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

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) inhibits the entry into DNA synthesis of murine spleen colony-forming units (CFU-S) and protects these cells during chemotherapy. This synthetic peptide also inhibits the growth of normal human marrow progenitors granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) and decreases their percentage in DNA synthesis at nanomolar concentration. In view of its clinical application as a marrow protector, we have investigated its effects on malignant cells. Studies were carried out on HL-60 cells and on fresh leukemic cells from patients with either chronic myeloid leukemia (CML) or acute myeloid leukemia (AML). Results showed that AcSDKP, whatever the doses used, did not modify the proliferation of both HL-60 cells and AML cells even when enhanced by stimulating factors such as interleukin 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, no change in the number and the percentage in S-phase of both HL-60 clonogenic cells and CML progenitors was observed. Our data clearly demonstrate that the tetrapeptide AcSDKP was ineffective on leukemic cells and therefore by acting selectively on normal progenitors represents a potent therapeutical agent for the protection of normal bone marrow progenitors during chemotherapy.
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PMID:The tetrapeptide AcSDKP, an inhibitor of the cell-cycle status for normal human hematopoietic progenitors, has no effect on leukemic cells. 154 96

This study aimed to evaluate the effect of melphalan on both terminal divisions and self-renewal capacity of acute myeloblastic leukemia (AML) progenitors (colony-forming units, CFU-L) grown in methylcellulose. Terminal divisions and self-renewal were assayed by primary (PE1) and secondary (PE2) colony formation, respectively. Thirteen cases of AML, were tested. Melphalan induced a negative exponential dose-effect on CFU-L survival. Moreover, melphalan was equally effective in inhibiting CFU-L growth in both PE1 and PE2 assays, with D10 values of 1.53 +/- 0.17 micrograms/ml and 1.59 +/- 0.21 micrograms/ml for PE1 and PE2, respectively (p = 0.48). Cytotoxicity of melphalan on CFU-L did not differ significantly from that observed for normal hemopoietic granulocyte-macrophage colony-forming units, erythroid burst-forming units, and granulocyte-erythroid-macrophage-megakaryocyte progenitors. Mafosfamide-lysine, a stable cyclophosphamide congener, strongly inhibited primary colony formation (PE1) with a D10 value of 14.46 +/- 1.76 micrograms/ml, but was much less efficient in the PE2 assay. Our findings suggest that the self-renewal capacity of AML progenitors can be differentially affected by alkylating agents. Moreover, since it is now considered that chemotherapy should be preferentially directed against the self-renewal of leukemic progenitors, melphalan might offer a greater potential than cyclophosphamide or cyclophosphamide derivatives in the therapy of AML.
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PMID:Effect of melphalan against self-renewal capacity of leukemic progenitors in acute myeloblastic leukemia. 156 57

1B2 is an IgM monoclonal antibody binding to glycoconjugates bearing the terminal N-acetyllactosamine structure. It agglutinates human erythrocytes. Various cell lines, peripheral blood leucocytes, normal marrow and blast cells from 179 acute myeloid leukaemia (AML) and 11 acute lymphoblastic leukaemia (ALL) patients were tested for reactivity with 1B2. Myelomonocytic (CFU-GM), erythroid (BFU-E), mixed (CFU-GEMM) and leukaemic (CFU-L) progenitor cells were tested in clonogenic assays. Granulocytes, monocytes, myeloid cell lines and 152 out of 179 AML were positive. All FAB subtypes were equally recognised. Lymphocytes, T-cell and Burkitt's cell lines, and 10 of 11 ALL samples were negative. 1B2 inhibited partially day 7 CFU-GM, whereas it was not toxic for BFU-E, CFU-GEMM and day 14 CFU-GM. Leukaemic clonogenic cells were killed in 33 out of 36 AML (more than 40% growth inhibition). 1B2 identifies the more mature steps of myeloid differentiation. It may be useful in the diagnosis of AML, and is a candidate for remission marrow purging before autologous transplantation.
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PMID:Specific binding of anti-N-acetyllactosamine monoclonal antibody 1B2 to acute myeloid leukaemia cells. 156 87

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

We studied the in vitro effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in 13 patients with acute myeloid leukemia (AML) and one patient with refractory anemia with excess of blasts in transformation using the AML blast (AML colony-forming units, AML-CFU) and mixed (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) colony culture assays. In parallel, these patients received GM-CSF s.c. at 125 micrograms/m2/day, or in escalated doses starting with 10 micrograms/m2/day for a week or until circulating blast counts reached 50 x 10(9)/liter, in an effort to sensitize leukemic blasts to cell-cycle-specific agents. Results of in vivo GM-CSF treatment were correlated with those of in vitro assays. In 9 of 12 patients (75%), GM-CSF treatment increased peripheral blood blast counts (in vivo effect). GM-CSF also stimulated in vitro AML blast colony proliferation in these nine patients and increased the S+G2M phases of the cell cycle in five out of five of these patients' samples. Two of three patients in whom an in vivo response could not be demonstrated also failed to have a detectable in vitro response. These observations suggest that the AML blast colony culture assay may be useful in predicting the response of AML to cytokine therapy. Finally, GM-CSF stimulated granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) and erythroid (erythroid burst-forming units, BFU-E) colony proliferation in 14 and 11 patients, respectively, including the 3 individuals who demonstrated no clinical effect on blast counts. It is, therefore, possible that GM-CSF may be used to stimulate proliferation of progenitors that differentiate into mature granulocyte, monocyte-macrophage, and erythroid cells.
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PMID:Comparison of in vivo and in vitro effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with acute myeloid leukemia. 158 2

A cell line (TI-1) has been established from the peripheral blood of a patient with acute myeloid leukemia (M2). A typical TI-1 cell displayed many abnormalities of its chromosomes, but not the Philadelphia (Ph1) chromosome. Light and electron microscopic examination and histochemical analysis indicated that the TI-1 cells were undifferentiated blast cells, but immunologic marker studies suggested that these cells had myeloid characteristics. The proliferation of TI-1 cells was dependent on the concentration of fetal bovine serum (FBS). Their doubling time was 13.8 hours when they were cultured in a medium containing 10% FBS. Phorbol-12 myristate 13-acetate (PMA) induced the TI-1 cells to differentiate into monocyte-like cells, as judged by their morphologic similarity to monocytes, their adhesion to the culture dish, and their increase of both nitroblue tetrazolium (NBT)-reducing ability and nonspecific esterase (NSE)-activity. PMA significantly inhibited the proliferation and DNA synthesis of TI-1 cells in a dose-dependent manner. The PMA-induced differentiation was significantly inhibited by the protein kinase C inhibitors (H-7, staurosporine). Hemin induced the TI-1 cells to differentiate into erythroid cells. The number of hemoglobin-producing cells and hemoglobin production was increased by hemin treatment. Hemin also inhibited the proliferation of the TI-1 cells. Thus, the TI-1 cell represents a bipotent, granulo-monocytoid, and erythroid cell line. The TI-1 cell line will be a useful model for monocytoid and erythroid differentiation.
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PMID:Characterization, growth, and differentiation of a human myeloid leukemia cell line, TI-1 cell. 161 Oct 97

Thirty-four patients with MDS or AML following MDS were studied with regard to survival, peripheral blood values and bone marrow morphology. The effects of 1,25 dihydroxyvitamin D3 (D3) on differentiation (NBT positivity) and proliferation (3H-thymidine incorporation) were studied in suspension cultures of bone marrow cells. Twelve bone marrow donors served as controls. Normal cells showed spontaneous differentiation in vitro, but only 2/12 were induced to differentiation by D3. Myelodysplastic cells did not differentiate spontaneously, but cells from 18/34 patients differentiated after incubation with D3. Normal cells showed increased proliferation, myelodysplastic cells showed a heterogeneous response and leukemic cells reacted with decreased proliferation after D3 incubation. Poor survival was associated with low platelet counts, high percentage of bone marrow blasts (BM blast %), low spontaneous in vitro proliferation and absence of hypogranulation of myeloid cells. Platelet counts and hypogranulation retained their predictive value in a multi-variate analysis. Progression to AML was predicted by a high BM blast % and low scores for erythroid and total dysplasia. In conclusion, the pattern of in vitro proliferation showed prognostic value while the pattern of vitamin D3-induced differentiation failed to correlate to other parameters. An estimation of bone marrow dysplasia can be used to predict the development of AML. Our results add to the information about the biology of MDS and may be important for the evaluation of therapeutic trials.
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PMID:In vitro suspension culture reactions to 1,25 dihydroxyvitamin D3 in relation to bone marrow morphology and prognosis in patients with myelodysplastic syndromes. 162 79

Mast cell growth factor (MGF), the ligand for the c-kit receptor, has been shown to be a hematopoietic growth factor that preferentially stimulates the proliferation of immature hematopoietic progenitor cells (HPC). We studied the effect of MGF on the in vitro growth of clonogenic leukemic precursor cells in the presence or absence of interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and/or erythropoietin (EPO). Leukemic blood and bone marrow cells from patients with various types of acute myeloid leukemia (AML), chronic myeloid leukemia (CML) in chronic phase, as well as bone marrow samples from patients with myelodysplastic syndromes (MDS) were studied. MGF as a single factor did not induce significant colony formation by clonogenic leukemic precursor cells. In the presence of IL-3 and/or GM-CSF, MGF weakly stimulated the colony formation by clonogenic precursor cells from patients with AML. In contrast, in the presence of IL-3 and/or GM-CSF, MGF strongly induced both size and number of leukemic colonies from patients with CML in chronic phase. Furthermore, in the presence of EPO, MGF strongly stimulated erythroid colony formation by CML precursor cells. Cytogenetic analysis of the colonies showed that all metaphases after 1 week of culture were derived from the leukemic clone. In patients with MDS, MGF strongly stimulated myeloid colony formation in the presence of IL-3 and/or GM-CSF (up to fourfold), and erythroid colony formation in the presence of EPO (up to eightfold). Not only the number, but also the size of the colonies increased. In the presence of MGF, the percentage of normal metaphases increased in three patients tested after 1 week of culture compared with the initial suspension, suggesting that the normal HPC were preferentially stimulated compared with the preleukemic precursor cells. In the absence of exogenous EPO and in the presence of 10% human AB serum, MGF in the presence of IL-3 and/or GM-CSF induced erythroid colony formation from normal bone marrow and patients with MDS or CML, illustrating that MGF greatly diminished the EPO requirement for erythroid differentiation. These results indicate that MGF may be a candidate as a hematopoietic growth factor to stimulate normal hematopoiesis in patients with acute myeloid leukemia, or with myelodysplastic syndromes.
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PMID:Effect of mast cell growth factor (c-kit ligand) on clonogenic leukemic precursor cells. 163 26

The findings of serial observation on 128 bone marrow biopsies following the completion of remission-induction chemotherapy from 12 patients with acute myeloid leukemia (AML), suggest that chemotherapy gave rise to various histologic changes, including hypoplasia, oedematous marrow stroma with widely dilated sinuses and large unilocular fat cells, ('structured fat') developed from multilocular preadipocyte. Early regenerating hemopoietic foci of erythroid, granulocytic and megakaryocytic cells were almost exclusively in the areas of structured fat. Our data showed that fat cells may play an important role in hemopoietic regeneration. and that chemotherapy does not eradicate leukemic cells even in those cases with clinically complete remission. If biopsy specimen showed abnormal localization of immature precursors, (ALIP) It would indicate that complete remission is not reached. and the Patients must receive consolidation chemotherapy until 'ALIP' clusters disappear.
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PMID:[A histopathological study of bone marrow following chemotherapy of acute myeloid leukemia]. 166 Jul 61

Southern blot hybridization was performed with probe v-erbB + A in 4 subjects. Two of them were patients with similar erythroid alterations of bone marrow: one of them was diagnosed as erythroleukemia (EL). The other two were members of a same family (husband and wife). The husband had normal erythroid cellularity of bone marrow but the wife and their 7 living sons and daughters had erythroid hypercellularity. In the second generation of this family 4 hematological patients (1 with AML and 3 with CAA) were found in the past decade. Rearrangement of cerbB and c-erbA genes was found in 3 of the 4 subjects (2 with EL and the wife mentioned above). They had 4 new hybridization bands besides 3 germlines, but the husband had only 3 germlines. The result suggests that using Southern blot hybridization technique with probe v-erbB + A, the rearrangement of c-erbB/c-erbA genes might be a diagnostic indicator of erythroleukemia at early stage of leukomogenesis in familial and sporadic patients. The etiological significance of the rearrangement of c-erbB/c-erbA in leukomogenesis was discussed.
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PMID:[Gene diagnosis of familial erythroleukemia at the early stage of leukomogenesis]. 168 Jun 13


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