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Biologic and structural differences of thrombopoietic growth factors

SEMINARS IN HEMATOLOGY 2000年第2期37卷 19-27页

作者： Begley, CG Basser, RL Western Australian Inst Med Res Perth WA 6000 Australia Ctr Dev Canc Therapeut Parkville Vic Australia Royal Melbourne Hosp Dept Clin Haematol & Med Oncol Melbourne Vic Australia Royal Melbourne Hosp Rotary Bone Marrow Res Labs Melbourne Vic Australia Walter & Eliza Hall Inst Med Res Parkville Vic Australia Ludwig Inst Canc Res CH-1066 Epalinges Switzerland

The search for a thrombopoietic agent has resulted in the identification of numerous cytokines and growth factors with thrombopoietic activity. However, with the exception of interleukin (IL)-11 and thrombopoietin (TPO), the megakaryopoietic activity of most of these molecules has not produced clearly identifiable clinical benefits. Despite the relatively modest effect of IL-11 on megakaryocyte and platelet production in vitro and in vivo, it does reduce the need for platelet transfusions in specialized clinical settings. In contrast, the c-Mpl ligand TPO has been shown to be a potent stimulator of megakaryocyte and platelet production both in vitro and in vivo. Clinical studies are being conducted with two different preparations of the c-Mpl ligand: recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). A recombinant form of the complete human molecule, rhTPO is glycosylated and produced in mammalian cells. PEG-rHuMGDF consists of only the receptor-binding domain linked to a polyethylene glycol (PEG) moiety and is generated in Escherichia coli. Although c-Mpl ligands are still being evaluated, preliminary evidence indicates that these molecules can elevate platelet counts and may be useful in a range of clinical contexts. This report discusses aspects of the biology behind the clinical actions of IL-11 and the c-Mpl ligands.

关键词：血小板/细胞学血小板/药物作用细胞因子类/血液细胞因子类/药理学细胞因子类/生理学生长物质/血液生长物质/药理学生长物质/生理学血细胞生成/药物作用白细胞介素11/血液白细胞介素11/药理学白细胞介素11/生理学巨核细胞/细胞学巨核细胞/药物作用血小板生成素/血液血小板生成素/药理学血小板生成素/生理学动物人类

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PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells

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BLOOD 2000年第3期95卷 879-885页

作者： Guerriero, A Langmuir, PB Spain, LM Scott, EW Univ Penn Inst Human Gene Therapy Philadelphia PA 19104 USA Wistar Inst Anat & Biol Philadelphia PA 19104 USA

The ets-family transcription factor PU.1 is required for the proper development of both myeloid and lymphoid progenitors. We used PU.1-deficient animals to examine the role of PU.1 during dendritic cell development. PU.1(-/-)animals produce lymphoid-derived dendritic cells (DC): low density class II major histocompatibility complex [MHC-II+] CD11c(+) CD8 alpha(+) DEC-205(+), But they lack myeloid-derived DC: low-density MHC-II+ CD11c(+) CD8 alpha(-) DEC-205(-). PU.1(-/-) embryos also lack progenitors capable of differentiating into myeloid DC in response to granulocyte-macrophage colony-stimulating factor plus interleukin-4. The appearance of lymphoid DC in developing PU.1(-/-)thymus was initially delayed, but this population recovered to wild type (WT) levels upon organ culture of isolated thymic lobes, PU.1(-/-)lymphoid DC were functionally equivalent to WT DC for stimulating T-cell proliferation in mixed lymphocyte reactions. These results demonstrate that PU.1 is required for the development of myeloid DC but not lymphoid DC. (C) 2000 by The American Society of Hematology.

关键词：抗原呈递骨髓/胚胎学骨髓细胞/细胞学细胞谱系克隆清除树突细胞/分类树突细胞/细胞学树突细胞/代谢粒细胞巨噬细胞集落刺激因子/药理学血细胞生成/药物作用血细胞生成/遗传学免疫表型分型白细胞介素4/药理学淋巴组织/细胞学淋巴组织/胚胎学小鼠基因敲除器官培养技术原癌基因蛋白质类/药物作用原癌基因蛋白质类/生理学胸腺/细胞学胸腺/胚胎学反式激活因子类/药物作用反式激活因子类/生理学动物小鼠

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Suppressive effects of swainsonine and N-butyldeoxynojirimycin on human bone marrow neutrophil maturation

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第1期269卷 219-225页

作者： Misago, M Tsukada, J Fukuda, MN Eto, S Univ Occupat & Environm Hlth Sch Hlth Sci Lab Clin Hematol Kitakyushu Fukuoka 8078555 Japan Univ Occupat & Environm Hlth Sch Med Dept Internal Med 1 Kitakyushu Fukuoka 8078555 Japan Burnham Inst Glycobiol Program La Jolla CA 92037 USA

The effects of the N-linked oligosaccharide inhibitors swainsonine and N-butyldeoxynojirimycin (NB-DNJ) on granulopoiesis was investigated using human bone marrow cells in in vitro liquid and agar cultures. The addition of the inhibitors into cultures containing granulocyte colony-stimulating factor (G-CSF) suppressed maturation from myelocytes into mature neutrophils. Swainsonine did not induce apoptosis, but NB-DNJ induced considerable apoptosis, especially in the presence of G-CSF. This result indicated that the decrease of mature neutrophils by swainsonine was not because of cell degeneration. In the case of NB-DNJ, it was thought to be because of both maturation suppression and apoptosis. In a colony-forming unit-granuloid (CFU-G) colony assay, the number of colonies was increased in the presence of the inhibitors, but the morphology of colonies was predominantly compact, or immature. The inhibitors also suppressed the expressions of mRNAs of CCAAT/enhancer binding protein epsilon (C/EBP epsilon) and G-CSF receptor as markers of terminal neutrophil maturation. These findings suggested that the incompleteness of N-linked oligosaccharide leads to the suppression of terminal neutrophil maturation. (C) 2000 Academic Press.

关键词： 1-脱氧野尻霉素/类似物和衍生物 1-脱氧野尻霉素/药理学细胞凋亡/药物作用碱基序列骨髓细胞/细胞学骨髓细胞/药物作用骨髓细胞/代谢 CCAAT增强子结合蛋白类细胞分化/药物作用细胞培养的集落形成单位测定 DNA引物/遗传学 DNA结合蛋白质类/遗传学酶抑制剂/药理学粒细胞集落刺激因子/药理学血细胞生成/药物作用甘露糖苷酶类/拮抗剂和抑制剂中性白细胞/细胞学中性白细胞/药物作用中性白细胞/代谢核蛋白质类/遗传学寡糖类/代谢 RNA 信使/遗传学 RNA 信使/代谢受体粒细胞集落刺激因子/遗传学苦马豆素/药理学衣霉素/药理学 α葡糖苷酶类/拮抗剂和抑制剂 α甘露糖苷酶人类

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A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells

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BLOOD 2000年第5期95卷 1616-1625页

作者： Han, W Ye, Q Moore, MAS Mem Sloan Kettering Canc Ctr Lab Dev Hematopoiesis New York NY 10021 USA

Two Notch ligand families, Delta and Serrate/Jagged, have been identified in vertebrates. Members of the Jagged family have been shown to affect in vitro hematopoiesis. To determine whether members of the Delta family might play a similar role in hematopoiesis, we examined the expression of mouse Delta like-1 (mDII1), mDII1 protein was detected in whole marrow and in a marrow stromal cell line MS-5. At the RNA level, both mDII1 and Notch1 were seen in marrow precursor, differentiated hematopoietic, marrow stromal, and MS-5 cells. We isolated a cDNA encoding the human homologue of mDII1, designated human Delta-like-1 (hDII1). A soluble form of hDII1, hDII1(NDSL), containing the DSL domain and the N-terminal sequences, was expressed and purified from bacteria as a glutathione S-transferase (GST) fusion protein. We observed that hDII1(NDSL) delayed the acquisition of differentiation markers by murine hematopoietic progenitor cells (Lin(-)) cultured in vitro with cytokines. In addition, it promoted greater expansion (more than 3 times) of the primitive hematopoietic precursor cell population, measured in high-proliferative potential colony assay and day 12 colony-forming unit spleen (CFU-S) assay, than GST controls. We also observed that the percentage of apoptotic cells decreased and that the number of cells in the S-phase of the cell cycle increased in the cultures of Lin- cells with hDII1NDSL The effects of hDII1NDSL were blocked by antibody against the mouse counterpart of hDII1(NDSL), mDII1(NDSL). These observations demonstrate that hDII1 plays a role in mediating cell fate decisions during hematopoiesis. (C) 2000 by The American Society of Hematology.

关键词：氨基酸序列抗原分化/分析细胞凋亡/药物作用细胞凋亡/生理学骨髓细胞/细胞学骨髓细胞/药物作用骨髓细胞/代谢细胞分化/药物作用细胞分化/生理学细胞系集落形成单位测定 DNA 互补/遗传学流式细胞术基因表达调控/药物作用血细胞生成/药物作用血细胞生成/生理学造血细胞生长因子/药理学造血干细胞/细胞学造血干细胞/药物作用膜蛋白质类/遗传学膜蛋白质类/代谢膜蛋白质类/生理学分子序列数据 RNA 信使/生物合成受体 Notch 重组融合蛋白质类/生理学序列比对序列同源性氨基酸种特异性间质细胞/代谢动物人类小鼠

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Induction of erythroid differentiation of human K562 cells by 3-O-acyl-1,2-O-isopropylidene-D-glucofuranose derivatives

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BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 1999年第21期9卷 3153-3158页

作者： Catelani, G Osti, F Bianchi, N Bergonzi, MC D'Andrea, F Gambari, R Univ Ferrara Dipartimento Biochim & Biol Mol I-44100 Ferrara Italy Univ Pisa Dipartimento Chim Bioorgan & Biofarm I-56126 Pisa Italy

In this paper we report the synthesis of twelve 3-O-acyl-1,2-O-isopropylidene-D-glucofuranose derivatives and the results obtained on their effects in inducing erythroid differentiation of human leukemic K562 cells. The data obtained demonstrate that two of the newly synthetized compounds are able to induce erythroid differentiation of K562 cells. In addition, these same compounds potentiate K562 erythroid differentiation induced by cytosine arabinoside, retinoic acid and mithramycin. Inducers of erythroid differentiation stimulating fetal gamma-globin synthesis could be considered for possible use in the experimental therapy of hematological diseases associated with a failure in the expression of adult beta-globin genes. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：细胞分化/药物作用阿糖胞苷/药理学基因表达调控/药物作用葡萄糖/类似物和衍生物血细胞生成/药物作用血红蛋白类/生物合成己糖类/化学合成己糖类/药理学 K562细胞普卡霉素/药理学维甲酸/药理学人类

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Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression

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BLOOD 2000年第3期95卷 837-845页

作者： MacVittie, TJ Farese, AM Smith, WG Baum, CM Burton, E McKearn, JP Univ Maryland Greenebaum Canc Ctr Baltimore MD 21201 USA Monsanto Co Searle R&D St Louis MO USA

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells, This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression, Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 (Co-60) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 mu g/kg/d (n = 4), or 50 mu g/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10), Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 mu g/kg/d, in a daily schedule(n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/mu L) and thrombocytopenia (platelet < 20 000/mu L) Versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophills (ANC to < 500/mu L) and platelets (PLT < 20 000/mu L) were significantly enhanced in the MPO-treated cohorts Versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression. (C) 2000 by The American Society of Hematology.

关键词：血细胞计数/药物作用输血骨髓疾病/病因学细胞谱系集落形成单位测定剂量效应关系辐射药物设计药物评价临床前粒细胞集落刺激因子重组血细胞生成/药物作用造血细胞生长因子/化学造血细胞生长因子/药理学造血细胞生长因子/治疗应用白细胞介素3 恒河猴中性粒细胞减少/药物疗法中性粒细胞减少/病因学蛋白质工程辐射损伤实验性/药物疗法受体粒细胞集落刺激因子/激动剂受体白细胞介素3/激动剂重组融合蛋白质类血小板减少/药物疗法血小板减少/病因学动物男(雄)性

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Elevated cyclin E levels, inactive retinoblastoma protein, and suppression of the p27^KIP1 inhibitor characterize early development of promyeloid cells into macrophages

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MOLECULAR AND CELLULAR BIOLOGY 1999年第9期19卷 6229-6239页

作者： Liu, Q VanHoy, RW Zhou, JH Dantzer, R Freund, GG Kelley, KW Univ Illinois Immunophysiol Lab Edward R Madigan Lab 207 Dept Anim Sci Urbana IL 61801 USA Univ Illinois Coll Med Dept Pathol Urbana IL 61801 USA INRA INSERM U394 Inst Francois Magendie F-33077 Bordeaux France Sun Yat Sen Univ Med Sci Ctr Canc Dept Hematol Oncol Guangzhou 510060 Peoples R China

Cyclin-dependent kinase inhibitors such as p27(KIP1) have recently been shown to lead to cellular differentiation by causing cell cycle arrest, but it is unknown whether similar events occur in differentiating promyeloid cells. Hematopoietic progenitor cells undergo lineage-restricted differentiation, which is accompanied by expression of distinct maturation markers. Here we show that the classical growth factor insulin-like growth factor I (IGP-I) potently promotes vitamin D-3-induced macrophage differentiation of promyeloid cells, as assessed by measurement of a coordinate increase in expression of the integrin alpha subunit CD11b, the CD14 lipopolysaccharide receptor, and the macrophage-specific esterase, alpha-naphthyl acetate esterase, as early as 24 h following initiation of terminal differentiation. Addition of IGF-I to cells undergoing vitamin D-3-induced differentiation also leads to an early increase in expression of cyclin E, phosphorylation of the retinoblastoma tumor suppressor protein, and a doubling of the cell number. Early expression of CD11b (24 h) is simultaneously accompanied by inhibition in the expression of p27(KIP1). Cell cycle analysis with propidium iodide revealed that CD11b expression at 24 h following initiation of differentiation occurs at all phases of the cell cycle instead of only those cells arrested in G(0)/G(1). Similarly, development of a novel double-labeling intra- and extracellular flow-cytometric technique demonstrated that single cells expressing the mature leukocyte differentiation antigen CD11b can also incorporate the thymidine analog bromodeoxyuridine. Likewise, expression of the intracellular DNA polymerase delta cofactor/proliferating-cell nuclear antigen at 24 h is also simultaneously expressed with the surface marker CD11b, indicating that these cells continue to proliferate early in their differentiation program. Finally, at 24 h following induction of differentiation, IGF-I promoted a fourfold increase in the uptak

关键词：细胞周期细胞周期蛋白质类细胞分裂/药物作用胆骨化醇/药理学细胞周期蛋白E/代谢周期素依赖激酶抑制剂p27 细胞周期蛋白质依赖激酶类/拮抗剂和抑制剂酶抑制剂/代谢酯酶类/代谢 HL-60细胞血细胞生成/药物作用血细胞生成/免疫学血细胞生成/生理学造血干细胞/细胞学造血干细胞/药物作用造血干细胞/代谢胰岛素样生长因子Ⅰ/药理学动力学巨噬细胞1抗原/代谢巨噬细胞/细胞学巨噬细胞/药物作用巨噬细胞/代谢微管相关蛋白质类/代谢磷酰化视网膜母细胞瘤蛋白质/代谢胸苷/代谢肿瘤抑制蛋白质类人类

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STIMULATORY EFFECT OF STAPHYLOCOCCAL LEUKOCIDIN ON GRANULOPOIESIS DISTURBED BY CYTOSTATIC AGENTS

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CANCER LETTERS 1976年第5期1卷 299-303页

作者： SZMIGIELSKI, S JELJASZEWICZ, J CTR RADIOPROTECTION & RADIOBIOL PL-00909 WARSZAWAPOLAND NATL INST HYG PL-00791 WARSZAWAPOLAND

Functional tests of granulopoiesis (leukocytosis, bone marrow picture, incubation in vitro of bone marrow with [3H]thymidine followed by radioautography and counting of labeled promyelocytes and myelocytes, serum muramidase level, liberation of granulocyte bone marrow reserve, Nitro-BT reduction in blood granulocytes, enzyme cytochemistry, and phagocytosis) were performed in rabbits given bubulphan (10 mg/kg) or 5-fluorouracil (200 mg/kg). Determinations were carried on serially during treatment with cytostatics. Some of the cytostatic-treated animals received intravenous (i.v.) injections of purified staphylococcal leukocidin in daily doses of 0.1 mg/kg. In control animals, theleukocidin resulted in stimulation of granulopoiesis (leukocytosis, increased number of [3H]thymidine-labeled myelocytes, elevated serum muramidase level). Animals receiving cytostatics suffered from marked inhibition of granulopoiesis accompanied by decrease of bone marrow granulocyte reserve. Injection of staphylococcal leukocidin during the period of myelosuppression evoked by cytostatics resulted in partial protection of granylopoiesis and faster regeneration of the leukocyte system.

关键词：骨髓/药物作用白消安/副作用氟尿嘧啶/副作用粒细胞/药物作用血细胞生成/药物作用杀白细胞素类/药理学白细胞/药物作用葡萄球菌属动物兔

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Therapeutic cytokine stimulation of thrombocytopoiesis

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TRANSFUSION SCIENCE 1998年第2期19卷 149-162页

作者： Harker, LA Emory Univ Yerkes Reg Primate Res Ctr Sch Med Div Hematol & Oncol Atlanta GA 30322 USA

Endogenous thrombopoietin (TPO) stimulates platelet production by inducing dose-dependent megakaryocyte development from early marrow hematopoietic progenitors and subsequent proliferation and endoreduplication. Recombinant human (rHu) TPO or pegylated recombinant human megakaryocyte growth and development factor (PEG-rHu MGDF) produce log-linear responses in experimental animals and humans when administered over the dose range of 0.05-25 mu g/kg/day with respect to peak peripheral platelet counts (or peripheral platelet mass turnover) and marrow megakaryocyte volume, ploidy, number and mass. Other cytokines stimulating megakaryocytopoiesis in various species using different dosing regimens include Interleukin 1 (IL-1), Interleukin 3 (IL-3), Interleukin 6 (IL-6), Interleukin 11 (IL-11), stem cell factor (SCF), granulocyte-macrophage colony stimulating factor, (GM-CSF), fusion proteins, such as pro-megapoietin, and a peptide agonist of TPO receptor. Whereas neither rHuTPO nor PEG-rHuMGDF induce platelet aggregation in vitro, they transiently enhance aggregatory responsiveness of platelets to physiologic agonists from several different experimental animals both in vitro and ex vivo. However, platelet recruitment into forming thrombus is not augmented by these agents when evaluated in quantitative rabbit or baboon models of platelet-dependent thrombus formation, except for the effect of platelet;concentration per se. These findings indicate that appropriate dosing of these agents following marrow suppression prevents thrombocytopenia without increasing the risk of platelet-dependent thrombo-occlusive complications. (C) 1998 Elsevier Science Ltd. All rights reserved.

关键词：血小板/药物作用细胞因子类/治疗应用血细胞生成/药物作用刺激化学性人类

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Adamantylamide dipeptide stimulates hematopoiesis and increases survival in irradiated mice

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INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY 2000年第1期22卷 91-97页

作者： Hofer, M Vacek, A Masek, K Juchelková, L Pipalová, I Acad Sci Czech Republ Inst Biophys CZ-61265 Brno Czech Republic Acad Sci Czech Republ Inst Pharmacol Prague Czech Republic

It has been demonstrated that the synthetic immunostimulatory compound, adamantylamide dipeptide (AdDP) produces hematopoiesis-stimulating effects in mice exposed to sublethal doses of ionizing radiation and increases survival in experimental animals irradiated with a lethal dose. These findings might suggest contingent extension of clinical indications for the administration of AdDP for the conditions of hematopoietic suppression, especially in oncology. (C) 2000 International Society for Immunopharmacology. Published by Elsevier Science Ltd. All rights reserved.

关键词：佐剂免疫/药理学金刚烷胺/类似物和衍生物金刚烷胺/药理学二肽类/药理学血细胞生成/药物作用造血干细胞/药物作用造血干细胞/辐射效应小鼠近交C57BL 小鼠近交CBA 动物女(雌)性小鼠

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