Posted by rob on February 18, 2010 under Uncategorized | 
Authors: Lin L, Chen J, Lin Q, Chen W, Chen J, Yao H, Liu A, Lin X, Chen Y
A novel electrochemical biosensor is described for detection of breakpoint cluster region gene and a cellular abl (BCR/ABL) fusion gene in chronic myelogenous leukemia (CML) by using thiolated-hairpin locked nucleic acids (LNA) as the capture probe. The hairpin LNA probe was immobilized on the nanogold (NG)/poly-eriochrome black T (EBT) film-modified glassy carbon electrode (GCE). The immobilized LNA probe could selectively hybridize with its target DNA on LNA/NG/EBT/GCE surface. The immobilization and hybridization of the LNA probe were characterized with cyclic voltammetry and electrochemical impedance spectroscopy. The hybridization of the immobilized LNA probe with the target DNA was detected by differential…
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Cause of death in patients with lower-risk myelodysplastic syndrome.
Cancer. 2010 Feb 16;
Authors: Dayyani F, Conley AP, Strom SS, Stevenson W, Cortes JE, Borthakur G, Faderl S, O’Brien S, Pierce S, Kantarjian H, Garcia-Manero G
BACKGROUND:: The authors have recently shown that a majority of patients with myelodysplastic syndrome (MDS) classified by the International Prognostic Scoring System as lower risk die without transformation to acute myelogenous leukemia (AML). The cause of death (COD) of these patients is not well understood. Identifying the COD could help to guide early therapy decisions. METHODS:: The authors retrospectively analyzed the COD in a cohort of 273 deceased patients with lower-risk MDS according to the International Prognostic Scoring System at presentation to The University of Texas M. D. Anderson Cancer Center from 1980 to 2004. MDS-related death was defined as infection, bleeding, transformation to AML, or disease progression. Remaining CODs were classified as non-MDS-related. RESULTS:: Median age at presentation was 66 years (range, 19-88 years). Overall median survival was 59 weeks (range, 1-831 weeks). All French-American-British leukemia classification subgroups were represented. The percentage of International Prognostic Scoring System low and intermediate-1 groups were 21% and 79%, respectively. The most common cytogenetic abnormality (9%) was del(5q). Patients received supportive care only. The COD was identified as MDS-related in 230 of 273 (84%) patients. The most common disease-related CODs were infection (38%), transformation to AML (15%), and hemorrhage (13%). The most frequent non-disease-related COD was cardiovascular events (19 of 43 patients). CONCLUSIONS:: The majority of patients with low- or intermediate-1 risk MDS will die because of causes related to their underlying disease. Although these results need to be validated in different populations, early therapeutic intervention could be considered in the management of these patients to improve survival. Cancer 2010. (c) 2010 American Cancer Society.
PMID: 20162709 [PubMed - as supplied by publisher]
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Discovery of 8-methoxypyrazino[1,2-a]indole as a New Potent Antiproliferative Agent Against Human Leukemia K562 Cells. A Structure-Activity Relationship Study.
Lett Drug Des Discov. 2009 Jun 1;6(4):298-303
Authors: Romagnoli R, Baraldi PG, Carrion MD, Cruz-Lopez O, Cara CL, Preti D, Tabrizi MA, Balzarini J, Hamel E, Fabbri E, Gambari R
Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. The indole nucleus, frequently encountered as a molecular fragment in natural products and pharmaceutically active compounds, was employed as the initial building block for the synthesis of a series of pyrazino[1,2-a]indoles 1a-k, variably substituted at the 6, 7, 8 and 9-positions. Compound 1e, bearing the methoxy group at the 8-position of the pyrazino[1,2-a]indole nucleus was identified as a novel potent antiproliferative agent against the human chronic myelogenous leukemia K562 cell line, but it was much less active against several other cancer cell lines. Comparison of positional isomers indicated that moving the methoxy group from the 8- to the 7- or 6-position, to furnish compounds 1f and 1g, respectively, yielded inactive compounds. The analysis of structure-activity relationships observed in the series of investigated compounds may represent the basis for the design of more active molecules.
PMID: 20161090 [PubMed - as supplied by publisher]
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MDCT Imaging Findings of Extramedullary Granulocytic Sarcoma of the Heart.
J Thorac Imaging. 2010 Feb;25(1):W14-6
Authors: Tsai J, Lee EY
Granulocytic sarcoma, also known as chloroma, is an uncommon tumor typically seen in patients with acute myelogenous leukemia (AML). Extramedullary cardiac involvement of granulocytic sarcoma is rare and there is a paucity of information regarding its multidetector computed tomography (MDCT) imaging appearance. We present a case of extramedullary granulocytic sarcoma of the heart detected on MDCT in a young adult male with AML. An understanding of how extramedullary granulocytic sarcoma of the heart appears on MDCT may decrease or prevent delays in diagnosing this uncommon, although important, complication from AML.
PMID: 20160585 [PubMed - in process]
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Acute myelogenous leukemia following treatment of invasive cervix carcinoma: A case report and a review of the literature.
J Cancer Res Ther. 2009 Oct-Dec;5(4):302-4
Authors: Samanta DR, Senapati SN, Sharma PK, Mohanty A, Samantaray S
Second malignancy is one of the late complications of long-term cancer survivors, treated with radiation or chemotherapy. Here is a case report on acute myelogenous leukemia, which developed after 63 months following the completion of treatment with surgery and platinum-based chemoradiation in a patient of carcinoma cervix IB. The above-mentioned second malignancy is one of the late sequelae of platinum-based chemoradiation. This case is reported here for documentation because of its rarity.
PMID: 20160368 [PubMed - in process]
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The FLT3 Internal Tandem Duplication Mutation Is a Secondary Target of the Aurora B Kinase Inhibitor AZD1152-HQPA in Acute Myelogenous Leukemia Cells.
Mol Cancer Ther. 2010 Feb 16;
Authors: Grundy M, Seedhouse C, Shang S, Richardson J, Russell N, Pallis M
Aurora kinases play an essential role in orchestrating chromosome alignment, segregation, and cytokinesis during mitotic progression and both aurora-A and B are frequently overexpressed in a variety of human malignancies. In this study, we report the effects of AZD1152-HQPA, a highly selective inhibitor of aurora-B kinase, in acute myeloid leukemia (AML) cell lines and primary samples. We show that AZD1152-HQPA inhibits the phosphorylation of Histone H3 (pHH3) on serine 10 resulting in polyploid cells, apoptosis, and loss of viability in a panel of AML cell lines. We also show that AZD1152-HQPA sensitivity in our cell lines is irrespective of p53 status and the FLT3-ITD-expressing MOLM-13 and MV4-11 cell lines are particularly sensitive to AZD1152-HQPA. Internal tandem duplications (ITD) within the FLT3 tyrosine kinase receptor are found in approximately 25% of AML patients and are associated with a poor prognosis. Here, we report that AZD1152-HQPA directly targets phosphorylated FLT3 along with inhibiting its downstream target phospho-signal transducer and activator of transcription 5 (STAT5) in the FLT3-ITD cell lines. We show pHH3 expression in primary AML blasts and its inhibition by AZD1152-HQPA at low doses in all of our primary samples tested. AZD1152-HQPA inhibits the clonogenic potential of primary AML samples, with FLT3-ITD samples being the most sensitive (P = 0.029). FLT3-ITD primary samples are also more sensitive to pHH3 inhibition (P = 0.022) and are particularly sensitive to pSTAT5 downregulation after treatment with AZD1152-HQPA compared with FLT3 wild-type samples (P = 0.007). We conclude that mutant FLT3 is a secondary target of AZD1152-HQPA and that FLT3-ITD primary samples are particularly sensitive to the drug. Mol Cancer Ther; 9(3); OF1-12.
PMID: 20159992 [PubMed - as supplied by publisher]
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Arsenic Trioxide-Dependent Activation of TAO2 and TAK1.
Mol Pharmacol. 2010 Feb 16;
Authors: McNeer JL, Goussetis DJ, Sassano A, Dolniak B, Kroczynska B, Glaser H, Altman JK, Platanias LC
Arsenic trioxide (As(2)O(3)) has potent antileukemic properties in vitro and in vivo, but the mechanisms by which it generates its effects on target leukemic cells are not well understood. Understanding cellular mechanisms and pathways that are activated in leukemic cells to control generation of As(2)O(3) responses should have important implications in the development of novel approaches using As(2)O(3) for the treatment of leukemias. In this study, we used immunoblotting and immune complex kinase assays to provide evidence that the kinases TAO2 and TAK1 are rapidly activated in response to treatment of acute leukemia cells with As(2)O(3). Such activation occurs after generation of reactive oxygen species and regulates downstream engagement of the p38 Map kinase. Our studies demonstrate that siRNA-mediated knockdown of TAO2 or TAK1 or pharmacological inhibition of TAK1 enhances the suppressive effects of As(2)O(3) on KT-1-derived leukemic progenitor colony formation and on primary leukemic progenitors from patients with acute myelogenous leukemia. These results indicate key negative-feedback regulatory roles for these kinases in the generation of the antileukemic effects of As(2)O(3). Thus, molecular or pharmacological targeting of these kinases may provide a novel approach to enhance the generation of arsenic-dependent antileukemic responses.
PMID: 20159944 [PubMed - as supplied by publisher]
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Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
Nature. 2010 Jan 28;463(7280):501-6
Authors: Zhang J, Adrián FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, Sim T, Powers J, Dierks C, Sun F, Guo GR, Ding Q, Okram B, Choi Y, Wojciechowski A, Deng X, Liu G, Fendrich G, Strauss A, Vajpai N, Grzesiek S, Tuntland T, Liu Y, Bursulaya B, Azam M, Manley PW, Engen JR, Daley GQ, Warmuth M, Gray NS
In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.
PMID: 20072125 [PubMed - indexed for MEDLINE]
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Allogeneic stem cell transplantation for pediatric and adolescent patients with CML: results from the prospective trial CML-paed I.
Klin Padiatr. 2009 Nov-Dec;221(6):351-7
Authors: Suttorp M, Claviez A, Bader P, Peters C, Gadner H, Ebell W, Dilloo D, Kremens B, Kabisch H, Führer M, Zintl F, Göbel U, Klingebiel T
PURPOSE: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon. PATIENTS AND METHODS: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis. RESULTS: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen – total body irradiation or busulfan – exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT. CONCLUSION: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.
PMID: 19890786 [PubMed - indexed for MEDLINE]
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MicroRNA expression profiling in Imatinib-resistant Chronic Myeloid Leukemia patients without clinically significant ABL1-mutations.
Mol Cancer. 2009;8:69
Authors: San José-Enériz E, Román-Gómez J, Jiménez-Velasco A, Garate L, Martin V, Cordeu L, Vilas-Zornoza A, Rodríguez-Otero P, Calasanz MJ, Prósper F, Agirre X
The development of Imatinib Mesylate (IM), the first specific inhibitor of BCR-ABL1, has had a major impact in patients with Chronic Myeloid Leukemia (CML), establishing IM as the standard therapy for CML. Despite the clinical success obtained with the use of IM, primary resistance to IM and molecular evidence of persistent disease has been observed in 20-25% of IM treated patients. The existence of second generation TK inhibitors, which are effective in patients with IM resistance, makes identification of predictors of resistance to IM an important goal in CML. In this study, we have identified a group of 19 miRNAs that may predict clinical resistance to IM in patients with newly diagnosed CML.
PMID: 19723306 [PubMed - indexed for MEDLINE]
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