murine leukemia model, with antileukemia activity resulting in significant prolongation of the survival of mice when treated with NVP-LAQ824 compared to control mice. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in myeloid malignancies.
Leukemia 2004 Dec
PMID:Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloid leukemia cells in vitro and in vivo. 1549 78


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