Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of fleroxacin and ciprofloxacin on hemopoietic progenitor cells was tested in vitro. Cryopreserved bone marrow samples from 5 patients with acute myeloid leukemia who underwent bone marrow transplantation as well as samples from the respective donors were investigated in parallel. Regarding burst and/or colony formation by erythroid, neutrophil and macrophage precursors, no significant differences were detected with donor and transplanted bone marrows between control cultures and cultures containing 100 mg/l fleroxacin, while 100 mg/l ciprofloxacin inhibited cell proliferation completely. At 50 and 10 mg/l ciprofloxacin had a 50% and no inhibitory effect, respectively.
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PMID:Effect of fleroxacin and ciprofloxacin on the formation of human mature colonies of healthy donor versus transplanted hemopoietic progenitor cells. 190 22

One of the major limitations of DNA flow cytometry (FCM) in hematologic malignancies is the lack of information about the proliferation activity of subpopulations of the heterogeneous bone marrow (BM) compartment. We studied the S-phase DNA content of immunophenotypically defined BM subpopulations (CD2+; CD19+; CD2/CD19+; glycophorin-A+; CD14+; CD13+; CD33+ and CD13/CD33+) in 18 patients with acute myeloid leukemia (AML), including three patients with M6 AML. The results were compared with the findings in twelve normal BM aspirates. The measurements were performed using a special protocol for bivariate FCM of DNA content and surface immunofluorescence (s-IF). In patients with AML the proportion of BM cells expressing the myelomonocytic and monocytic markers (M1-M5 AML) or erythroid marker (M6 AML) was expanded. However, in many patients other subpopulations were 4% or higher permitting the calculation of their S-phase DNA. No essential differences in median S-phase DNA percentages of the distinct subpopulations were observed between normal and leukemic bone marrow though the ranges in AML patients were much wider. These data suggest that AML is not characterized by an increased nor a decreased proliferation activity, but rather by a situation of cell growth independent to the normal regulatory mechanisms. Additional information was obtained upon DNA aneuploidy using CD2+ or CD2/CD19+ cells as an intrinsic DNA standard which allowed us to define differences in the DNA index as small as 2% as aneuploid. This approach appeared suitable for detecting small-degree numerical chromosomal aberrencies, as found by cytogenetics, in 4/6 cases.
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PMID:S-phase DNA content and aneuploidy of immunophenotypic defined subpopulations in acute myeloid leukemia determined by multi-parameter flow cytometry. 192 60

We have tested folinic acid (FA) for ability to increase peripheral blood stem cells (PBSC) after chemotherapeutic aplasia in acute leukaemia. Five adult patients (four AML, one ALL) entered the study, each patient underwent two series of three leukapheresis, the first following induction chemotherapy and the second following the first course of consolidation. The first leukapheresis of each series was done when the white blood cell count reached 10(9)/l with subsequent leukapheresis every other day. Folinic acid (Lederle Laboratories, France) was administered at a dose of 50 mg (i.v.) per day, 15 days from initiation of chemotherapy and continuing through the third leukapheresis of the series (days 25-30). PBSC were collected on a Haemonetics V50 cell separator. In these five cases we observed an increased yield of both colony-forming units, granulocyte macrophage (CFU-GM) and burst forming units-erythroid (BFU-E) expressed per ml of cytapheresis product: CFU-GM x 18, BFU-E x 3 and if expressed per 10(4)/kg of body weight: CFU-GM x 30, BFU-E x 3 (CFU-GM P less than 0.05, BFU-E less than 0.01). Long-term blood culture (LTSC) from FA stimulated leukapheresis, in an attempt to quantitate the most primitive stem cells, demonstrated that this expansion of the PBSC was sustained in time. We found by means of LTSC that FA did not stimulate CFU-L from patients with AML (two cases tested). Finally two AML patients were grafted with FA-PBSC after Cytotoxan and total body irradiation (TBI). Haematopoietic reconstitution was rapid complete and sustained in time in both patients. This indication for folinic acid should be further studied with or as an alternative to haematopoietic growth factors.
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PMID:Expansion by folinic acid of the peripheral blood progenitor pool after chemotherapy: its use in autografting in acute leukaemia. 204 85

The process of cellular iron uptake involves a specific receptor for the plasma carrier transferrin and a pathway of receptor-mediated endocytosis. Transferrin receptor expression is closely related to the rate of cell proliferation, and conjugates between anti-transferrin receptor monoclonal antibodies and toxins have been shown to have potent cytotoxic activity. We have constructed an anti-transferrin receptor immunotoxin by conjugating the anti-transferrin receptor monoclonal antibody B3/25 to a ribosome-inactivating protein, the saporin-6 (SO6), which is derived from the seeds of the plant Saponaria officinalis. The immunotoxin B3/25-SO6 was tested for in vitro cytotoxic activity against the human cell lines K-562 and HL-60 and against normal human bone marrow hematopoietic progenitors and acute myeloid leukemia clonogenic cells. The immunotoxin proved to be an effective inhibitor of K-562 and HL-60 clonogenic cell growth, in vitro colony formation being completely inhibited at immunotoxin concentrations ranging from 10(-7) to 10(-10) M. B3/25-SO6 markedly reduced the recloning efficiency of HL-60 clonogenic cells at 10(-12) M. Exposure of HL-60 cells in suspension culture to 10(-9) M B3/25-SO6 for 48-72 h completely abolished their clonogenic potential. The immunotoxin was also found to be cytotoxic against normal human bone marrow progenitor cells (burst-forming unit-erythroid and colony-forming unit-granulocyte, macrophage) in a dose-dependent manner. However, exposure of normal colony-forming unit-granulocyte, macrophage in suspension culture to 10(-9) M B3/25-SO6 for 72 h resulted in only 50% suppression of their clonogenic potential. Finally, B3/25-SO6 was found to be a potent inhibitor of in vitro growth of acute myeloid leukemia clonogenic cells. The cytotoxic effects of B3/25-SO6 were shown to be specific, since both saporin alone and irrelevant immunotoxins did not have any effect in the cellular systems examined. We conclude that the immunotoxin B3/25-SO6 has dose-related cytotoxic effects on both normal and leukemic human hematopoietic progenitors. Since there are substantial differences between normal and leukemic progenitors with respect to the proportion of cycling cells and the expression of transferrin receptors, B3/25-SO6 or similar immunotoxins may have clinical application in bone marrow-purging procedures.
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PMID:Cytotoxic activity of an anti-transferrin receptor immunotoxin on normal and leukemic human hematopoietic progenitors. 198 71

In newly diagnosed patients with acute lymphoblastic leukemia (ALL), bone marrow (BM) morphology always shows "replacement" by blasts with decreased or absent normal hematopoietic elements. To answer the question of whether ALL blasts inhibit replication and maturation of normal marrow progenitors, we studied the interaction of normal marrow with BM specimens from 16 new cases of ALL. Irradiated ALL blasts, supernatant derived from ALL blasts in suspension cultures, and conditioned medium prepared from ALL blasts augmented the colony-forming ability of normal marrow erythroid burst-forming unit (BFU-E), granulocyte-macrophage colony-forming unit (CFU-GM), megakaryocyte colony-forming unit (CFU-MK), and multilineage colony-forming unit (CFU-GEMM) progenitors. In sharp contrast to published data on the suppressive effects of acute myeloblastic leukemia cells on normal hematopoiesis in vitro, our results indicate that the growth advantage of ALL cells over normal marrow elements is not mediated through an inhibitory mechanism derived from leukemia cells.
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PMID:Acute lymphoblastic leukemia blast cells do not inhibit bone marrow hematopoietic progenitor colony formation. 199 13

We report the results of a preclinical study comparing four different purging protocols using a promyelocytic human cell line HL-60 and myeloid leukemic progenitor cells (colony-forming unit-leukemic [CFU-L]) from acute myelogenous leukemia (AML) patients assayed in semisolid culture. We studied the antileukemic effect of (1) Single-cycle complement-mediated lysis by two different monoclonal antibodies (MoAbs) (M195 [CD33] and F23 [CD13] 40 micrograms/mL), reactive with distinct antigens found on early myeloid cells and monocytes, used alone and in combinations; (2) 4-Hydroperoxycyclophosphamide (4-HC) (80 mumol/L or 100 mumol/L) alone; or (3) combined with VP-16 (5 micrograms/mL) and (4) a cocktail of 1 through 3 as above (combined immunochemotherapy). More than 4 logs of HL-60 tumor cell elimination were observed after 1 hour of incubation with both MoAbs plus 4-HC + VP-16 while the single treatment (immunotherapy or chemotherapy) provided 1.5 and 3.5 logs of colony-forming inhibition, respectively. When the same protocols were tested on cryopreserved leukemic cells from eight patients with AML, we observed a mean value of CFU-L inhibition of 92.3% +/- 2.5% SD, 95.5% +/- 1.4% SD, and 99% +/- 0.8% SD after MoAbs and complement lysis, 4-HC, and 4-HC + VP-16 treatment, respectively. The combined treatment of MoAbs and 4-HC + VP-16 produced more than 3-log reduction of CFU-L colony formation. By comparison, the mean recovery of committed normal bone marrow progenitors after incubation with MoAbs and complement was 12% for CFU-granulocyte-macrophage (CFU-GM), 22.9% for burst-forming unit erythroid (BFU-E), and the recovery following 4-HC + VP-16 treatment was 4.4% for CFU-GM and 5.6% BFU-E. In subsequent experiments, highly purified CD34+ blast cells, enriched by positive selection, and stimulated in liquid culture by cytokines (interleukin-1 [IL-1], IL-3, and combination of both) or MO-conditioned medium (MoCM), demonstrated that immunochemotherapy spares hematopoietic colony-forming cells earlier than day 14 CFU-GM, in vitro.
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PMID:Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination. 201 6

The immunophenotype of 72 cases with acute myelocytic leukemia was investigated with a panel of monoclonal antibodies. When the morphologic criteria of the FAB classification was compared with the normal myeloid and erythroid pathway of differentiation identified by MoAbs, a relationship was found with FAB M5 and M6. Moreover, a constant negativity to HLA-DR and CD15 antigens in M3 and the contemporaneous expression of HLA-DR and CD11b antigens on the M4 and M5 leukemic cells were observed. We identified phenotypically distinct groups of patients with different responses to therapy. In fact, patients whose leukemic cells did not express the HLA-DR antigen showed, in a univariate analysis, a significantly higher percentage of complete remissions than did HLA-DR-positive patients. Multivariate discriminant analysis, in line with this result, showed that the parameters of discriminant capacity were, in order of statistical significance, young age, low WBC count and the lack of DR expression, respectively. A trend for a better response to therapy, without any statistical relevance, was also observed in CD11b-negative and CD33-positive cases. Similar results were detected in patients who expressed either DR or CD11b, or none of these markers. These findings indicate that immunophenotype may identify some FAB subtypes. Moreover, in some cases the phenotypic profile can provide useful information about the clinical outcome.
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PMID:Diagnostic and prognostic relevance of the immunophenotype in acute myelocytic leukemia. 201 95

The use of immunotoxins (IT) to selectively destroy acute myeloid leukemia (AML) cells in vivo or in vitro is complicated by both the antigenic similarity of AML cells to normal progenitor cells and the difficulty of producing a sufficiently toxic conjugate. The monoclonal antibody (MoAb) anti-MY9 is potentially ideal for selective recognition of AML cells because it reacts with an antigen (CD33) found on clonogenic AML cells from greater than 80% of cases and does not react with normal pluripotent stem cells. In this study, we describe an immunotoxin that is selectively active against CD33+ AML cells: Anti-MY9-blocked-Ricin (Anti-MY9-bR), comprised of anti-MY9 conjugated to a modified whole ricin that has its nonspecific binding eliminated by chemical blockage of the galactose binding domains of the B-chain. A limiting dilution assay was used to measure elimination of HL-60 leukemic cells from a 20-fold excess of normal bone marrow cells. Depletion of CD33+ HL-60 cells was found to be dependent on the concentration of Anti-MY9-bR and on the duration of incubation with IT at 37 degrees C. More than 4 logs of these leukemic cells were specifically depleted following short exposure to high concentrations (10(-8) mol/L) of Anti-MY9-bR. Incubation with much lower concentrations of Anti-MY9-bR (10(-10) mol/L), as compatible with in vivo administration, resulted in 2 logs of depletion of HL-60 cells, but 48 to 72 hours of continuous exposure were required. Anti-MY9-bR was also shown to be toxic to primary AML cells, with depletion of greater than 2 logs of clonogenic cells following incubation with Anti-MY9-bR 10(-8) mol/L at 37 degrees C for 5 hours. Activity of Anti-MY9-bR could be blocked by unconjugated Anti-MY9 but not by galactose. As expected, Anti-MY9-bR was toxic to normal colony-forming unit granulocyte-monocyte (CFU-GM), which expresses CD33, in a concentration- and time-dependent manner, and also to burst-forming unit-erythroid and CFU-granulocyte, erythroid, monocyte, megakaryocyte, although to a lesser extent. When compared with anti-MY9 and complement (C'), Anti-MY9-bR could be used in conditions that provided more effective depletion of AML cells with substantially less depletion of normal CFU-GM. Therefore, Anti-MY9-bR may have clinical utility for in vitro purging of AML cells from autologous marrow when used at high IT concentrations for short incubation periods. Much lower concentrations of Anti-MY9-bR that can be maintained for longer periods may be useful for elimination of AML cells in vivo.
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PMID:Anti-MY9-blocked-ricin: an immunotoxin for selective targeting of acute myeloid leukemia cells. 203 21

Because chronic benzene exposure is associated with acute myeloblastic leukemia and other myeloproliferative disorders, we sought to determine whether short-term benzene exposure provides a growth advantage for granulopoietic elements over erythropoietic elements. Groups of male DBA/2J mice were exposed to 0, 10, 30, or 100 ppm benzene (6 h/day for 5 days). One day and 5 days after the benzene exposures, the numbers of the two most primitive erythroid progenitor cells (BFU-E and CFU-E) and the numbers of the most primitive granulocytic progenitor cells (GM-CFU-C) were assessed. Additional groups of mice were given hemolytic doses of phenylhydrazine (PHZ) during the 5 days of benzene exposure, while other groups of mice were given PHZ during the 5 days of recovery from benzene exposure. These experiments were designed to determine the effects of benzene exposure on progenitor cell numbers during periods of markedly heightened erythropoiesis. The results demonstrate that short-term benzene exposure does induce a growth advantage for granulocytic cells in both the bone marrow and spleen of exposed mice. Moreover, a benzene-induced shift toward granulopoiesis is observed even in those mice treated with a powerful erythropoietic stimulus. These effects disappear 5 days after cessation of benzene exposure in the bone marrow but persist in the spleen of mice treated with phenylhydrazine.
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PMID:Short term benzene exposure provides a growth advantage for granulopoietic progenitor cells over erythroid progenitor cells. 207 27

An increasing amount of data provides strong evidence for the complex multifactorial control of primary hemopoietic functions. Here we present a new multicellular functional unit, the Hematon, isolated from the light-density floating fraction of normal human bone marrow (BM) aspirates. The Hematon is organized in a compact, three-dimensional spheroid complex from central adipocytes, fibroblastoid cells, and resident macrophages that compartmentalize myeloid, erythroid, and megakaryocyte progenitor cells and their progenies. The Hematon fraction is more than twofold more abundant in progenitor cells when compared to the mononuclear cell (MNC) fraction as gauged by cytological techniques and by analysis of granulocyte-macrophage colony-forming unit (GM-CFU) populations. Individual Hematons may produce, within 2-3 weeks, up to 50,000 hemopoietic cells of different cell lineages in organotypic microcultures. Recombinant human hematopoietic growth factors interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF) significantly stimulated the endogenous cell production of some but not all of the individually treated Hematons, indicating the heterogeneity of factor-responsive cells within the Hematon population. Comparative observations of 184 BM aspirates support the hypothesis that the presence of Hematons in a BM aspirate correlates positively with homeostatic blood cell production, because the Hematon was present in normal BM (31/40) and it was rare among patients with myelodysplastic syndromes (15/53), acute myeloblastic leukemia (7/39), and chronic myelocytic leukemia (5/52). We suggest that the Hematon represents a unifying model around which the variability of fundamental BM functions and dysfunctions can be explored.
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PMID:Hematon, a multicellular functional unit in normal human bone marrow: structural organization, hemopoietic activity, and its relationship to myelodysplasia and myeloid leukemias. 218 30


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