Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Monocytes and macrophages have receptors for the iron-binding protein lactoferrin. Lactoferrin acts as a potent inhibitor of granulocyte-macrophage colony stimulating factor production when it binds to these cells. Using a rosette assay and immunofluorescence, we have shown that cultured leukemia cells, including the human erythroid leukemia cell line K562, also have lactoferrin binding sites. The number of binding sites on K562 cells was estimated using soluble 59Fe-lactoferrin. Inhibition studies demonstrate that lactoferrin binding sites are distinct and unrelated to receptors for transferrin or the Fc portion of IgG, which are present on K562 cells. However, electrostatic forces may be important for lactoferrin binding, since other polycationic proteins (eg, protamine) inhibit lactoferrin binding. Prior treatment of K562 cells with trypsin nearly abolishes lactoferrin binding. However, these cells recover their ability to bind lactoferrin when trypsin is removed. Unlike transferrin receptors, the expression of lactoferrin binding sites is not regulated by cellular iron status. Cytosine arabinoside arrests the proliferation of K562 cells and simultaneously leads to a reduction in lactoferrin surface binding, suggesting that lactoferrin binding may be dependent on cell proliferation.
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PMID:Lactoferrin binding by leukemia cell lines. 303 77

The aim of this study was to test whether colony stimulating factors (CSF) and other cytokines facilitate the recovery of a variety of immunohematopoietic functions in lethally irradiated mice undergoing bone marrow transplantation (BMT). Two experimental systems were employed: (a) lethally irradiated mice transplanted with syngeneic or T cell-depleted semi-allogeneic bone marrow (BM) cells (0.1-10 x 10(6)), subsequently treated by multiple doses of cytokines; and (b) lethally irradiated mice transplanted with BM cells that had previously been cultivated with cytokines. The cytokines used were: pure natural mouse interleukin-3 (IL-3); recombinant mouse granulocyte-macrophage CSF (rGM-CSF); recombinant human interleukin-2 (rIL-2); and crude cytokine preparations obtained from the culture supernatants of murine leukemia WEHI-3b cells (containing mainly IL-3), and of phorbol myristate acetate (PMA)-stimulated EL4 leukemia cells and concanavalin A-stimulated rat splenocytes (each containing a multitude of cytokines). For BM cultures (1-9 days), the cytokines were used at a dosage of 1-100 U/ml; for in vivo treatment, 2 x 10(2)-5 x 10(4) units were administered intraperitoneally and subcutaneously at different schedules for varying periods (1-3 weeks). The following parameters were tested 1-10 weeks post-BMT: white blood cell count, colony formation in agar and in the spleen of lethally irradiated mice, proliferative responses to mitogens and alloantigens, allocytotoxicity and antibody production (serum agglutinins and plaque-forming cells) against sheep red blood cells. Under appropriate conditions, cytokine treatment either in vitro or in vivo significantly enhanced (2- to 50-fold compared with controls) most functions tested at 2-8 weeks post-BMT, and shortened the time interval required for full immunohematopoietic recovery by 2-5 weeks. In recipients of semi-allogeneic, T lymphocyte-depleted BM no evidence of graft-versus-host disease was found. It is suggested that judicious application in vitro and/or in vivo of certain pure cytokines (e.g. GM-CSF, IL-3) or cytokine 'cocktails' might be beneficial in enhancing hematopoiesis and in the treatment of immunodeficiency associated with BMT.
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PMID:In vitro and in vivo cytokine-induced facilitation of immunohematopoietic reconstitution in mice undergoing bone marrow transplantation. 304 95

Since freshly obtained acute lymphoblastic leukemia (ALL) cells rarely replicate spontaneously in vitro in a sustained way, development of a useful clonogenic assay for ALL blast progenitors is dependent on identifying the cellular growth requirements. Thus, marrows from 25 ALL cases were cultured in methylcellulose to determine the optimal conditions for cell growth. Blast colonies were confirmed as leukemic by morphology, cytochemistry, surface markers, and cytogenetics. Irradiated (7000 rads) normal peripheral blood feeder cells were an absolute requirement and produced number-dependent increases in ALL colonies; added growth factors enhanced the feeder cell effect. ALL cell-feeder cell contact was essential since their physical separation in a two-layer culture system drastically interfered with colony growth. Feeder cells from various donors, including new and relapsed cases of ALL, yielded colony numbers that differed widely when tested on the same marrow with and without added growth factor; thus, identification of a "good" feeder cell donor was key to an optimal assay. Neither recombinant interleukin-2 nor recombinant GM-CSF had ALL growth-promoting properties when tested alone or in combination but in the presence of feeder cells they moderately enhanced the feeder cell effect. The most effective growth factors were derived from cells exposed to phytohemagglutinin (PHA) for 72 h. In order of magnitude for colony growth-promoting activity, PHA-T cell conditioned medium (CM) was more stimulatory than PHA-blast cell CM followed by PHA-leukocyte CM; removal of PHA from CM by affinity chromotography did not alter the results. The most potent PHA-TCM was prepared from T-cells from a phlebotomized hemochromatosis patient; PHA-TCM from transfused thalassemia patients and normal donors were less active. Concanavalin-A blast cell CM had modest colony promoting properties whereas CM prepared with other B-cell mitogens and supernatants from ALL blasts in liquid culture had none. Our studies illustrate the complex and fastidious growth needs of ALL cells. The data have allowed us to refine a clonogenic blast progenitor assay that should facilitate study of proliferative properties of B and T lineage leukemias. The assay could be adapted further for detection of residual leukemia cells in marrow samples used for autologous transplantation, and in patients during complete hematological "remission."
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PMID:Growth requirements for human acute lymphoblastic leukemia cells: refinement of a clonogenic assay. 304 51

In the first clinical study on GM-CSF in acute leukemias continuous infusion of the growth factor is given to patients in aplasia and at high risk of early death due to age over 65 years and/or intensive chemotherapy for resistance or relapse. Among 6 patients (4 AML, 2 ALL) receiving a total of 7 courses two died too early to contributing adequate data. Three patients and 4 courses showed earlier neutrophil recovery than related control groups and a fourth patient with secondary AML showed a neutrophil recovery time in the normal range, but much shorter than her platelet and reticulocyte recovery. No evidence was obtained so far for leukemic regrowth in these patients including blood and bone marrow cytology, monitoring of DNA aneuploidy by flow cytometry and clonogenic cells by colony assays. Thus, GM-CSF may be useful for rescue after intensive chemotherapy of AML and ALL and may not necessarily increase the risk of leukemia progression.
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PMID:Human recombinant granulocyte macrophage colony stimulating factor (GM-CSF) treatment of patients with acute leukemias in aplasia and at high risk of early death. 307 45

We have identified a leukemia-differentiating activity (LDA) in medium conditioned by the LD-1 melanoma, a G-CSF secreting human tumor line. Partially-purified LDA induces HL-60 cells to produce superoxide, become phagocytic, and to develop macrophage-like morphology and surface markers. The LDA markedly suppresses clonal growth in agar of HL-60 cells, and cells of the human myeloid leukemia lines PBL 985 and K562, but does not suppress clonal growth of the B-lymphoblast lines Raji and Daudi. The molecular weight of this material is approx. 40,000 daltons. It can be separated from the bulk of the colony stimulating activity on phenyl sepharose chromatography. The LDA is not neutralized by antibodies to G-CSF, GM-CSF, IFN alpha, IFN gamma, TNF, urokinase, and tissue plasminogen activator, and is not inhibited by preincubation with aprotinin. The LDA in conditioned medium may be different from previously described differentiating factors, and may represent an additional class of human growth regulators.
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PMID:Leukemia-differentiating activity expressed by the human melanoma cell line LD-1. 316 98

Cells of the human myelomonocytic line RC-2A can be induced to differentiate towards mature monocytes by culture in the presence of phytohaemagglutinin-treated lymphocyte conditioned medium (Lyons and Ashman, Leukemia Res. 11, 797, 1987). We have now examined the effect on RC-2A cells of some (recombinant) cytokines which might be present in conditioned medium. Gamma interferon most closely mimicked the effect of conditioned medium in inducing clonogenic suppression and the induction of monocytic maturation over 7 days of culture. Granulocyte colony stimulating factor induced enhancement of proliferation followed by clonogenic suppression, while granulocyte-macrophage colony stimulating factor had a purely stimulatory effect on proliferation over a 7-day period. Tumour necrosis factor alpha failed to affect cell proliferation or to induce characteristic monocytic differentiation, but did increase the expression of C3bi receptors. We conclude that RC-2A cells have receptors for all four cytokines studied, and that gamma interferon is a major differentiation-inducing stimulus for these cells.
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PMID:The effect of recombinant cytokines on the proliferative potential and phenotype of cells of the human myelomonocytic leukaemia line, RC-2A. 318 82

There are 4 different normal myeloid hematopoietic cell growth-inducing proteins MGI-1 (CSF or IL-3) that induce normal precursor cells to multiply and form clones containing only macrophages (MGI-1M = M-CSF = CSF-1), only granulocytes (MGI-1G = G-CSF), both granulocytes and macrophages (MGI-1GM = GM-CSF), or granulocytes, macrophages, eosinophils, mast cells, megakaryocytes and erythroid cells (interleukin-3) (IL-3). There is another type of normal myeloid regulatory protein (MGI-2) with no MGI-1 (CSF or IL-3) activity which can induce differentiation of normal myeloid precursors and certain clones of myeloid leukemic cells. The present results with MGI-2 and pure recombinant MGI-1G, MGI-1GM and IL-3 have shown that different clones of myeloid leukemic cells can be induced to differentiate by different hematopoietic regulatory proteins. One type of leukemic clone is induced to differentiate to mature cells only by MGI-2 and is partially differentiated by MGI-1G, a second type is differentiated only by MGI-1GM or IL-3, and other workers have found a third type that is differentiated only by MGI-1G. The presence of surface receptors does not necessarily make leukemic cells differentiation-competent for these hematopoietic regulatory proteins. All 4 types of MGI-1 (CSF or IL-3) induce endogenous synthesis of MGI-2 in normal myeloid precursor cells. It is suggested that, in addition to their potential therapeutic effect on the development of normal hematopoietic cells, MGI-2, MGI-1G, MGI-1GM and IL-3 all have the potential for differentiation-directed therapy of leukemia in leukemic cells that can be differentiated by one of these normal hematopoietic regulatory proteins.
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PMID:Role of different normal hematopoietic regulatory proteins in the differentiation of myeloid leukemic cells. 325 7

Human recombinant GM-CSF (rGM-CSF) is under investigation as a growth-protective agent for normal hematopoietic elements in phase I trials of myelosuppressive chemotherapy and in bone marrow transplantation. We determined the effect of rGM-CSF on the metabolism of high dose Ara-C in bone marrow mononuclear cells (BMMCs) from healthy volunteers and patients with ANLL. Cells were incubated with rGM-CSF alone, Ara-C alone, or a combination of the two drugs. Treatment with rGM-CSF alone yielded approximately a twofold increment in intracellular dCTP pools in normal BMMCs but not in leukemic blasts. Exposure to rGM-CSF in conjunction with Ara-C corrected Ara-C-mediated declines in dCTP levels and decreased cytosine arabinoside triphosphate (Ara-CTP) accumulation in normal BMMCs but not in their leukemic counterparts. Furthermore, when exposure to Ara-C was preceded by treatment with rGM-CSF for 18 hr, an even greater reduction in the Ara-CTP/dCTP pool ratio was observed in normal versus leukemic elements; however, this did not significantly change Ara-C DNA incorporation in the two cell types. The differential effect of rGM-CSF on the phosphorylation of Ara-C in normal BMMCs versus leukemic blasts has potential implications for the use of a regimen consisting of rGM-CSF and high dose Ara-C in the treatment of ANLL with chemotherapy or autologous bone marrow transplantation.
Leukemia 1988 Dec
PMID:Effect of recombinant GM-CSF on the metabolism of cytosine arabinoside in normal and leukemic human bone marrow cells. 326 63

Besides its effect on bone marrow progenitors, GM-CSF is able to modulate functions of mature cells such as neutrophils. It inhibits random migration and chemotaxis through action on both cells and chemotactic factors, and stimulates oxidative metabolism as well as elastase release. Furthermore, it strongly enhances the response of the cells to the usual stimulants such as f-Met-Leu-Phe and phorbol esters. The role of neutral proteinases and activated oxygen species in different diseases such as ARDS, emphysema, coagulation defects, arthritis, and inflammation, is recognized. The remarkable in vitro release of neutral proteinases and activated oxygen species from granulocytes after GM-CSF stimulation may be of importance in vivo. This should be considered in clinical application of GM-CSF, particularly with high-dose therapy.
Leukemia 1988 Dec
PMID:Modulation of functions of granulocytes by recombinant human GM-CSF and possible complications of GM-CSF therapy. 326 66

Proliferation in vitro of the murine hemopoietic cell line FDC-P1 is dependent on stimulation by granulocyte-macrophage colony stimulating factor or multipotential colony stimulating factor. Although immortalized, the cells are not tumorigenic on subcutaneous inoculation. Intravenous injection of FDC-P1 cells into syngeneic DBA/2 mice was followed by the development of transplantable leukemias in 15% of nonirradiated animals and in virtually all animals that had received 100-350 rad whole-body irradiation prior to injection. Karyotypic analysis showed that the leukemias originated from FDC-P1 cells, and primary tumor cells from different animals displayed a wide spectrum of altered growth patterns when cultured in agar. In most cases, colony formation by leukemic cells in vitro exhibited autonomy with respect to stimulation by exogenous colony stimulating factors. These observations indicate that leukemic transformation of FDC-P1 cells is enhanced by irradiation of recipient mice and document a useful model for analyzing the mechanisms by which irradiation induces leukemia.
Leukemia 1988 Jun
PMID:A model system for leukemic transformation of immortalized hemopoietic cells in irradiated recipient mice. 328 20


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