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1. Lin YW, Beharry ZM, Hill EG, Song JH, Wang W, Xia Z, Zhang Z, Aplan PD, Aster JC, Smith CD, Kraft AS: A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood; 2010 Jan 28;115(4):824-33
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  • [Title] A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma.
  • We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive.
  • Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme.
  • In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells.
  • In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries.
  • Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL.

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  • (PMID = 19965690.001).
  • [ISSN] 1528-0020
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / P30 CA138313; United States / NCRR NIH HHS / RR / UL1 RR029882; United States / NCI NIH HHS / CA / P30 CA 138313
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Intracellular Signaling Peptides and Proteins; 0 / MYC protein, human; 0 / PIM2 protein, human; 0 / Pim2 protein, mouse; 0 / Protein Kinase Inhibitors; 0 / Proto-Oncogene Proteins; 0 / Proto-Oncogene Proteins c-myc; EC 2.7.1.1 / MTOR protein, human; EC 2.7.1.1 / TOR Serine-Threonine Kinases; EC 2.7.1.1 / mTOR protein, mouse; EC 2.7.11.1 / PIM1 protein, human; EC 2.7.11.1 / PIM3 protein, human; EC 2.7.11.1 / Pim1 protein, mouse; EC 2.7.11.1 / Pim3 protein, mouse; EC 2.7.11.1 / Protein-Serine-Threonine Kinases; EC 2.7.11.1 / Proto-Oncogene Proteins c-pim-1; EC 2.7.11.24 / Extracellular Signal-Regulated MAP Kinases
  • [Other-IDs] NLM/ PMC2941996
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2. Real PJ, Ferrando AA: NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia; 2009 Aug;23(8):1374-7
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  • [Title] NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia.
  • Inhibition of NOTCH1 signaling with gamma-secretase inhibitors (GSIs) has been proposed as a molecularly targeted therapy in T-cell acute lymphoblastic leukemia (T-ALL).
  • Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid sensitivity and co-treatment with glucocorticoids inhibited GSI-induced gut toxicity.
  • Thus, combination therapies with GSIs plus glucocorticoids may offer a new opportunity for the use of anti-NOTCH1 therapies in human T-ALL.

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  • (PMID = 19357700.001).
  • [ISSN] 1476-5551
  • [Journal-full-title] Leukemia
  • [ISO-abbreviation] Leukemia
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / R01 CA120196-03; United States / NCI NIH HHS / CA / R01 CA129382; United States / NCI NIH HHS / CA / CA120196-03; United States / NCI NIH HHS / CA / R01CA120196; United States / NCI NIH HHS / CA / R01CA129382; United States / NCI NIH HHS / CA / R01 CA120196
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Basic Helix-Loop-Helix Transcription Factors; 0 / Enzyme Inhibitors; 0 / GKLF protein; 0 / Glucocorticoids; 0 / Hes1 protein, mouse; 0 / Homeodomain Proteins; 0 / Kruppel-Like Transcription Factors; 0 / NOTCH1 protein, human; 0 / Neoplasm Proteins; 0 / Notch1 protein, mouse; 0 / Receptor, Notch1; 149348-15-2 / HES1 protein, human; EC 3.4.- / Amyloid Precursor Protein Secretases
  • [Number-of-references] 58
  • [Other-IDs] NLM/ NIHMS153167; NLM/ PMC2814171
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3. Sanda T, Li X, Gutierrez A, Ahn Y, Neuberg DS, O'Neil J, Strack PR, Winter CG, Winter SS, Larson RS, von Boehmer H, Look AT: Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia. Blood; 2010 Mar 4;115(9):1735-45
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia.
  • To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL.
  • The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappaB and PI3K/AKT pathways.
  • Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators.
  • When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells.

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  • (PMID = 20007543.001).
  • [ISSN] 1528-0020
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / P01 CA109901; United States / NCI NIH HHS / CA / CA98543; United States / NCI NIH HHS / CA / 5P01CA109901-040001; None / None / / K08 CA133103-03; United States / NCI NIH HHS / CA / K08 CA133103-04; United States / NCI NIH HHS / CA / CA114766; United States / NCI NIH HHS / CA / K08 CA133103-03; United States / NCI NIH HHS / CA / U24 CA114766; None / None / / K08 CA133103-01; None / None / / K08 CA133103-04; United States / NCI NIH HHS / CA / K08 CA133103; United States / NCI NIH HHS / CA / K08 CA133103-02; United States / NCI NIH HHS / CA / U10 CA098543; United States / NCI NIH HHS / CA / K08 CA133103-01; None / None / / K08 CA133103-02
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Enzyme Inhibitors; 0 / NOTCH1 protein, human; 0 / Notch1 protein, mouse; 0 / Receptor, Notch1; EC 3.4.- / Amyloid Precursor Protein Secretases
  • [Other-IDs] NLM/ PMC2832805
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4. Liu Q, Zhao X, Frissora F, Ma Y, Santhanam R, Jarjoura D, Lehman A, Perrotti D, Chen CS, Dalton JT, Muthusamy N, Byrd JC: FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. Blood; 2008 Jan 1;111(1):275-84
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma.
  • FTY720 is an immunosuppressant developed to prevent organ transplant rejection.
  • Recent studies indicate an additional role for FTY720 in inducing cell apoptosis.
  • We demonstrate here that FTY720 mediates toxic effects in cell lines representing different B-cell malignancies and primary B cells from patients with chronic lymphocytic leukemia (CLL).
  • In contrast to previous reports in T-cell lines, FTY720-induced toxicity in the Raji cell line and primary CLL B cells is independent of activation of caspases or poly(ADP-ribose) polymerase processing.
  • Further, FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency (SCID) mouse model of disseminated B-cell lymphoma/leukemia.
  • These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL.

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  • (PMID = 17761520.001).
  • [ISSN] 0006-4971
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / P01 CA095426; United States / NCI NIH HHS / CA / R01 CA095512; United States / NCI NIH HHS / CA / CA095512; United States / NCI NIH HHS / CA / P01 CA95426
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Immunosuppressive Agents; 0 / Lysophospholipids; 0 / Mcl1 protein, mouse; 0 / Myeloid Cell Leukemia Sequence 1 Protein; 0 / Neoplasm Proteins; 0 / Propylene Glycols; 0 / Proto-Oncogene Proteins c-bcl-2; 26993-30-6 / sphingosine 1-phosphate; EC 3.1.3.16 / Protein Phosphatase 2; EC 3.4.22.- / Caspases; EC 3.4.22.- / Cysteine Endopeptidases; G926EC510T / Fingolimod Hydrochloride; NGZ37HRE42 / Sphingosine
  • [Other-IDs] NLM/ PMC2200813
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5. Turner BC, Eves T, Refaeli Y: Small-molecule inhibitors of Bcl-2 family proteins are able to induce tumor regression in a mouse model of pre-B-cell acute lymphocytic lymphoma. DNA Cell Biol; 2008 Mar;27(3):133-42
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  • [Title] Small-molecule inhibitors of Bcl-2 family proteins are able to induce tumor regression in a mouse model of pre-B-cell acute lymphocytic lymphoma.
  • There has been great interest in a novel set of agents that are able to mimic the function of the BH3 domain by binding to the groove of Bcl-2-like proteins and initiating the cell death sequence.
  • We sought to examine the efficacy of BH3 mimetics in a spontaneous mouse model of B-cell neoplasia.
  • We report here that two BH3 mimetics (HA-14-1 and BH3-I-2') were able to induce apoptosis of murine B-cell lymphoma cells in vitro and in vivo.
  • Tumors that arose from transplantation of primary lymphoma cells regressed following 7 days of treatment with BH3-mimetic drugs.
  • The long-term benefits of the transient treatment of tumor-bearing mice with the BH3 mimetics, however, could not be properly evaluated, due to the high levels of toxicity we observed in vivo with these drugs.
  • Decreased expression of either Bim or Puma from B-cell tumor cells was able to protect these cells from the apoptosis induced by these BH3 mimetics, suggesting that they function through other means.
  • We conclude that while the BH3-mimetic drugs are effective at inducing cell death of lymphoma cells in vitro and in vivo, their unclear molecular specificity and their ability to kill normal cells may limit their therapeutic uses in humans.
  • [MeSH-major] Antineoplastic Agents / therapeutic use. Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology. Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors. Tumor Burden / drug effects
  • [MeSH-minor] Animals. Apoptosis / drug effects. Apoptosis / genetics. Apoptosis Regulatory Proteins / genetics. Biomimetics. Cell Line, Tumor. Cell Proliferation. Disease Models, Animal. Female. Humans. Membrane Proteins / genetics. Mice. Mice, Inbred C57BL. Molecular Weight. Protein Structure, Tertiary / physiology. Proto-Oncogene Proteins / genetics. Remission Induction. Treatment Outcome. Tumor Suppressor Proteins / genetics. Xenograft Model Antitumor Assays

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  • (PMID = 18163880.001).
  • [ISSN] 1044-5498
  • [Journal-full-title] DNA and cell biology
  • [ISO-abbreviation] DNA Cell Biol.
  • [Language] eng
  • [Grant] United States / NCI NIH HHS / CA / CA-11802
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Apoptosis Regulatory Proteins; 0 / Bcl-2-like protein 11; 0 / Membrane Proteins; 0 / PUMA protein, mouse; 0 / Proto-Oncogene Proteins; 0 / Proto-Oncogene Proteins c-bcl-2; 0 / Tumor Suppressor Proteins
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6. Williams RT, Sherr CJ: The ARF tumor suppressor in acute leukemias: insights from mouse models of Bcr-Abl-induced acute lymphoblastic leukemia. Adv Exp Med Biol; 2007;604:107-14
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  • [Title] The ARF tumor suppressor in acute leukemias: insights from mouse models of Bcr-Abl-induced acute lymphoblastic leukemia.
  • The prototypical Bcr-Abl chimeric oncoprotein is central to the pathogenesis of chronic myelogenous leukemias (CMLs) and a subset of acute lymphoblastic leukemias (Ph+ ALLs).
  • In murine bone marrow transplant models and after transfer of syngeneic Bcr-Abl-transformed pre-B cells into immunocompetent recipient animals, Arf gene inactivation dramatically decreases the latency and enhances the aggressiveness of Bcr-Abl-induced lymphoblastic leukemia.
  • Targeted inhibition of the Bcr-Abl kinase with imatinib provides highly effective therapy for CML, but Ph+ ALL patients do not experience durable remissions.
  • Despite exquisite in vitro sensitivity of Arf-null, BCR-ABL+ pre-B cells to imatinib, these cells efficiently establish lethal leukemias when introduced into immunocompetent mice that receive continuous, maximal imatinib therapy.
  • Bcr-Abl confers interleukin-7 (IL-7) independence to pre-B cells, but imatinib treatment restores the requirement for this cytokine.
  • [MeSH-major] Fusion Proteins, bcr-abl / metabolism. Gene Expression Regulation, Neoplastic. Genes, Tumor Suppressor. Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism. Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology. Tumor Suppressor Protein p14ARF / physiology
  • [MeSH-minor] Animals. Antineoplastic Agents / pharmacology. Benzamides. Disease Models, Animal. Drug Resistance, Neoplasm. Humans. Imatinib Mesylate. Interleukin-7 / metabolism. Mice. Piperazines / pharmacology. Pyrimidines / pharmacology

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  • (PMID = 17695724.001).
  • [ISSN] 0065-2598
  • [Journal-full-title] Advances in experimental medicine and biology
  • [ISO-abbreviation] Adv. Exp. Med. Biol.
  • [Language] eng
  • [Grant] United States / NCI NIH HHS / CA / T32-CA70089
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Interleukin-7; 0 / Piperazines; 0 / Pyrimidines; 0 / Tumor Suppressor Protein p14ARF; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / Fusion Proteins, bcr-abl
  • [Number-of-references] 20
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7. Kawaguchi Y, Jinnai I, Nagai K, Yagasaki F, Yakata Y, Matsuo T, Kuriyama K, Tomonaga M: Effect of a selective Abl tyrosine kinase inhibitor, STI571, on in vitro growth of BCR-ABL-positive acute lymphoblastic leukemia cells. Leukemia; 2001 Apr;15(4):590-4
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  • [Title] Effect of a selective Abl tyrosine kinase inhibitor, STI571, on in vitro growth of BCR-ABL-positive acute lymphoblastic leukemia cells.
  • By employing a new semi-quantitative assay system that includes co-culturing leukemia cells with the mouse bone marrow-derived stromal cell line MS-5, we examined the suppressive effect of a selective inhibitor of ABL tyrosine kinase, STI571, on acute lymphoblastic leukemia (ALL) cells with BCR-ABL fusion.
  • Leukemic blast cells from eight patients with B-precursor ALL, including three patients with BCR-ABL-positive ALL, were cultured on monolayers of MS-5 cells for 3 weeks with or without addition of variable amounts of STI571.
  • In all cases, cobblestone areas (CAs) were formed, showing clear linear cell dose-dependent curves, allowing quantitative assessment of blast cell growth.
  • The progenitor frequencies obtained by this direct CA-forming cell (CAFC) assay were equivalent to ALL progenitor frequencies assessed by the standard limiting dilution assay.
  • [MeSH-major] Piperazines / pharmacology. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Proto-Oncogene Proteins c-abl / antagonists & inhibitors. Pyrimidines / pharmacology
  • [MeSH-minor] Adolescent. Adult. Aged. Animals. Benzamides. Cell Division / drug effects. Female. Genes, abl. Humans. Imatinib Mesylate. Male. Mice

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  • (PMID = 11368361.001).
  • [ISSN] 0887-6924
  • [Journal-full-title] Leukemia
  • [ISO-abbreviation] Leukemia
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.2 / Proto-Oncogene Proteins c-abl
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8. Fiorentino S, Chopin M, Dastot H, Boissel N, Reboul M, Legrès L, Janin A, Aplan P, Sigaux F, Regnault A: Disruption of T cell regulatory pathways is necessary for immunotherapeutic cure of T cell acute lymphoblastic leukemia in mice. Eur Cytokine Netw; 2005 Dec;16(4):300-8
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Disruption of T cell regulatory pathways is necessary for immunotherapeutic cure of T cell acute lymphoblastic leukemia in mice.
  • Acute lymphoblastic leukemia (ALL) is the most common cancer in children.
  • In recent years, the outcome has been globally improved by current therapies, but it remains poor in patients with high, persistent residual disease following the first course of chemotherapy, prompting evaluation of the possible beneficial effects of immunotherapy protocols.
  • In this study, we hypothesized that the disruption of two immunoregulatory pathways controlling the auto-reactive T cell response might synergize with dendritic cell-based immunotherapy of the disease, which is considered to be poorly immunogenic.
  • In this study, we used TAL1xLMO1 leukemia cells adoptively transferred in mice, to generate murine leukemia with poorly immunogenic cells as a model for human T-ALL.
  • We compared the efficiency of a classical, dendritic cell-based immunotherapy (injection of dendritic cells loaded with tumor-derived antigenic products), to a combined treatment associating injection of antigen-loaded dendritic cells and disruption of the two immunoregulatory pathways: CD25+ suppressive T cells and cytotoxic T lymphocyte-associated antigens (CTLA-4).
  • We show that this combined treatment resulted in cure, concomitantly with in vivo generation of immune memory, and TNF-alpha secretion.
  • [MeSH-major] Immunotherapy, Adoptive. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / immunology. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / therapy. Signal Transduction / immunology. T-Lymphocytes / immunology
  • [MeSH-minor] Animals. Antigens, CD / metabolism. Antigens, Neoplasm / administration & dosage. CTLA-4 Antigen. Cell Line, Tumor. Dendritic Cells / immunology. Dendritic Cells / metabolism. Dendritic Cells / transplantation. Disease Models, Animal. Immunologic Memory. Interleukin-2 Receptor alpha Subunit / biosynthesis. Lymphocyte Depletion. Mice. Mice, Inbred C3H. Mice, Inbred C57BL. T-Lymphocytes, Regulatory / immunology. T-Lymphocytes, Regulatory / metabolism. Tumor Necrosis Factor-alpha / secretion

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  • (PMID = 16464745.001).
  • [ISSN] 1148-5493
  • [Journal-full-title] European cytokine network
  • [ISO-abbreviation] Eur. Cytokine Netw.
  • [Language] eng
  • [Publication-type] Comparative Study; Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] France
  • [Chemical-registry-number] 0 / Antigens, CD; 0 / Antigens, Neoplasm; 0 / CTLA-4 Antigen; 0 / CTLA4 protein, human; 0 / Ctla4 protein, mouse; 0 / Interleukin-2 Receptor alpha Subunit; 0 / Tumor Necrosis Factor-alpha
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9. Verrills NM, Po'uha ST, Liu ML, Liaw TY, Larsen MR, Ivery MT, Marshall GM, Gunning PW, Kavallaris M: Alterations in gamma-actin and tubulin-targeted drug resistance in childhood leukemia. J Natl Cancer Inst; 2006 Oct 4;98(19):1363-74
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  • [Title] Alterations in gamma-actin and tubulin-targeted drug resistance in childhood leukemia.
  • BACKGROUND: Proteomic investigations have revealed alterations in cytoskeletal proteins expressed in human acute lymphoblastic leukemia cells that are resistant to microtubule-disrupting agents.
  • We characterized gamma-actin expression in antimicrotubule drug-resistant leukemia and examined the effect of altered gamma-actin in resistance of acute lymphoblastic leukemia to antimicrotubule agents.
  • METHODS: Two-dimensional polyacrylamide gel electrophoresis and mass spectrometry were used to identify actin proteins in human acute lymphoblastic leukemia cell lines resistant to vinblastine (CCRF-CEM/VLB100 cells) and desoxyepothilone B (CCRF-CEM/dEpoB140 cells).
  • Site-directed mutagenesis was used to generate mutant gamma-actin expression plasmids, which were used to transfect mouse NIH/3T3 cells.
  • Clonogenic analysis was used for drug sensitivity studies.
  • Expression of gamma-actin (normalized to that of beta2-microglobulin [beta2M]) in primary leukemia cells obtained from patients at diagnosis (n = 44) and relapse (n = 25) was examined using semiquantitative reverse transcription-polymerase chain reaction.
  • RESULTS: We identified novel mutant forms of gamma-actin and the concomitant loss of wild-type gamma-actin in CCRF-CEM/VLB100 cells and CCRF-CEM/dEpoB140 cells.
  • Mouse NIH/3T3 cells that expressed the mutant gamma-actin proteins were more resistant to antimicrotubule agents than cells transfected with empty plasmid.
  • No gamma-actin gene mutations were identified in 37 samples of primary leukemia cells (eight from patients at diagnosis, 29 from patients at relapse).
  • Gamma-actin gene expression was lower in acute lymphoblastic leukemia samples collected at clinical relapse (n = 25; mean gamma-actin/beta2M = 0.53) than in samples collected at diagnosis (n = 44; mean gamma-actin/beta2M = 0.68; difference = 0.15, 95% confidence interval [CI] = 0.04 to 0.27, P = .01).
  • CONCLUSIONS: These data provide functional and associative clinical evidence of a novel form of drug resistance that involves interactions between gamma-actin and microtubules.
  • [MeSH-major] Actins / drug effects. Antineoplastic Agents / pharmacology. Drug Resistance, Neoplasm / drug effects. Microtubules / drug effects. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism. Tubulin / drug effects. Tubulin Modulators / pharmacology
  • [MeSH-minor] Animals. Blotting, Western. Cell Line, Tumor. Child. DNA Mutational Analysis. Electrophoresis, Gel, Two-Dimensional. Epothilones / pharmacology. Fluorescent Antibody Technique, Indirect. Gene Expression Regulation, Neoplastic / drug effects. Gene Silencing / drug effects. Humans. Leucine. Mass Spectrometry. Mice. Mutation / drug effects. Neuroblastoma / drug therapy. Neuroblastoma / metabolism. Plasmids. Proline. RNA, Small Interfering / metabolism. Reverse Transcriptase Polymerase Chain Reaction. Transfection. Tumor Stem Cell Assay. Valine. Vinblastine / pharmacology

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  • [CommentIn] J Natl Cancer Inst. 2006 Oct 4;98(19):1345-7 [17018774.001]
  • (PMID = 17018783.001).
  • [ISSN] 1460-2105
  • [Journal-full-title] Journal of the National Cancer Institute
  • [ISO-abbreviation] J. Natl. Cancer Inst.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Actins; 0 / Antineoplastic Agents; 0 / Epothilones; 0 / RNA, Small Interfering; 0 / Tubulin; 0 / Tubulin Modulators; 0 / desoxyepothilone B; 5V9KLZ54CY / Vinblastine; 9DLQ4CIU6V / Proline; GMW67QNF9C / Leucine; HG18B9YRS7 / Valine
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10. Golay J, Di Gaetano N, Amico D, Cittera E, Barbui AM, Giavazzi R, Biondi A, Rambaldi A, Introna M: Gemtuzumab ozogamicin (Mylotarg) has therapeutic activity against CD33 acute lymphoblastic leukaemias in vitro and in vivo. Br J Haematol; 2005 Feb;128(3):310-7
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  • [Title] Gemtuzumab ozogamicin (Mylotarg) has therapeutic activity against CD33 acute lymphoblastic leukaemias in vitro and in vivo.
  • Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated with the cytotoxic drug calicheamicin and approved for the treatment of relapsed acute myeloid leukaemia.
  • As approximately 18% of acute lymphoblastic leukaemias (ALL) are also CD33 positive, we have investigated the cytotoxic activity of GO on CD33+ ALL cells in vitro and in vivo.
  • 10 ng/ml GO induced 30-95% inhibition of thymidine uptake and 30-70% cell death in four freshly isolated and one in vivo passaged CD33+ ALL-cell cultures.
  • To test the therapeutic activity of GO, 50 or 100 microg immunotoxin was inoculated i.p. on days 7, 11 and 15 following tumour-cell inoculation.
  • GO treatment dramatically inhibited expansion of ALL-2 cells in all tested organs and increased survival of tumour-injected animals by 28-41 d, relative to controls.
  • [MeSH-major] Aminoglycosides / therapeutic use. Antibodies, Monoclonal / therapeutic use. Antigens, CD / analysis. Antigens, Differentiation, Myelomonocytic / analysis. Immunotoxins / therapeutic use. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • [MeSH-minor] Animals. Antibodies, Monoclonal, Humanized. Cell Death / drug effects. Female. Humans. Immunophenotyping. Mice. Mice, SCID. Neoplasm Transplantation. Sialic Acid Binding Ig-like Lectin 3. Transplantation, Heterologous. Tumor Cells, Cultured

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  • (PMID = 15667532.001).
  • [ISSN] 0007-1048
  • [Journal-full-title] British journal of haematology
  • [ISO-abbreviation] Br. J. Haematol.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Aminoglycosides; 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / Antigens, CD; 0 / Antigens, Differentiation, Myelomonocytic; 0 / CD33 protein, human; 0 / Cd33 protein, mouse; 0 / Immunotoxins; 0 / Sialic Acid Binding Ig-like Lectin 3; 0 / gemtuzumab
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11. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, Sulis ML, Barnes K, Sawai C, Homminga I, Meijerink J, Aifantis I, Basso G, Cordon-Cardo C, Ai W, Ferrando A: Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med; 2009 Jan;15(1):50-8
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  • [Title] Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
  • Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (NOTCH1) in T cell acute lymphoblastic leukemia (T-ALL).
  • However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs.
  • Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo.
  • Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor autoupregulation and induced apoptotic cell death through induction of the gene encoding BCL-2-like apoptosis initiator-11 (BCL2L11).
  • GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of the gene encoding the transcription factor Krüppel-like factor-4 (Klf4), a negative regulator of the cell cycle required for goblet cell differentiation.
  • In contrast, glucocorticoid treatment induced transcriptional upregulation of cyclin D2 (Ccnd2) and protected mice from developing the intestinal goblet cell metaplasia typically induced by inhibition of NOTCH signaling with GSIs.
  • These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL.

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  • (PMID = 19098907.001).
  • [ISSN] 1546-170X
  • [Journal-full-title] Nature medicine
  • [ISO-abbreviation] Nat. Med.
  • [Language] ENG
  • [Databank-accession-numbers] GEO/ GSE11184/ GSE7067
  • [Grant] United States / NCI NIH HHS / CA / 1R01 CA105129; United States / NCI NIH HHS / CA / CA133379-01A1; United States / NCI NIH HHS / CA / R01 CA120196-03; United States / NCI NIH HHS / CA / R01 CA133379; United States / NCI NIH HHS / CA / R01 CA105129-04; United States / NCI NIH HHS / CA / R01 CA129382; United States / NCI NIH HHS / CA / 1R01 CA133379; United States / NCI NIH HHS / CA / R01 CA149655; United States / NCI NIH HHS / CA / R01 CA105129; United States / NCI NIH HHS / CA / R01 CA133379-01A1; United States / NCI NIH HHS / CA / CA120196-03; United States / NIAID NIH HHS / AI / R56 AI070310-01A1; United States / NCI NIH HHS / CA / R01 CA120196; United States / NIAID NIH HHS / AI / AI070310-01A1; United States / NIAID NIH HHS / AI / R56 AI070310; United States / NCI NIH HHS / CA / CA105129-04
  • [Publication-type] Evaluation Studies; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Apoptosis Regulatory Proteins; 0 / Bcl-2-like protein 11; 0 / Ccnd2 protein, mouse; 0 / Cyclin D2; 0 / Cyclins; 0 / Enzyme Inhibitors; 0 / Glucocorticoids; 0 / Membrane Proteins; 0 / NR3C1 protein, human; 0 / Proto-Oncogene Proteins; 0 / Receptor, Notch1; 0 / Receptors, Glucocorticoid; 7S5I7G3JQL / Dexamethasone; EC 3.4.- / Amyloid Precursor Protein Secretases
  • [Other-IDs] NLM/ NIHMS103250; NLM/ PMC2692090
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12. Schmidt S, Rainer J, Riml S, Ploner C, Jesacher S, Achmüller C, Presul E, Skvortsov S, Crazzolara R, Fiegl M, Raivio T, Jänne OA, Geley S, Meister B, Kofler R: Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia. Blood; 2006 Mar 1;107(5):2061-9
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  • [Title] Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.
  • The ability of glucocorticoids (GCs) to kill lymphoid cells led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL).
  • Here, we present a comparative whole-genome expression profiling approach using lymphoblasts (purified at 3 time points) from 13 GC-sensitive children undergoing therapy for ALL.
  • For comparisons, expression profiles were generated from an adult patient with ALL, peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and -resistant ALL cell lines, and mouse thymocytes treated with GCs in vivo and in vitro.
  • Our analysis argued against most of the model-based hypotheses and instead identified a small number of novel candidate genes, including PFKFB2, a key regulator of glucose metabolism; ZBTB16, a putative transcription factor; and SNF1LK, a protein kinase implicated in cell-cycle regulation.
  • [MeSH-major] Apoptosis / drug effects. Drug Resistance, Neoplasm / genetics. Gene Expression Regulation, Leukemic / drug effects. Glucocorticoids / pharmacology. Neoplasm Proteins / genetics. Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics

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  • [ErratumIn] Blood. 2007 Apr 15;109(8):3234
  • (PMID = 16293608.001).
  • [ISSN] 0006-4971
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] eng
  • [Publication-type] Comparative Study; Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Glucocorticoids; 0 / Neoplasm Proteins
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13. Levy DS, Kahana JA, Kumar R: AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood; 2009 Feb 19;113(8):1723-9
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines.
  • We evaluated the effect of a novel, pan-AKT kinase inhibitor, GSK690693, on the proliferation of 112 cell lines representing different hematologic neoplasia.
  • Fifty-five percent of all cell lines tested were sensitive to AKT inhibitor (EC(50)<1 microM), with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma, and Burkitt lymphoma showing 89%, 73%, and 67% sensitivity to GSK690693, respectively.
  • The antiproliferative effect was selective for the malignant cells, as GSK690693 did not inhibit the proliferation of normal human CD4(+) peripheral T lymphocytes as well as mouse thymocytes.
  • Phosphorylation of downstream substrates of AKT was reduced in both sensitive and insensitive cell lines on treatment with GSK690693, suggesting that the cause of resistance was not related to the lack of AKT kinase inhibition.
  • Consistent with the role of AKT in cell survival, GSK690693 also induced apoptosis in sensitive ALL cell lines.
  • [MeSH-major] Apoptosis / drug effects. Oxadiazoles / pharmacology. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • [MeSH-minor] Animals. B-Lymphocytes / cytology. B-Lymphocytes / drug effects. CD4-Positive T-Lymphocytes / cytology. CD4-Positive T-Lymphocytes / drug effects. Cell Division / drug effects. Cell Line, Tumor. Cell Survival / drug effects. Drug Resistance, Neoplasm. Female. Humans. Leukemia, B-Cell / drug therapy. Leukemia, B-Cell / pathology. Lymphoma / drug therapy. Lymphoma / pathology. Mice. Mice, Inbred C57BL. Phosphorylation / drug effects. Signal Transduction / drug effects

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  • (PMID = 19064730.001).
  • [ISSN] 1528-0020
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / GSK690693; 0 / Oxadiazoles; EC 2.7.11.1 / Proto-Oncogene Proteins c-akt
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14. Teachey DT, Sheen C, Hall J, Ryan T, Brown VI, Fish J, Reid GS, Seif AE, Norris R, Chang YJ, Carroll M, Grupp SA: mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia. Blood; 2008 Sep 1;112(5):2020-3
NCI CPTC Antibody Characterization Program. NCI CPTC Antibody Characterization Program .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] mTOR inhibitors are synergistic with methotrexate: an effective combination to treat acute lymphoblastic leukemia.
  • We have previously demonstrated that mTOR inhibitors (MTIs) are active in preclinical models of acute lymphoblastic leukemia (ALL).
  • We tested this hypothesis using multiple ALL cell lines and nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenografted with human ALL.
  • Mice treated with both drugs went into a complete and durable remission whereas single agent treatment caused an initial partial response that ultimately progressed.

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  • (PMID = 18544682.001).
  • [ISSN] 1528-0020
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / K08 CA104882-04; United States / NCI NIH HHS / CA / K08 CA104882; United States / PHS HHS / / ACS RSG0507101; United States / NCI NIH HHS / CA / R01 CA102646; United States / NCI NIH HHS / CA / CA104882-04; United States / NCI NIH HHS / CA / CA102646; United States / NCI NIH HHS / CA / CA1116660
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antimetabolites, Antineoplastic; 0 / Cyclin D; 0 / Cyclins; 0 / Protein Kinase Inhibitors; EC 1.5.1.3 / Tetrahydrofolate Dehydrogenase; EC 2.7.- / Protein Kinases; EC 2.7.1.1 / MTOR protein, human; EC 2.7.1.1 / TOR Serine-Threonine Kinases; EC 2.7.1.1 / mTOR protein, mouse; YL5FZ2Y5U1 / Methotrexate
  • [Other-IDs] NLM/ PMC2518903
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15. Lucas DM, Edwards RB, Lozanski G, West DA, Shin JD, Vargo MA, Davis ME, Rozewski DM, Johnson AJ, Su BN, Goettl VM, Heerema NA, Lin TS, Lehman A, Zhang X, Jarjoura D, Newman DJ, Byrd JC, Kinghorn AD, Grever MR: The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood; 2009 May 7;113(19):4656-66
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  • [Title] The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo.
  • Therapeutic options for advanced B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) are limited.
  • Available treatments can also deplete T lymphocytes, leaving patients at risk of life-threatening infections.
  • In the National Cancer Institute cell line screen, the structurally unique natural product silvestrol produces an unusual pattern of cytotoxicity that suggests activity in leukemia and selectivity for B cells.
  • We investigated silvestrol efficacy using primary human B-leukemia cells, established B-leukemia cell lines, and animal models.
  • In vivo, silvestrol causes significant B-cell reduction in Emu-Tcl-1 transgenic mice and significantly extends survival of 697 xenograft severe combined immunodeficient (SCID) mice without discernible toxicity.
  • These data indicate silvestrol has efficacy against B cells in vitro and in vivo and identify translational inhibition as a potential therapeutic target in B-cell leukemias.

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  • (PMID = 19190247.001).
  • [ISSN] 1528-0020
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / U19 CA052956; United States / NCI NIH HHS / CA / P01CA125066; United States / NCI NIH HHS / CA / P01 CA125066; United States / NCI NIH HHS / CA / P01 CA081534; United States / NCI NIH HHS / CA / CA52956
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Mcl1 protein, mouse; 0 / Myeloid Cell Leukemia Sequence 1 Protein; 0 / Proto-Oncogene Proteins; 0 / Proto-Oncogene Proteins c-bcl-2; 0 / RNA, Messenger; 0 / Reactive Oxygen Species; 0 / Tcl1 protein, mouse; 0 / Triterpenes; 0 / silvestrol
  • [Other-IDs] NLM/ PMC2680369
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16. Kang MH, Kang YH, Szymanska B, Wilczynska-Kalak U, Sheard MA, Harned TM, Lock RB, Reynolds CP: Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo. Blood; 2007 Sep 15;110(6):2057-66
Hazardous Substances Data Bank. VINCRISTINE .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Activity of vincristine, L-ASP, and dexamethasone against acute lymphoblastic leukemia is enhanced by the BH3-mimetic ABT-737 in vitro and in vivo.
  • Defects in apoptosis signaling contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), and overexpression of antiapoptotic Bcl-2 (Bcl-2 and Bcl-X(L)) family proteins has been observed in ALL.
  • We evaluated the cytotoxicity of ABT-737 in combination with vincristine, dexamethasone, and L-asparaginase (VXL) in 7 ALL cell lines.
  • Multilog synergistic cytotoxicity was observed in all 7 cell lines with ABT-737 plus L-asparaginase or vincristine, and in 5 of 7 cell lines with ABT-737 plus dexamethasone or VXL.
  • In leukemia cells, but not in normal lymphocytes, ABT-737 plus L-asparaginase induced greater mitochondrial depolarization (JC-1 staining); mitochondrial cytochrome c release; activation of Bax, Bid, and caspases (immunoblotting); and eventually apoptosis (annexin V staining) than did either drug alone.
  • In mouse xenografts derived from patients with ALL at diagnosis (ALL-7) or at relapse (ALL-19), event-free survival (EFS) was significantly enhanced with ABT-737 plus VXL relative to VXL or ABT-737 alone (P </= .02).
  • Thus, ABT-737 synergistically enhanced VXL cytotoxicity in ALL cell lines via a mitochondrial death pathway and enhanced EFS in VXL-treated mice bearing ALL xenografts.
  • Combining VXL with a BH3-mimetic warrants clinical investigation in ALL at relapse and potentially in chemotherapy-resistant ALL subgroups.
  • [MeSH-major] Apoptosis / drug effects. Asparaginase / pharmacology. Biphenyl Compounds / pharmacology. Dexamethasone / pharmacology. Nitrophenols / pharmacology. Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Sulfonamides / pharmacology. Vincristine / pharmacology
  • [MeSH-minor] Animals. Anti-Inflammatory Agents / pharmacology. Antineoplastic Agents / pharmacology. Blotting, Western. Cell Line, Tumor. Child. Cytochromes c / metabolism. Drug Therapy, Combination. Female. Flow Cytometry. Humans. In Vitro Techniques. Leukemia, T-Cell / drug therapy. Leukemia, T-Cell / metabolism. Leukemia, T-Cell / pathology. Membrane Potential, Mitochondrial / drug effects. Mice. Mice, Inbred NOD. Mice, SCID. Mitochondria / drug effects. Piperazines / pharmacology. Proto-Oncogene Proteins c-bcl-2 / metabolism. Survival Rate

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  • (PMID = 17536015.001).
  • [ISSN] 0006-4971
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / ABT-737; 0 / Anti-Inflammatory Agents; 0 / Antineoplastic Agents; 0 / Biphenyl Compounds; 0 / Nitrophenols; 0 / Piperazines; 0 / Proto-Oncogene Proteins c-bcl-2; 0 / Sulfonamides; 5J49Q6B70F / Vincristine; 7S5I7G3JQL / Dexamethasone; 9007-43-6 / Cytochromes c; EC 3.5.1.1 / Asparaginase
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17. Tammam J, Ware C, Efferson C, O'Neil J, Rao S, Qu X, Gorenstein J, Angagaw M, Kim H, Kenific C, Kunii K, Leach KJ, Nikov G, Zhao J, Dai X, Hardwick J, Scott M, Winter C, Bristow L, Elbi C, Reilly JF, Look T, Draetta G, Van der Ploeg L, Kohl NE, Strack PR, Majumder PK: Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol; 2009 Nov;158(5):1183-95

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia.
  • BACKGROUND AND PURPOSE: gamma-Secretase inhibitors (GSIs) block NOTCH receptor cleavage and pathway activation and have been under clinical evaluation for the treatment of malignancies such as T-cell acute lymphoblastic leukaemia (T-ALL).
  • The ability of GSIs to decrease T-ALL cell viability in vitro is a slow process requiring >8 days, however, such treatment durations are not well tolerated in vivo.
  • EXPERIMENTAL APPROACH: Inhibition of the Notch pathway in mouse intestinal epithelium was used to evaluate the effect of GSIs and guide the design of dosing regimens for xenograft models.
  • GSI-induced conversion of mouse epithelial cells to a secretory lineage was time- and dose-dependent.
  • Anti-tumour efficacy was associated with cell cycle arrest and apoptosis that was in part due to Notch-dependent regulation of mitochondrial homeostasis.
  • [MeSH-major] Amyloid Precursor Protein Secretases / antagonists & inhibitors. Antineoplastic Agents / pharmacology. Cyclic S-Oxides / pharmacology. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Receptor, Notch1 / physiology. Thiadiazoles / pharmacology
  • [MeSH-minor] Amyloid beta-Peptides / blood. Animals. Apoptosis. Cell Differentiation. Cell Line, Tumor. Colon / cytology. Colon / drug effects. Down-Regulation. Drug Administration Schedule. Humans. Intestinal Mucosa / cytology. Intestinal Mucosa / drug effects. Membrane Potential, Mitochondrial / drug effects. Mice. Mice, Nude. Mitochondrial Proteins / biosynthesis. Mitochondrial Proteins / genetics. Neoplasm Transplantation. Peptide Fragments / blood. Signal Transduction. Transplantation, Heterologous

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  • (PMID = 19775282.001).
  • [ISSN] 1476-5381
  • [Journal-full-title] British journal of pharmacology
  • [ISO-abbreviation] Br. J. Pharmacol.
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Amyloid beta-Peptides; 0 / Antineoplastic Agents; 0 / Cyclic S-Oxides; 0 / MRK 003; 0 / Mitochondrial Proteins; 0 / Peptide Fragments; 0 / Receptor, Notch1; 0 / Thiadiazoles; 0 / amyloid beta-protein (1-40); EC 3.4.- / Amyloid Precursor Protein Secretases
  • [Other-IDs] NLM/ PMC2782329
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18. Buonamici S, Trimarchi T, Ruocco MG, Reavie L, Cathelin S, Mar BG, Klinakis A, Lukyanov Y, Tseng JC, Sen F, Gehrie E, Li M, Newcomb E, Zavadil J, Meruelo D, Lipp M, Ibrahim S, Efstratiadis A, Zagzag D, Bromberg JS, Dustin ML, Aifantis I: CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature; 2009 Jun 18;459(7249):1000-4
The Lens. Cited by Patents in .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia.
  • T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents.
  • T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse.
  • For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy.
  • The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy.
  • Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance.
  • These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting.
  • Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.

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  • (PMID = 19536265.001).
  • [ISSN] 1476-4687
  • [Journal-full-title] Nature
  • [ISO-abbreviation] Nature
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / P30 CA016087; United States / NCI NIH HHS / CA / P01 CA097403; United States / NCI NIH HHS / CA / R01 CA133379; United States / NIAID NIH HHS / AI / R56AI070310; United States / NCI NIH HHS / CA / R01CA133379; United States / NIAID NIH HHS / AI / R01 AI062765; United States / NCI NIH HHS / CA / R01 CA149655; United States / NCI NIH HHS / CA / R01 CA105129; United States / NIAID NIH HHS / AI / R01AI072039; United States / NIAID NIH HHS / AI / R01 AI072039; United States / NCI NIH HHS / CA / R21 CA141399; United States / NIAID NIH HHS / AI / R56 AI041428; United States / NIAID NIH HHS / AI / R56 AI072039; United States / NIAID NIH HHS / AI / R01 AI041428; United States / NIAID NIH HHS / AI / R01AI41428; United States / NCI NIH HHS / CA / R01CA105129; United States / NIAID NIH HHS / AI / R56 AI070310; United States / NCI NIH HHS / CA / P30CA016087; United States / NCI NIH HHS / CA / 1 P01 CA97403; United States / NIAID NIH HHS / AI / R21 AI041428
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] England
  • [Chemical-registry-number] 0 / CCR7 protein, human; 0 / Ccl19 protein, mouse; 0 / Ccr7 protein, mouse; 0 / Chemokine CCL19; 0 / Chemokine CCL21; 0 / Receptor, Notch1; 0 / Receptors, CCR7
  • [Other-IDs] NLM/ NIHMS488881; NLM/ PMC3750496
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19. Appert A, Nam CH, Lobato N, Priego E, Miguel RN, Blundell T, Drynan L, Sewell H, Tanaka T, Rabbitts T: Targeting LMO2 with a peptide aptamer establishes a necessary function in overt T-cell neoplasia. Cancer Res; 2009 Jun 01;69(11):4784-90

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Targeting LMO2 with a peptide aptamer establishes a necessary function in overt T-cell neoplasia.
  • LMO2 is a transcription regulator involved in human T-cell leukemia, including some occurring in X-SCID gene therapy trials, and in B-cell lymphomas and prostate cancer.
  • LMO2 functions in transcription complexes via protein-protein interactions involving two LIM domains and causes a preleukemic T-cell development blockade followed by clonal tumors.
  • The peptide inhibits Lmo2 function in a mouse T-cell tumor transplantation assay by preventing Lmo2-dependent T-cell neoplasia.
  • Lmo2 is, therefore, required for sustained T-cell tumor growth, in addition to its preleukemic effect.
  • Interference with LMO2 complexes is a strategy for controlling LMO2-mediated cancers, and the finger structure of LMO2 is an explicit focus for drug development.
  • [MeSH-major] Aptamers, Peptide / pharmacology. DNA-Binding Proteins / antagonists & inhibitors. DNA-Binding Proteins / physiology. Drug Delivery Systems / methods. Metalloproteins / antagonists & inhibitors. Metalloproteins / physiology. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics

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  • (PMID = 19487290.001).
  • [ISSN] 1538-7445
  • [Journal-full-title] Cancer research
  • [ISO-abbreviation] Cancer Res.
  • [Language] eng
  • [Grant] United Kingdom / Medical Research Council / / G0600914; United Kingdom / Medical Research Council / / MC/ U105178807; United Kingdom / Medical Research Council / /
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Validation Studies
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Adaptor Proteins, Signal Transducing; 0 / Aptamers, Peptide; 0 / DNA-Binding Proteins; 0 / LIM Domain Proteins; 0 / Lmo2 protein, mouse; 0 / Metalloproteins
  • [Other-IDs] NLM/ PMC2690635; NLM/ UKMS4469
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20. Uno S, Kinoshita Y, Azuma Y, Tsunenari T, Yoshimura Y, Iida S, Kikuchi Y, Yamada-Okabe H, Fukushima N: Antitumor activity of a monoclonal antibody against CD47 in xenograft models of human leukemia. Oncol Rep; 2007 May;17(5):1189-94
The Lens. Cited by Patents in .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Antitumor activity of a monoclonal antibody against CD47 in xenograft models of human leukemia.
  • To confirm whether the ligation of CD47 caused cell death in vivo, we examined the antitumor activity of F(ab')2 of mAb-MABL in two xenograft models: The acute lymphoblastic leukemia (CCRF-CEM) and the B-cell chronic lymphocytic leukemia (JOK-1) cell line.
  • Male SCID mice were intravenously injected with CCRF-CEM (5 x 10(6) cells/mouse) or JOK-1 cells (5 x 10(6) cells/mouse) and intraperitoneally with JOK-1 cells (2 x 10(7) cells/mice).
  • Significantly, 40% of the mice intraperitoneally injected with JOK-1 cells became tumor-free when administered F(ab')2 of mAb-MABL, whereas even a high dose of fludarabine only slightly prolonged the median survival time.
  • Thus, monoclonal antibodies that cause cell death from the ligation of CD47 could be novel therapeutic agents for incurable leukemia after further optimization such as humanization or making single chain diabodies.
  • [MeSH-major] Antibodies, Monoclonal / pharmacology. Antigens, CD47 / immunology. Leukemia, Lymphocytic, Chronic, B-Cell / therapy. Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • [MeSH-minor] Animals. Apoptosis / drug effects. Cell Line, Tumor. Humans. Leukemia L1210. Male. Mice. Mice, SCID. Xenograft Model Antitumor Assays

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  • (PMID = 17390064.001).
  • [ISSN] 1021-335X
  • [Journal-full-title] Oncology reports
  • [ISO-abbreviation] Oncol. Rep.
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] Greece
  • [Chemical-registry-number] 0 / Antibodies, Monoclonal; 0 / Antigens, CD47
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21. Lim WS, Tardi PG, Xie X, Fan M, Huang R, Ciofani T, Harasym TO, Mayer LD: Schedule- and dose-dependency of CPX-351, a synergistic fixed ratio cytarabine:daunorubicin formulation, in consolidation treatment against human leukemia xenografts. Leuk Lymphoma; 2010 Aug;51(8):1536-42
The Lens. Cited by Patents in .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Schedule- and dose-dependency of CPX-351, a synergistic fixed ratio cytarabine:daunorubicin formulation, in consolidation treatment against human leukemia xenografts.
  • CPX-351, a liposomal formulation co-encapsulating cytarabine (Cyt) and daunorubicin (Daun), has been developed, which delivers synergistic Cyt:Daun molar ratios to bone marrow.
  • CPX-351 has demonstrated markedly superior anti-leukemic activity over free Cyt:Daun drug cocktails in preclinical models.
  • Given the prolonged plasma lifetime of CPX-351, we examined the relationship between therapeutic efficacy and the frequency of treatment in the consolidation setting using a bone marrow-engrafting human leukemia xenograft model.
  • Adding a day 1,3,5 consolidation treatment course for CPX-351 therapy improved the increase in lifespan (ILS) from 116% and no cures for a single induction course, to 268% plus a 33% cure rate for an induction plus consolidation course.
  • In contrast, free Cyt:Daun cocktail treatment provided much lower ILS values with no cures.
  • Administering CPX-351 as consolidation therapy starting on day 42 using a day 1,3, day 1,5, or day 1,7 schedule yielded ILS values of 154%, 185%, and 108%, respectively.
  • The increased efficacy observed for the day 1,3 and day 1,5 consolidation schedules was associated with elevated bone marrow drug accumulation for the second doses.
  • The enhanced efficacy obtained for intermediate dosing frequency in the consolidation setting suggests that the anti-leukemic activity of synergistic drug ratios is dependent on both duration of exposure and maintenance above a therapeutic threshold.
  • [MeSH-major] Antineoplastic Combined Chemotherapy Protocols / therapeutic use. Dosage Forms. Drug Synergism. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • [MeSH-minor] Animals. Bone Marrow Cells / drug effects. Chemistry, Pharmaceutical. Cytarabine / administration & dosage. DNA-Binding Proteins / physiology. Daunorubicin / administration & dosage. Dose-Response Relationship, Drug. Drug Administration Schedule. Female. Flow Cytometry. Humans. Liposomes. Maximum Tolerated Dose. Mice. Survival Rate. Tissue Distribution. Tumor Cells, Cultured. Xenograft Model Antitumor Assays

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  • (PMID = 20528246.001).
  • [ISSN] 1029-2403
  • [Journal-full-title] Leukemia & lymphoma
  • [ISO-abbreviation] Leuk. Lymphoma
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] England
  • [Chemical-registry-number] 0 / DNA-Binding Proteins; 0 / Dosage Forms; 0 / Liposomes; 0 / Rag2 protein, mouse; 04079A1RDZ / Cytarabine; ZS7284E0ZP / Daunorubicin
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22. Porkka K, Koskenvesa P, Lundán T, Rimpiläinen J, Mustjoki S, Smykla R, Wild R, Luo R, Arnan M, Brethon B, Eccersley L, Hjorth-Hansen H, Höglund M, Klamova H, Knutsen H, Parikh S, Raffoux E, Gruber F, Brito-Babapulle F, Dombret H, Duarte RF, Elonen E, Paquette R, Zwaan CM, Lee FY: Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood; 2008 Aug 15;112(4):1005-12
NCI CPTAC Assay Portal. NCI CPTAC Assay Portal .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.
  • Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier.
  • Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia.
  • Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed.
  • The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia.
  • In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS.
  • Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy.
  • [MeSH-major] Blood-Brain Barrier / metabolism. Central Nervous System Neoplasms / drug therapy. Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy. Pyrimidines / administration & dosage. Pyrimidines / pharmacokinetics. Thiazoles / administration & dosage. Thiazoles / pharmacokinetics
  • [MeSH-minor] Adolescent. Adult. Aged. Animals. Child. Cytogenetic Analysis. Dasatinib. Disease Models, Animal. Drug Evaluation, Preclinical. Drug Monitoring. Female. Humans. Male. Mice. Middle Aged. Precursor Cell Lymphoblastic Leukemia-Lymphoma. Remission Induction. Spinal Puncture. Survival Rate. Treatment Outcome. Tumor Burden / drug effects

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  • (PMID = 18477770.001).
  • [ISSN] 1528-0020
  • [Journal-full-title] Blood
  • [ISO-abbreviation] Blood
  • [Language] eng
  • [Databank-accession-numbers] ClinicalTrials.gov/ NCT00108719/ NCT00110097
  • [Publication-type] Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Pyrimidines; 0 / Thiazoles; RBZ1571X5H / Dasatinib
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23. Pituch-Noworolska A: [Biological properties and sensitivity to induction therapy of differentiated cells expressing atypical immunophenotype in acute leukemia of children]. Folia Med Cracov; 2001;42(3):5-80
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  • [Title] [Biological properties and sensitivity to induction therapy of differentiated cells expressing atypical immunophenotype in acute leukemia of children].
  • [Transliterated title] Właściwości biologiczne i wrazliwość na leczenie indukcyjne komórek rozrostowych o nietypowym immunofenotypie w ostrych białaczkach u dzieci.
  • The atypical immunophenotype (expression of determinant from the another cell lines than line of origin) of acute leukaemia blast cells are noted in a part of cases.
  • The purpose of the study was: precise description of atypical immunophenotypes and analysis of their frequency in different types of acute leukaemia, analysis of association between expression of atypical immunophenotypes and the level of initial leukocytosis, percentage of blast cells in peripheral blood, expression of CD34, analysis of frequency of multidrug resistance molecule (MDR) expression and association between MDR and immunophenotypes of leukaemia cells, analysis of association between atypical immunophenotypes and proliferation, secretion of cytokines (IL-6, TNF) and spontaneous apoptosis of leukaemia cells, analysis of association between atypical immunophenotypes and sensitivity to induction therapy.
  • The type of proliferation (autocrine, paracrine) was defined based on comparison of shorter (3-days) and longer (6-days) culture of leukaemia cells.
  • The biological activity of TNF was determined in the bioassay using L929 mouse cells line.
  • The effect of induction therapy was estimated base on time of cytoreduction in peripheral blood and time of reaching the haematological remission in bone marrow.
  • The study included 230 children with acute leukaemia: lymphoblastic (ALL)--189 children (ALL-proB--19, common ALL--139, ALL-B--5 and ALL-T--26) and myeloid (AML)--34 children.
  • The all studies of leukaemia cells had been done before the therapy was installed.
  • The most common form of atypical immunophenotypes was coexpression of determinants from the other cell line.
  • The expression of CD34, recognised as the one of markers of poorer prognosis, was analysed regarding the leukaemia type and immunophenotype of leukaemia cells.
  • The autocrine type of proliferation was observed frequently in AML (35.3% of cases) than in ALL (14.2%).
  • This type of spontaneous proliferation was observed only when the leukaemia cells without changes in immunophenotype had been cultured.
  • There were no differences of the time of cytoreduction of leukaemia cells in peripheral blood in B cell origin ALL and AML with or without changes in immunophenotype of blastic cells.
  • In ALL-T + My the time of cytoreduction was significantly longer.
  • However, the expression of CD10 in ALL-T had no effect on cytoreduction time.
  • The expression of MDR in ALL-T with typical immunophenotype was independent marker associated with elongation of cytoreduction time.
  • The time of reaching the complete haematological remission was analysed in 186 children with ALL (ALL-proB--18 children, common ALL--137 children, ALL-T--26) and only 19 children with AML.
  • The longest period of time for reaching the remission was observed in AML, shortest--in ALL-T.
  • In common ALL and ALL-T the expression of myeloid determinants was associated with significant elongation of time of reaching the remission.
  • The time needed for the reaching of remission was similar in AML with or without coexpression of lymphoid determinants.
  • The results of this study suggest that coexpression of determinants from the other cell line modify the biological properties of leukaemia cells into the cells from the line of origin of these additional determinants.
  • In ALL the combined expression of MDR and atypical immunophenotype of leukaemia cells were associated with poorer response to induction therapy.
  • In AML the combined expression of CD34 and atypical immunophenotype were associated with response to induction therapy by reaching the complete remission, but without any influence on the time of reaching this remission.
  • The results of analysis of cytoreduction time and time of reaching the remission improved the usefulness of these parameters for the estimation of response to the induction therapy.
  • The clinical importance of these observations consist in characterisation of leukaemia cells potentially resistant to the induction therapy what may suggest the modification and individualization of the induction therapy.
  • [MeSH-major] Leukemia, Myeloid, Acute / immunology. Leukemia, Myeloid, Acute / therapy. Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology. Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • [MeSH-minor] Adolescent. Animals. Antigens, CD34 / immunology. Apoptosis. Child. Child, Preschool. Cytokines / secretion. Drug Resistance, Multiple / immunology. Humans. Immunophenotyping. Infant. Mice. Multidrug Resistance-Associated Proteins / immunology. Remission Induction

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  • (PMID = 12353422.001).
  • [ISSN] 0015-5616
  • [Journal-full-title] Folia medica Cracoviensia
  • [ISO-abbreviation] Folia Med Cracov
  • [Language] pol
  • [Publication-type] English Abstract; Journal Article; Review
  • [Publication-country] Poland
  • [Chemical-registry-number] 0 / Antigens, CD34; 0 / Cytokines; 0 / Multidrug Resistance-Associated Proteins
  • [Number-of-references] 160
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24. Schlereth B, Kleindienst P, Fichtner I, Lorenczewski G, Brischwein K, Lippold S, da Silva A, Locher M, Kischel R, Lutterbüse R, Kufer P, Baeuerle PA: Potent inhibition of local and disseminated tumor growth in immunocompetent mouse models by a bispecific antibody construct specific for Murine CD3. Cancer Immunol Immunother; 2006 Jul;55(7):785-96
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Potent inhibition of local and disseminated tumor growth in immunocompetent mouse models by a bispecific antibody construct specific for Murine CD3.
  • High efficacy at low effector-to-target ratios, independence of T cell costimuli and a potent activation of previously unstimulated polyclonal T cells were identified as hallmarks of this class of bispecific antibodies.
  • Here we studied a bispecific single-chain antibody construct (referred to as 'bispecific T cell engager', BiTE) in an immunocompetent mouse model.
  • This was possible by the use of a murine CD3-specific BiTE, and a syngeneic melanoma cell line (B16F10) expressing the human Ep-CAM target.
  • Treatment with 2C11x4-7 was effective even when it was started 10 days after tumor cell inoculation but delayed treatments showed a reduction in the number of cured animals.
  • When treatment was started on the day of intravenous tumor cell injection, seven out of eight animals stayed free of lung tumors, and three out of eight animals when treatment was started on day 5.
  • [MeSH-major] Antibodies, Bispecific / therapeutic use. Antigens, CD3 / immunology. Antigens, Neoplasm / immunology. Cell Adhesion Molecules / immunology. Immunotherapy. Melanoma, Experimental / therapy. Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • [MeSH-minor] Animals. Antibody Specificity. Cell Line, Tumor / transplantation. Dose-Response Relationship, Immunologic. Drug Screening Assays, Antitumor. Humans. Immunocompetence. Lung Neoplasms / secondary. Lung Neoplasms / therapy. Mice. Mice, Inbred C57BL. Mice, Inbred NOD. Mice, SCID. Neoplasm Transplantation. Recombinant Fusion Proteins / immunology. Subcutaneous Tissue. Xenograft Model Antitumor Assays

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  • (PMID = 16187083.001).
  • [ISSN] 0340-7004
  • [Journal-full-title] Cancer immunology, immunotherapy : CII
  • [ISO-abbreviation] Cancer Immunol. Immunother.
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] Germany
  • [Chemical-registry-number] 0 / Antibodies, Bispecific; 0 / Antigens, CD3; 0 / Antigens, Neoplasm; 0 / Cell Adhesion Molecules; 0 / EPCAM protein, human; 0 / Recombinant Fusion Proteins
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25. Borgmann A, Baldy C, von Stackelberg A, Beyermann B, Fichtner I, Nürnberg P, Henze G: Childhood all blasts retain phenotypic and genotypic characteristics upon long-term serial passage in NOD/SCID mice. Pediatr Hematol Oncol; 2000 Dec;17(8):635-50
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  • For children with an early bone marrow relapse or relapsed T-cell acute lymphoblastic leukemia (ALL), allogeneic bone marrow transplantation (BMT) is currently the only therapeutic option with a curative approach.
  • Here, the graft versus leukemia (GvL) effect seems to play an important role for long-term immunological control of leukemia.
  • If a bone marrow donor is not available, autologous stem cell transplantation after high-dose chemotherapy has been used as an alternative option.
  • The first step was the establishment of an optimized and reliable mouse model.
  • The second step was the induction of a GvL effect in an allogeneic approach to serve as a basis for further GvL experiments in an autologous approach in this mouse model.
  • The antileukemic activity of allogeneic human MNC as a GvL reaction and an accompanying GvHD in the mouse model was shown.
  • [MeSH-major] Neoplasm Transplantation / methods. Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics. Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • [MeSH-minor] Adolescent. Animals. Cell Division. Child. Child, Preschool. DNA Fingerprinting. Female. Genotype. Graft vs Host Disease / immunology. Graft vs Host Disease / pathology. Humans. Immunophenotyping. Interleukin-2 / pharmacology. Leukocytes, Mononuclear / drug effects. Leukocytes, Mononuclear / immunology. Male. Mice. Mice, Inbred NOD. Mice, SCID. Phenotype. T-Lymphocytes, Cytotoxic / drug effects. T-Lymphocytes, Cytotoxic / immunology. Transplantation, Heterologous

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  • (PMID = 11127395.001).
  • [ISSN] 0888-0018
  • [Journal-full-title] Pediatric hematology and oncology
  • [ISO-abbreviation] Pediatr Hematol Oncol
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Interleukin-2
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26. Fukuyama T, Tajima Y, Ueda H, Hayashi K, Shutoh Y, Harada T, Kosaka T: Apoptosis in immunocytes induced by several types of pesticides. J Immunotoxicol; 2010 Mar;7(1):39-56
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Apoptosis in immunocytes induced by several types of pesticides.
  • Several types of pesticides, such as organophosphates and organochlorines, can induce thymocyte apoptosis, resulting in thymic atrophy and predisposing the highly sensitive fetal immune system to loss of tolerance to self-antigens and subsequent increased risk for autoimmune disease and allergies.
  • In the studies here, mouse primary thymocytes and a human acute T-cell leukemia cell line (J45.01) were employed to examine potential thymocyte apoptosis induced by several types of chemicals, including several commonly-used pesticides.
  • Apoptosis, cell viability, the proportion of Annexin-V+ cells, the activities of caspases 3/7, 8, and 9, and the levels of DNA fragmentation in both the J45.01 cells and thymocytes were then examined.
  • The results here show that with both cell types, there was an increase in the proportion of annexin-V+ cells and levels of DNA fragmentation following exposure to parathion, PNMC, methoxychlor, or dexamethasone (positive control); however, the levels of sensitivity appeared to differ between the cell types.
  • A more precise characterization of these inter-cellular differences is the logical next step in our studies of the effects of these (and other) pesticides on immune cell integrity.
  • These specific types of follow-on mechanistic experiments are currently underway in our laboratories.
  • [MeSH-major] Apoptosis / drug effects. Pesticides / toxicity. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. T-Lymphocytes / drug effects. Thymus Gland / drug effects
  • [MeSH-minor] Animals. Cell Line, Tumor. Cell Survival / drug effects. DNA Fragmentation. DNA, Neoplasm / analysis. Female. Humans. Mice. Mice, Inbred BALB C

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  • (PMID = 19911945.001).
  • [ISSN] 1547-6901
  • [Journal-full-title] Journal of immunotoxicology
  • [ISO-abbreviation] J Immunotoxicol
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] England
  • [Chemical-registry-number] 0 / DNA, Neoplasm; 0 / Pesticides
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27. Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE: Direct inhibition of the NOTCH transcription factor complex. Nature; 2009 Nov 12;462(7270):182-8
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • Here we report the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex.
  • Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL).
  • The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes.
  • Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.

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  • (PMID = 19907488.001).
  • [ISSN] 1476-4687
  • [Journal-full-title] Nature
  • [ISO-abbreviation] Nature
  • [Language] ENG
  • [Databank-accession-numbers] GEO/ GSE18198/ GSE18351
  • [Grant] United States / NCI NIH HHS / CA / R56 CA092433; United States / NCI NIH HHS / CA / R56 CA092433-06A1; United States / NIGMS NIH HHS / GM / T32 GM007598-30; United States / NCI NIH HHS / CA / CA119070-049001; United States / NIGMS NIH HHS / GM / GM007598-30; United States / NCI NIH HHS / CA / R01 CA092433; United States / NIGMS NIH HHS / GM / T32 GM007598; None / None / / R01 CA092433-06A2; United States / NIGMS NIH HHS / GM / 5T32GM007598; United States / NCI NIH HHS / CA / N01CO12400; None / None / / R56 CA092433-06A1; United States / NCI NIH HHS / CA / R01 CA092433-06A2; United States / NCI NIH HHS / CA / P01 CA119070-049001; United States / NCI NIH HHS / CO / N01-CO-12400; United States / NCI NIH HHS / CA / P01 CA119070
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] England
  • [Chemical-registry-number] 0 / DNA-Binding Proteins; 0 / Drosophila Proteins; 0 / Immunoglobulin J Recombination Signal Sequence-Binding Protein; 0 / MAML1 protein, human; 0 / NOTCH1 protein, human; 0 / Notch1 protein, mouse; 0 / Nuclear Proteins; 0 / Peptides; 0 / RBPJ protein, human; 0 / Receptor, Notch1; 0 / Transcription Factors; 0 / mastermind protein, Drosophila
  • [Other-IDs] NLM/ NIHMS186490; NLM/ PMC2951323
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28. Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, Schahin-Reed D, Dow GJ, Shelton A, Stawicki S, Watts RJ, Zhang J, Choy R, Howard P, Kadyk L, Yan M, Zha J, Callahan CA, Hymowitz SG, Siebel CW: Therapeutic antibody targeting of individual Notch receptors. Nature; 2010 Apr 15;464(7291):1052-7
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Therapeutic antibody targeting of individual Notch receptors.
  • The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth.
  • Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs.
  • To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models.
  • Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis.
  • Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.
  • [MeSH-major] Antibodies / pharmacology. Antibodies / therapeutic use. Neoplasms / drug therapy. Neoplasms / metabolism. Receptors, Notch / antagonists & inhibitors
  • [MeSH-minor] Angiogenesis Inhibitors / immunology. Angiogenesis Inhibitors / pharmacology. Angiogenesis Inhibitors / therapeutic use. Animals. Antibody Specificity / immunology. Cell Line, Tumor. Cell Proliferation / drug effects. Goblet Cells / drug effects. Goblet Cells / pathology. Humans. Mice. Mice, Inbred BALB C. NIH 3T3 Cells. Neovascularization, Pathologic / drug therapy. Peptide Library. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism. Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology. Receptor, Notch1 / antagonists & inhibitors. Receptor, Notch1 / immunology. Receptor, Notch2 / antagonists & inhibitors. Receptor, Notch2 / immunology. Signal Transduction / drug effects






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