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)

The availability of an in vitro assay able to detect hematopoietic progenitor cells closely related to those responsible for marrow engraftment following autologous bone marrow transplantation (ABMT) prompted us to establish a procedure aimed at maximally increasing the concentration of the cyclophosphamide derivative mafosfamide used for marrow purging. It, therefore, was the aim of the present study to investigate in a group of patients with acute nonlymphoblastic leukemia (ANLL; n = 19) and acute lymphoblastic leukemia (ALL; n = 19) in complete remission the effect of mafosfamide at the level of adherent blast colony-forming units (blast colony-forming units, CFU-Blast), as well as multipotential (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM), erythroid (erythroid burst-forming units, BFU-E), and granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) progenitor cells. When nonadherent marrow mononuclear cells (MNCs) were incubated (30 min, 37 degrees C) with increasing doses of mafosfamide (30-120 micrograms/ml), a statistically significant (p less than or equal to 0.0005) dose-dependent suppression of CFU-Blast growth was observed. The mean (+/- 1 standard error of the mean [SEM]) values of 50% inhibition (ID50) of the CFU-Blast growth were not significantly different for ANLL (106 +/- 5) and ALL (107 +/- 5) patients. Analysis of CFU-Blast ID50 distribution demonstrated that ID50 ranged from 100 to 120 micrograms/ml in 17 cases (45%), whereas it ranged from 60 to 100 micrograms/ml in 12 cases and from 120 to 160 micrograms/ml in 9 cases. A statistically significant (p less than or equal to 0.05), dose-dependent suppression of colony growth from multi-potential and lineage-restricted progenitor cells was also observed. However, the value of CFU-Blast ID50 was significantly higher (p less than or equal to 0.05) than CFU-GEMM, BFU-E, and CFU-GM ID50 and ID95 values. In conclusion, our data demonstrate that: 1) the CFU-Blast assay allows to detect on an individual basis the doses of mafosfamide used for marrow purging, and 2) the concentrations of mafosfamide extrapolated by using the CFU-Blast assay are significantly higher than those obtained with the CFU-GM assay. The absence of any detrimental effect on marrow engraftment in vivo supports the safety of the CFU-Blast assay to evaluate the dose of mafosfamide used for marrow purging before ABMT.
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PMID:Differential sensitivity of adherent CFU-blast, CFU-mix, BFU-E, and CFU-GM to mafosfamide: implications for adjusted dose purging in autologous bone marrow transplantation. 156 48

The CD33 antigen, identified by murine monoclonal antibody anti-MY9, is expressed by clonogenic leukemic cells from almost all patients with acute myeloid leukemia; it is also expressed by normal myeloid progenitor cells. Twelve consecutive patients with de novo acute myeloid leukemia received myeloablative therapy followed by infusion of autologous marrow previously treated in vitro with anti-MY9 and complement. Anti-MY9 and complement treatment eliminated virtually all committed myeloid progenitors (colony-forming unit granulocyte-macrophage) from the autografts. Nevertheless, in the absence of early relapse of leukemia, all patients showed durable trilineage engraftment. The median interval post bone marrow transplantation (BMT) required to achieve an absolute neutrophil count greater than 500/microL was 43 days (range, 16 to 75), to achieve a platelet count greater than 20,000/microL without transfusion was 92 days (range, 35 to 679), and to achieve red blood cell transfusion independence was 105 days (range, 37 to 670). At the time of BM harvest, 10 patients were in second remission, one patient was in first remission, and one patient was in third remission. Eight patients relapsed 3 to 18 months after BMT. Four patients transplanted in second remission remain disease-free 34+, 37+, 52+, and 57+ months after BMT. There was no treatment-related mortality. Early engraftment was significantly delayed in patients receiving CD33-purged autografts compared with concurrently treated patients receiving CD9/CD10-purged autografts for acute lymphoblastic leukemia or patients receiving CD6-purged allografts from HLA-compatible sibling donors. In contrast, both groups of autograft patients required a significantly longer time to achieve neutrophil counts greater than 500/microL and greater than 1,000/microL than did patients receiving normal allogeneic marrow. CD33(+)-committed myeloid progenitor cells thus appear to play an important role in the early phase of hematopoietic reconstitution after BMT. However, our results also show that human marrow depleted of CD33+ cells can sustain durable engraftment after myeloablative therapy, and provide further evidence that the CD33 antigen is absent from the human pluripotent hematopoietic stem cell.
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PMID:Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. 157 39

Primitive cells defined as long-term culture initiating cells (LTCIC) and blast colony-forming cells (Bl-CFC) bind to cultured stromal layers, but cells at later stages of maturation [granulocyte-erythroid-macrophage-monocyte colony-forming cells (GEMM-CFC) granulocyte-macrophage (CM-CFC) and erythroid burst-forming units (BFU-E)] do not. The precise relationship between the LTCIC and Bl-CFC is not known and this study was undertaken to determine their relative positions in the haemopoietic hierarchy. We have defined the Bl-CFC population in terms of its density profile and antigenic phenotype and compared these characteristics with GM-CFC and BFU-E. The progenitor cell populations did not differ in density. The major phenotypic difference was seen using the myeloid monoclonal antibody S17-25 which reacted with fewer Bl-CFC than GM-CFC. Also, we have cytochemically analysed the cells in colonies derived from Bl-CFC. Our studies indicate that the Bl-CFC precede BFU-E and GM-CFC but not the LTCIC.
Leukemia 1992 Apr
PMID:Physical, phenotypic and cytochemical characterisation of stroma-adherent blast colony-forming cells. 158 97

We have examined the effect of a combined 24 h exposure to cytosine arabinoside (ara-C) and the protein kinase C activator bryostatin 1, either alone or in conjunction with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), on the clonogenic growth of 14 primary samples from acute myelogenous leukemia (AML) patients, as well as normal human committed and early hematopoietic progenitors. Incubation of blasts with 1 microM ara-C and 12.5 nM bryostatin 1(+/- 1.25 ng/ml rGM-CSF) resulted in a heterogeneous pattern of inhibitory effects toward primary leukemic colonies, ranging from 32-98%, and subadditive to synergistic drug interactions. However, exposure of blasts to ara-C and bryostatin 1, either with or without rGM-CSF, eliminated leukemic cell self-renewal in 80-93% of samples, and very substantially reduced growth in the remainder. Exposure of normal human bone marrow mononuclear cells to identical concentrations of ara-C and byostatin 1 permitted the survival of 23% of committed myeloid progenitors (granulocyte-macrophage colony-forming units), and greater than 50% when rGM-CSF was included. Finally, exposure of bone marrow populations highly enriched for progenitor cells (CD34+, DR-, CD71-) to ara-C and bryostatin 1 +/- rGM-CSF for 24 h led to minimal reductions (e.g. 10-15%) in the survival of early hematopoietic progenitors (high proliferative potential colony-forming cells). Together, these findings indicate that combined exposure in vitro to ara-C and bryostatin 1, both with and without rGM-CSF, effectively inhibits the growth of leukemic cells with self-renewal capacity, while sparing a significant fraction of normal committed and primitive hematopoietic progenitors.
Leukemia 1992 May
PMID:Effect of a combined exposure to cytosine arabinoside, bryostatin 1, and recombinant granulocyte-macrophage colony-stimulating factor on the clonogenic growth in vitro of normal and leukemic human hematopoietic progenitor cells. 159 8

The efficacy of hexamethylene bisacetamide (HMBA), a potent polar-planar solvent which is capable of differentiating leukemias and solid tumors in vitro at clinically achievable concentrations, was studied in 16 patients with severe myelodysplastic syndromes (MDS). An adaptive control dosing algorithm was used to maintain HMBA steady-state concentrations (Css) within a narrow therapeutic window (1-2 mM) for five days every four weeks. Despite achieving the target HMBA Css during at least two courses in each of 15 patients, HMBA did not produce clinically relevant improvements in blood cell counts nor in other functional indices. Instead, HMBA induced cytopenias in the majority of these patients, most of whom had preexisting cytopenias and limited hematopoietic reserves. These disappointing results correlated with concurrent in vitro bone marrow studies from these patients in which both the HMBA concentrations that were optimal for differentiation in vitro (2-5 mM) and the HMBA Css that were achieved in this study (1-2 mM) substantially inhibited the growth of granulocyte-macrophage colony-forming units and erythroid burst-forming units. Although the mechanism responsible for the anti-proliferative effects of HMBA on hematopoietic progenitors (cytotoxicity versus terminal differentiation) could not be determined, the induction of cytopenias and lack of significant clinical improvements suggest that HMBA is cytotoxic and will not be useful alone as a differentiating agent on this schedule of administration in the treatment of MDS.
Leukemia 1992 Jun
PMID:Hexamethylene bisacetamide in myelodysplastic syndrome: effect of five-day exposure to maximal therapeutic concentrations. 160 91

Myeloid leukemia development requires the acquisition by a cell of two abnormalities: an abnormal capacity for self-replication; and a capacity for autocrine stimulation, usually involving the known growth factors for granulocyte-macrophage cells. Curiously, in human leukemia, this does not usually result in autonomous growth when assessed in clonal in vitro cultures. Depending on gene programming, in particular in human or murine myeloid leukemias, the hemopoietic growth factors can also suppress the leukemic population by inhibiting the capacity of the leukemic stem cells for self-generation. The regulator showing the highest suppressive activity varies from leukemia to leukemia, with G-CSF. GM-CSF, IL-6, or leukemia-inhibitory factor (LIF) all having high activity on appropriate target cells. Combinations of these regulators are more effective than single agents alone. Analyses of human HL60, U937 and murine M1 leukemic models indicate that the development of morphological maturation in the leukemic cells is not a necessary feature of stem-cell suppression. LIF has an anomalous action on stem-cell self-generation, being highly effective in the suppression of certain myeloid leukemic cell lines, but being necessary to maintain self-generation in normal embryonic cells. This suggests the existence of a common control medium governing self-generation decisions in cells of different lineages, but that the outcome of the decision is determined by the differentiation program operating in different cells. The colony-stimulating factors are being used in combination with chemotherapy in the treatment of patients with acute myeloid leukemia, but the above principles require caution in certain situations.
Leukemia 1992
PMID:Role of hemopoietic growth factors in the development and suppression of myeloid leukemia. 160 21

Acute myelomonocytic leukemia develops in 10-30% of irradiated (300 rad) SJL/J mice, after a lag period of around one year. Additional treatment with dexamethasone shortly after irradiation increased leukemia incidence up to 50%. Experiments were conducted in order to demonstrate the existence of preleukemic cells in irradiated mice and to explore the possible role of dexamethasone, cyclophosphamide, and different hemopoietic growth factors on their promotion to overt leukemia. Transplantation of bone marrow cells from mice exposed to 300 rad plus dexamethasone into appropriate recipients, performed 4-5 months after leukemogenic treatment, resulted in acute myeloid leukemia (AML) development of donor origin in 70% of the recipients. Transfer of fractionated preleukemic bone marrow showed that the highest AML incidence developed in the recipients of fractions enriched in early hemopoietic precursors. The promoting effect of dexamethasone on preleukemic cells was confirmed by demonstrating its similar coleukemogenic effect whether administered within several hours or 130 days after radiation. Treatment with cyclophosphamide shortly after radiation could not replace the dexamethasone effect but was found to be complementary to the coleukemogenic effect of dexamethasone. Early administration of hemopoietic growth factors (starting 14 days after radiation and dexamethasone) showed that colony-stimulating factor (CSF) 1 increased the AML incidence (75%) and reduced its latency. Treatment with recombinant granulocyte-CSF (rG-CSF) had a reduced effect and recombinant granulocyte-macrophage CSF (rGM-CSF) had no promoting effect. However, administration of different factors several months after the leukemogenic treatment revealed that rGM-CSF increased AML incidence (75%) and shortened its latency, whereas rG-CSF and CSF-1 had no effect. In contrast, the late administration of recombinant interleukin 6 reduced AML incidence significantly (23%). The present results indicate that murine radiation induced AML is a multiphase process involving radiation induced preleukemia that can be promoted by different treatments.
Leukemia 1992 Jul
PMID:Initiation and promotion in radiation-induced myeloid leukemia. 162 87

The interactions of purified recombinant human leukemia inhibitory factor (LIF), interleukin-6 (IL-6), granulocyte colony stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) on the clonogenicity of HL60 cells and U937 cells were studied in vitro. IL-6 alone strongly suppressed colony formation by U937 cells with induction of differentiation and loss of clonogenicity. GM-CSF interacted synergistically with IL-6 to further reduce colony number and suppress the growth of clonogenic cells formed by HL60 and U937 cells. LIF synergized with IL-6 to reduce colony number and enhance the suppression of the clonogenic U937 cells. The results suggest that these 4 glycoproteins, acting alone or in combination, may be able to suppress human leukemia cells of appropriate type and be of value in the clinical management of myeloid leukemia.
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PMID:Enhanced suppression of human myeloid leukemic cell lines by combinations of IL-6, LIF, GM-CSF and G-CSF. 168 77

For granulocytic-macrophage progenitor populations and their progeny, five glycoproteins have been identified: GM-CSF, G-CSF, multi-CSF, M-CSF and IL-6 that can regulate their proliferative activity, maturation and functional activities. The same glycoproteins also have a capacity to induce irreversible differentiation commitment in normal bipotential granulocyte-macrophage progenitors and in some myeloid leukaemic cell lines, which suggests that common cellular processes exist in both situations. The leukaemia inhibitory factor (LIF) is a glycoprotein, with intriguing properties, which can either induce differentiation in some myeloid leukaemic cell lines or prevent differentiation in normal totipotential embryonic stem cells. The data from the LIF studies suggest a genetic mechanism controlling self-generation that is relatively simple and may be common to all cells. However, the actual cellular response observed appears to depend on the nature of the responding cell.
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PMID:The induction and inhibition of differentiation in normal and leukaemic cells. 169 Sep 2

Monoclonal antibody YB5.B8 was previously shown to inhibit haemopoietic colony formation in response to a complex growth factor supplement in vitro (Cambareri A. C., Ashman L. K., Cole S. R. & Lyons A. B. (1988), Leukemia Res. 12, 929). We now report studies of the effect of the antibody on colony formation by normal human bone marrow cells in response to recombinant human colony-stimulating factors GM-CSF, G-CSF and IL-3. MAb YB5.B8 significantly reduced the yield of colonies of all types examined (granulocyte-macrophage, granulocyte, macrophage and eosinophil) in response to GM-CSF but not to IL-3 or G-CSF. However, MAb YB5.B8 failed to influence the proliferation of the myelomonocytic leukaemia cell line RC-2A in response to GM-CSF, G-CSF or IL-3. Direct binding studies demonstrated the presence of low numbers of receptors for GM-CSF on RC-2A cells, however, the binding of this cytokine was not influenced by co- and/or pre-incubation with MAb YB5.B8. Therefore the antigen identified by YB5.B8 is probably not a receptor for GM-CSF and may indirectly influence the response of normal haemopoietic progenitors to this cytokine.
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PMID:A monoclonal antibody that inhibits the action of GM-CSF on normal but not leukaemic progenitors. 169 6


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