Abstract:
OBJECTIVE:The mechanism for anagrelide's potent platelet lowering activity in human subjects is not well defined. Studies related to anagrelide function have been hampered by its lack of activity in nonhuman primates and water insolubility. In an effort to define the mechanism whereby anagrelide exerts its therapeutic effect, we identified a water-soluble metabolite (anagrelide.met). The availability of anagrelide.met allowed, for the first time, parallel in vitro and in vivo animal studies centered on the mechanisms by which anagrelide lowers platelet levels. MATERIALS AND METHODS:The effects of anagrelide.met on proliferation and maturation of mega-karyocytes (MKs) as well as platelet production were studied both in vitro and in vivo. RESULTS:Anagrelide.met is capable of blocking in vitro MK migration by 20% to 40%. At 100 ng/mL, anagrelide.met selectively blocked in vitro MK maturation, resulting in a 50% decrease in the total number of CD41a(+) MKs, corresponding with a 30% decrease in MK ploidy by day 10 and a 60% decrease by day 20. Daily intraperitoneal injections of anagrelide.met 100 microg into BALB/c mice was sufficient to significantly decrease platelet counts within 24 to 48 hours, stabilizing to 40 to 50% of normal levels by day 5. This was associated with a 45% decrease in the number of developing MKs and an increase in thrombopoietin levels. Anagrelide.met did not alter WBC counts, hematocrit, or bleeding time, or lead to any apparent signs of toxicity. Furthermore, unlike the parent anagrelide compound, anagrelide.met did not inhibit ADP-induced platelet aggregation even at high concentrations (10 microg/mL). CONCLUSIONS:We describe a cross-species reactive anagrelide metabolite that selectively inhibits MK maturation and migration, lowering platelet levels without influencing platelet aggregation.
journal_name
Exp Hematoljournal_title
Experimental hematologyauthors
Lane WJ,Hattori K,Dias S,Peerschke EI,Moore MA,Blanset DL,Lang PC,Petrone M,Rafii Sdoi
10.1016/s0301-472x(01)00742-1keywords:
subject
Has Abstractpub_date
2001-12-01 00:00:00pages
1417-24issue
12eissn
0301-472Xissn
1873-2399pii
S0301472X01007421journal_volume
29pub_type
杂志文章abstract:OBJECTIVE:Progenipoietin-1 is an agonist of both the granulocyte colony-stimulating factor and fetal liver tyrosine kinase-3 receptors capable of inducing the proliferation of multiple hematopoietic cell lineages. The potential of progenipoietin-1 to mobilize transplantable hematopoietic stem cells into the peripheral ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(01)00675-0
更新日期:2001-08-01 00:00:00
abstract::Media conditioned by B-lymphocytes of patients with chronic lymphocytic leukemia (B-CLL) induced the formation of multilineage colonies (CFU-GEMM) in cultures of human target marrow cells. Maximum levels of stem cell colony-stimulating activity (CFU-GEMMCSA) were detected by day 3 of leukemic B-cell cultures, remainin...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract::Hematopoiesis in continuous bone marrow culture is dependent upon close-range interaction between hematopoietic cells and marrow-derived adherent cells. The latter have been shown to include a significant proportion of fibroblastic elements, synthesizing the attachment protein fibronectin. The role of fibronectin in c...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1983-02-01 00:00:00
abstract::Lentinan, an antitumor polysaccharide, has been assessed for its potential in vivo to augment erythroid progenitor cells and protect them from the cytotoxic effects of antitumor chemotherapeutics. Lentinan augmented the level of burst-forming units-erythroid (BFU-E) and accelerated the recovery of the reduced number o...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1996-02-01 00:00:00
abstract::Delayed platelet recovery and altered marrow megakaryocytopoiesis was observed in highly irradiated mice following transplantation with 1000 lineage-negative, stem cell antigen-positive (Lin-Sca-1+) cells. Thirty days after transplantation, the mice were thrombocytopenic. Normal platelet levels were reestablished by 9...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1993-12-01 00:00:00
abstract::Cyclooxygenase (COX) plays a key regulatory role in prostaglandin synthesis. COX-2 is inducible and is the major isoform of inflammatory cells. COX-2-deficient mice were shown to have normal basal hematopoiesis and hematology. We hypothesized that COX-2 induction plays a role in the recovery phase of 5-fluorouracil (5...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(99)00087-9
更新日期:1999-10-01 00:00:00
abstract:OBJECTIVE:T lymphocytes can be activated by soluble factors such as cytokines or through direct cell-cell interactions. Although cytokine receptors are known to signal through STAT family transcription factors, the mechanisms by which other cell-surface molecules, such as CD2, transduce signals is unclear. The goal of ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(00)00652-4
更新日期:2001-02-01 00:00:00
abstract::We previously reported an in vitro bioassay permissive to eosinophil production from naive mouse bone marrow cells. Based on cytosmear analysis, recombinant murine (rm) interleukin (IL)-3 combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) provided better quantitative cellular yields compared with ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1998-06-01 00:00:00
abstract:OBJECTIVE:Myeloid ectropic viral integration site 1 (MEIS1) is a Hox cofactor known for its role in development and is strongly linked to normal and leukemic hematopoiesis. Although previous studies have focused on identifying protein partners of MEIS1 and its transcriptionally regulated targets, little is known about ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2010.06.006
更新日期:2010-09-01 00:00:00
abstract::Familial platelet disorder with propensity to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease associated with a germline mutation in the RUNX1 gene and is characterized by thrombocytopenia and an increased risk of developing myeloid malignancies. We generated induced pluripotent stem cells (iPSCs) fr...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2015.05.004
更新日期:2015-10-01 00:00:00
abstract::Recombinant human interleukin 6 (rhIL-6) was administered s.c. every 12 h at a daily dose of 10 micrograms/kg body weight to normal healthy mice. After 4 days the numbers of progenitor cells (erythroid burst-forming units, BFU-E and granulocyte-macrophage colony-forming cells, GM-CFC) were significantly increased (p l...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1990-10-01 00:00:00
abstract::The immunostimulant poly(A)-poly(U) induces a rapid enhancement of circulating colony-stimulating activity (CSA) in normal mice, culminating 2 h after i.v. injection. A dose of 200 micrograms per mouse is sufficient for a maximal effect. The colonies formed in response to sera from poly(A)-poly(U)-injected mice are ma...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1991-05-01 00:00:00
abstract::We have attempted to evaluate in vivo effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on acute radiation hematopoietic injury in mice. BDF1 mice, irradiated with 7.5-Gy x-rays, were injected i.p. twice daily for 10 days with 10(5) U recombinant hum...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1989-09-01 00:00:00
abstract:OBJECTIVE:Morbidity and mortality occurring in patients with multiple myeloma, AL amyloidosis, and light chain deposition disease can result from the pathologic deposition of monoclonal immunoglobulin light chains (LCs) in kidneys and other organs. To reduce synthesis of such components, therapy for these disorders typ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2010.07.001
更新日期:2010-11-01 00:00:00
abstract::Septins are a family of filament-forming GTP-binding proteins that serve as scaffolds and diffusion barriers in various cellular processes. Septin 6 is known as a fusion partner of mixed-lineage leukemia in infant acute myeloid leukemia. The occurrence of the fusion gene is associated with a reduced expression of sept...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2017.07.005
更新日期:2017-11-01 00:00:00
abstract:OBJECTIVE:Among Philadelphia chromosome-negative myeloproliferative neoplasms (Ph(-) MPN), essential thrombocythemia (ET) and the prefibrotic phase of primary myelofibrosis (PMF) represent two subtypes with considerable overlap. MATERIALS AND METHODS:In this study, histopathological classification of 490 MPN cases was...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2009.07.005
更新日期:2009-10-01 00:00:00
abstract::Somatic mutations of calreticulin (CALR) have been observed in many cases of essential thrombocythemia (ET) or primary myelofibrosis that harbor non-mutated Janus kinase 2 (JAK2). CALR mainly localizes within the endoplasmic reticulum lumen, but a small fraction of the total CALR pool is distributed over the cell surf...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2016.05.001
更新日期:2016-09-01 00:00:00
abstract::Serum erythropoietin (Epo) levels are depressed in anemic AIDS patients relative to controls. The basis for abnormal regulation of Epo has not been defined. The hepatoma cell line Hep3B produces Epo in response to hypoxia and serves as a model for the study of Epo regulation. Hep3B cells are infectible with human immu...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1993-05-01 00:00:00
abstract::Human umbilical cord blood (CB) appears to be an exciting new source of transplantable stem cells for a variety of clinical conditions. In this study, we have attempted to further characterize the primitive progenitors in CB. First we analyzed the effects of early-acting growth factors on blast cell colony formation f...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1995-12-01 00:00:00
abstract::This review of adjunctive therapy with subcutaneous granulocyte-colony stimulating factor (G-CSF) to patients with acute myocardial infarction (AMI) focus on the cardioprotective effects and potential mechanisms of G-CSF and discuss the therapeutic potential of G-CSF. All clinical trials published in peer-reviewed jou...
journal_title:Experimental hematology
pub_type: 杂志文章,评审
doi:10.1016/j.exphem.2008.01.010
更新日期:2008-06-01 00:00:00
abstract::Anamorsin (AM) is an antiapoptotic molecule that confers factor-independent survival on hematopoietic cells. AM-deficient (AM(-/-)) mice are embryonic lethal because of a defect in definitive hematopoiesis; however, the significance of AM in embryonic hematopoiesis remains unknown. This study characterized the hematop...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2014.01.002
更新日期:2014-05-01 00:00:00
abstract::Injection of mice with either natural bovine bone-derived or human recombinant transforming growth factor beta 1 (TGF-beta 1) resulted in a significant increase of the macrophage and macrophage-granulocyte-forming capacity of their macrophage colony-stimulating factor (M-CSF)- and granulocyte-macrophage colony-stimula...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract::The kinetics of cell turnover for myeloid/monocyte cells that form colonies in agar (GM-CFC) were measured through the progressive increase in their sensitivity to 313-nm light during a period of cell labeling with BrdCyd. Two components of cell killing with distinctly separate labeling kinetics revealed both the pres...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1985-07-01 00:00:00
abstract::An evaluation of the effectiveness of a genetically engineered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin 3 (IL-3) fusion protein (FP) as a means of delivering cytokine combinations to megakaryocyte (MK) progenitor cells was performed, utilizing a serum-depleted clonal assay syst...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract:OBJECTIVE:Approximately 60% of all anaplastic large-cell lymphomas (ALCL) contain a specific t(2;5)(p23;q35) chromosomal translocation leading to overexpression of NPM-ALK. As the chimeric tyrosine kinase is involved in tumorigenesis and pathogenesis of ALCL, we were interested to inhibit NPM-ALK expression using an ex...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(02)01084-6
更新日期:2003-03-01 00:00:00
abstract::The comparative influences of phytohemagglutinin-stimulated leukocyte conditioned medium (PHALCM), hemin, prostaglandin E1 (PGE1), and growth of cells at low oxygen tension (5% O2) were evaluated for their capacity to enhance colony formation in vitro from normal human bone marrow erythroid progenitor cells (BFU-E). E...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1985-11-01 00:00:00
abstract::Benign constitutional neutropenia (BCN) is an asymptomatic condition characterized by mild chronic neutropenia in patients with no history of recurrent infections. Most patients are referred for further testing, increasing health care costs. We present an alternative form of assessment of individuals with BCN based on...
journal_title:Experimental hematology
pub_type: 临床试验,杂志文章
doi:10.1016/j.exphem.2018.10.007
更新日期:2019-01-01 00:00:00
abstract::Transcription factors are essential to govern differentiation along the lymphoid lineage from uncommitted hematopoietic stem cells. Although many of these transcription factors have putative roles based on murine knockout experiments, their function in human lymphoid development is less known and was studied further. ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(00)00680-9
更新日期:2001-04-01 00:00:00
abstract::The expression of exogenous genes in long-lived primary T cells is potentially beneficial for the treatment of various diseases including cancer, AIDS, genetic defects of the lymphoid compartment, and systemic enzyme deficiencies such as hemophilia. One approach for genetic modification of T cells is to introduce ther...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1996-10-01 00:00:00
abstract:OBJECTIVE:To examine whether oncogenic Ras affects transforming growth factor (TGF)-beta-mediated cell-cycle arrest in hematopoietic cells and the downstream signal transduction pathway involved in the interference with TGF-beta-induced cell-cycle arrest. MATERIALS AND METHODS:Two leukemic cell lines bearing N-Ras(L61...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2005.04.006
更新日期:2005-07-01 00:00:00