[Prognosis in liver cirrhosis].
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Humans↗
Biomedical subjects
M Hozumi
Publications and source records attributed to M Hozumi.
Specific inhibition by prostaglandin D2 and its metabolites of lysozyme synthesis in mouse macrophage-like cell line, Mm-1.
The cultured mouse macrophage-like cell line Mm-1 synthesizes and secretes lysozyme continuously like normal macrophages. Culture of the cells in the presence of prostaglandin D2 for 3 days strongly inhibited their production of lysozyme activity. Prostaglandin D2 caused dose-dependent inhibition of the activity: 1 X 10(-6) M prostaglandin D2 caused about 50% inhibition. Inhibition by prostaglandin D2 was not related to cytotoxicity and was reversible. The rate of synthesis of lysozyme protein was measured by culturing Mm-1 cells with radioactive amino acids and then immunoprecipitating the protein. At the concentrations used, prostaglandin D2 inhibited the synthesis of lysozyme dose-dependently, but did not suppress the synthesis of total protein. Of the various types of prostaglandin, only prostaglandin D2 inhibited the production of lysozyme in Mm-1 cells. Moreover, prostaglandin D2 did not inhibit the production of other lysosomal enzymes, such as acid proteinase, acid phosphatase and beta-glucuronidase, and did not affect Fc receptors on the cell surface, adherence of cells to the culture dish or the cell morphology. These results indicate that prostaglandin D2 specifically inhibits the synthesis of lysozyme in Mm-1 cells. When Mm-1 cells were cultured for 3 days in the presence of the ethyl acetate extract from the culture medium in which Mm-1 cells had been cultured with prostaglandin D2 for 3 days, the production of lysozyme activity of Mm-1 cells was also markedly inhibited by the extract. After the incubation of prostaglandin D2 for 3 days with Mm-1 cells, less than 10% of the initial prostaglandin D2 remained and two major metabolites appeared. These results suggest that the metabolites of prostaglandin D2 were involved in the inhibitory action of prostaglandin D2 in Mm-1 cells.
Animals↗
Discrepancy between in-vitro and in-vivo inductions of differentiation by retinoids of human acute promyelocytic leukemia cells in relapse.
In-vitro studies of leukemic cells with retinoic acid and a therapeutic clinical trial with its derivative, etretinate, in a 58 yr-old male patient with 15;17 translocation-positive acute promyelocytic leukemia (APL) in relapse are reported. Actinomycin D was used in combination. Bone marrow promyelocytes from the patient prior to etretinate and actinomycin D matured morphologically in the liquid culture with retinoic acid; 98% were matured myeloid cells after 6 days at a concentration of 10(-6) M of retinoic acid as compared with 2% in the control culture. Positive NBT reactions were seen in none of the cells in the latter but in 95% of the cells in the former. Actinomycin D, when added alone, only induced NBT positivity, but, when used in combination with retinoic acid, increased both NBT positivity and morphologically matured cells. The patient was treated daily with 2 micrograms/kg of actinomycin D (or 20 mg/m2 or 33 mg/m2 cytosine arabinoside after the 6th day) in 24-h infusions and per oral 90 mg/body of etretinate. No effectiveness was observed both morphologically and clinically. The patient expired 15 days after the initiation of etretinate. Thus, a discrepancy existed in the response of leukemic cells from this relapsed patient with APL to the in-vitro and in-vivo attempts to include differentiation by retinoids and actinomycin D.
Cell Differentiation↗
Established leukemia cell lines: their role in the understanding and control of leukemia proliferation.
For investigation of mechanisms of leukemogenesis and control of proliferation of leukemia cells, various preleukemic hematopoietic progenitor cell lines and leukemia cell lines have been established. The role of these established cell lines in understanding leukemogenesis and control of leukemia cell proliferation is described. The results of studies on biological characteristics of numerous human leukemia-lymphoma cell lines suggest that the heterogeneity in various markers of the cell lines reflects different patterns of normal hematopoietic cell differentiation. Then, recent studies on the control of proliferation of leukemia cells by induction of terminal differentiation with the use of established leukemia cell lines both in vitro and in vivo are described. Therapeutic significance of the results obtained with these leukemia cell lines is also discussed.
Animals↗
Characterization of a differentiation-inhibitory activity from nondifferentiating mouse myeloid leukemia cells.
Mouse myeloid leukemic M1 cells are induced to differentiate by various differentiation inducers. Activity for inhibition of induction of differentiation of M1 cells (I-activity) has been found in conditioned medium of variant M1 cell clones resistant to differentiation inducers, and this I-activity has been shown to be closely associated with resistance of the cells to differentiation inducers. In this work, the I-activity in the conditioned medium of the resistant M1 cells was shown to bind to Carboxymethyl-Sepharose CL-6B and to be eluted with 0.27-0.4 M NaCl. The profile of gel filtration of I-activity from Sephadex G-200 indicated considerable heterogeneity in molecules with I-activity; the apparent molecular range of the main I-activity was 60,000-80,000. On chromatofocusing, the I-activity was eluted with Polybuffer 96-acetic acid at pH 8.8-9.0. The I-activity was inactivated by treatment with trypsin or by heating at 75 degrees C for 30 min. Therefore, the main I-activity seemed to be due to a basic protein(s).
Animals↗
Induction of differentiation of cultured mouse monocytic leukemia cells (Mm-A) by inducers different from those of parent myeloblastic leukemia cells (M1).
Mouse monocytic Mm-A cells are a highly leukemogenic variant line of the monocytic and non-leukemogenic cell line Mm-1, which developed spontaneously from mouse myeloid leukemia M1 cells. Studies were made on whether Mm-A cells could be induced to differentiate further by agents that were effective for inducing differentiation of the parent M1 cells and other leukemic cells. Of the agents tested, butyrate, conditioned medium from concanavalin A-stimulated spleen cells, lipopolysaccharide (LPS) and N6,O2-dibutyryl adenosine 3'5'-cyclic-monophosphate (dbcAMP) significantly stimulated the lysozyme activity of Mm-A cells, which is one of the most characteristic biochemical markers of monocytes and macrophages. Butyrate was the most effective agent for increasing lysozyme production by Mm-A cells; culture with 0.5mM butyrate for 3 days increased lysozyme production by Mm-A cells about 50-fold. Inducers of M1 cell differentiation such as dexamethasone, 1 alpha,25-dihydroxyvitamin D3, arginase, and proteinous inducer did not increase the lysozyme activity. Butyrate also induced NBT reduction and stimulated other differentiation-associated functions, such as expressions of Fc receptors on the cell surface, immune phagocytosis and production of inducer for M1 cell differentiation. Its effect in stimulating differentiation of Mm-A cells was synergistic with that of dbcAMP or LPS. Incubation with butyrate inhibited the proliferation of Mm-A cells, about 0.3mM butyrate causing 50% inhibition. These results indicate that monocytic, leukemogenic Mm-A cells can be induced to differentiate further by butyrate and that the inducers of differentiation of Mm-A cells are markedly different from those of the parent myeloblastic M1 cells.
Animals↗
[A case of severe disopyramide poisoning, treated successfully by haemodialysis].
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Adult↗
Characterization of a factor inducing differentiation of mouse myeloid leukemic cells purified from conditioned medium of mouse Ehrlich ascites tumor cells.
A factor inducing differentiation of mouse myeloid leukemic cells (MI) into macrophages was purified to apparent homogeneity from 168 1 of CM of Ehrlich ascites tumor cells. The purified factor was half-maximally active at 2 X 10(-11) M. The factor was analyzed by radioiodination, SDS-polyacrylamide gel electrophoresis and autoradiography. Its Mr was 40 000-50 000. On reduction, the factor lost activity, but showed no subunit structure. Treatment of the factor with endo-beta-N-acetylglucosaminidase F, but not endo-beta-N-acetylglucosaminidase H, gave rise to a molecule of Mr 20 000-28 000. The activity of the factor from Ehrlich cells was completely neutralized by antiserum to the factor of Mr 50 000-70 000 from mouse fibroblast L929 cells.
Animals↗
Purification of a factor inducing differentiation of mouse myeloid leukemic M1 cells from conditioned medium of mouse fibroblast L929 cells.
A procedure is described for purification of a factor (D-factor)-inducing differentiation of mouse myeloid leukemic cells (M1) into macrophages from serum-free mouse L929 cell-conditioned medium. The procedure included ammonium sulfate precipitation, DEAE-cellulose, Sephadex G-200 and phenyl-Sepharose column chromatographies, reverse-phase high-performance liquid chromatography on a C18 hydrophobic support, and high-performance liquid chromatography on a gel-filtration column. The purified factor gave a single band of protein with a molecular weight of 62,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis which coincided with biological activity. Its half-maximal concentration for inducing differentiation of M1 cells into macrophages was 1.7 X 10(-11) M. Even at 2.6 X 10(-9) M, it did not induce colony formation of normal bone marrow cells, suggesting that it was distinct from the growth factor for normal precursors of macrophages and/or granulocytes.
Animals↗
Selection of mouse macrophage-like sublines that differ in leukemogenic potential and characterization.
The murine macrophage-like cell line (Mm-1), which is nonleukemogenic to syngeneic SL mice, was originally derived from spontaneously differentiated cells of a clonal line of mouse myeloid leukemia cells (M1). In the present experiment, variant cell lines with a high (Mm-A), moderate (Mm-P), and little or no (Mm-S1 and Mm-S2) leukemogenic potential were obtained from the Mm-1 cells. The mean survival times of syngeneic SL mice inoculated i.p. with 5 X 10(6) Mm-A and Mm-P cells were 17 and 33 days, respectively, whereas almost all the mice inoculated with Mm-S1 or Mm-S2 cells survived for more than 90 days. These variant cell lines did not lose their macrophage-like characteristics in vitro. These variant cell lines phagocytized latex beads and sensitized sheep erythrocytes, produced lysozyme, and adhered to culture dishes. The four variant cell lines showed no significant difference in proliferation rates in vitro in liquid medium containing 10% calf serum, but Mm-A cells could grow both in soft agar medium in the absence of ascitic fluid containing colony-stimulating factor (CSF) and in liquid medium containing 1% serum, whereas Mm-P cells could grow in the liquid medium but not in soft agar medium without ascitic fluid, and Mm-S1 and Mm-S2 cells could not grow in either medium. The ratio of the nuclear area to the cell area (NCR) of Mm-A cells was a high (51%) but those of Mm-S1 and Mm-S2 cells were low (40-41%), and that of Mm-P cells was intermediate (44%). The leukemogenicity of Mm-1 cell lines was roughly correlated with their NCR. The possibility that interactions between Mm-1 variant cells and host immune cells might be involved in the mechanisms of their different leukemogenicities was not supported by results on the in vitro susceptibilities of Mm-1 variant cells to the cytostatic actions by normal macrophages and spleen cells and on leukemogenicities of the Mm-1 variant cells in athymic nude mice. A possible method of control of the leukemogenicity of Mm-1 variant cells is discussed.
Animals↗
Syntheses and biological activities of N-alkyl- and N-alkenylcarbamoyl phospholipids.
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Animals↗
Differentiation in vitro of human myelogenous leukemia cells from patients in relapse.
Leukemia cells from patients with acute myeloid leukemia in relapse were treated with various inducers of differentiation of human myeloid leukemia cell lines. Leukemia cells in primary culture from most, but not all, patients underwent morphological, cytochemical and biochemical changes after treatment with inducers of differentiation such as 12-O-tetradecanoylphorbol-13-acetate (TPA), retinoic acid, actinomycin D, aclarubicin, and alkyl lysophospholipid. The most effective inducer varied from specimen to specimen. Leukemia cells from patients in relapse were compared with those from untreated patients. The responsiveness to TPA of leukemia cells from patients in relapse was similar to that of leukemia cells from untreated patients. However, retinoic acid or actinomycin D resistance was more frequently observed in leukemia cells from patients in relapse than in those from patients before initial therapy. This is the first report to indicate that leukemic cells from relapsed patients who are resistant to cytotoxic chemotherapeutic drugs can be induced to differentiate into mature cells by appropriate inducers. However, the responsiveness to inducers of leukemia cells from patients in relapse is not the same as that of leukemia cells before therapy.
Adolescent↗
[Differentiation induction of leukemic cells in acute myeloid leukemia].
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Anemia, Aplastic↗
Preparation and neutralization characteristics of an antibody to the factor inducing differentiation of mouse myeloid leukemic cells.
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Animals↗
Antileukemic effect of alkyl phospholipids. I. Inhibition of proliferation and induction of differentiation of cultured myeloid leukemia cells by alkyl ethyleneglycophospholipids.
Various alkyl ethyleneglycophospholipids, i.e., alkyl phospholipids, with ethyleneglycol or its congener in place of glycerol as a molecular backcone, were synthesized and their effects on cell proliferation and differentiation of cultured human (HL-60) and mosue (Ml) myeloid leukemia cells were studied. On incubation with alkyl ethyleneglycophospholipids, proliferation of both cell lines was inhibited and the cells were induced to differentiate into morphologically and functionally mature granulocytes and macrophages. Among the compounds tested, dodecyl ethyleneglycophospholipid with a pyridinioethyl group was the most effective in induction of differentiation of both cell lines.
Cell Differentiation↗
Antileukemic effect of alkyl phospholipids. II. Prolongation of survival times of leukemic mice by alkyl ethyleneglycophospholipids.
Alkyl ethyleneglycophospholipids induced differentiation in vitro of mouse myeloid leukemia M1 cells into mature granulocytes and macrophages. The compounds also prolonged the survival of syngeneic SL mice inoculated with M1 cells. Although in mice with florid leukemia these compounds alone scarcely affected survival, administration of dodecyl ethyleneglycophospholipid with pyridinioethyl as a polar group plus actinomycin D significantly prolonged survival.
Animals↗
Stimulation of cell proliferation by tumor-promoting phorbol esters and inhibition by some inhibitors of tumor promotion in suspension cultures of a human lymphoblastoid cell line.
A human lymphoblastoid cell line, SCC-1, was established from the bone marrow of a patient with acute nonlymphocytic leukemia. 12-O-Tetradecanoylphorbol-13-acetate (TPA) enhanced cell proliferation of SCC-1 cells in suspension culture. A positive correlation was found between the tumor-promoting activities of several plant diterpenes and their enhancing effects on the growth of SCC-1 cells. Various compounds that inhibit tumor promotion were tested for their capacity to inhibit cell proliferation at a physiological concentration. These compounds were not cytotoxic but cytostatic even at high concentration.
B-Lymphocytes↗
Cooperative effect of 1 alpha,25-dihydroxyvitamin D3 and dexamethasone in inducing differentiation of mouse myeloid leukemia cells.
Murine myeloid leukemia cells (MI) are induced to differentiate into macrophages by the metabolically active form of vitamin D3,1 alpha,25-dihydroxyvitamin D3[1 alpha,25(OH)2D3] (E. Abe et al., (1981) Proc. Natl. Acad. Sci. USA 78, 4990-4994). At 0.12-120 nM, 1 alpha,25(OH)2D3 suppressed cell growth in a dose-dependent manner and markedly induced phagocytic activity, lysozyme activity, and C3-receptor formation. The potency of 1 alpha,25(OH)2D3, at 0.12-120 nM, in inducing differentiation was nearly equivalent to that of 10-10,000 nM of dexamethasone, one of the most potent stimulators of Ml cells. Simultaneous treatment with low physiological plasma concentrations of 1 alpha,25(OH)2D3 (0.12 nM) and dexamethasone (10 nM) induced differentiation of Ml cells equivalent to the responses obtained only by using much higher concentrations of the respective steroids when used separately. In addition, two variant clones of Ml cells resistant to either 1 alpha,25(OH)2D3 or dexamethasone were isolated. One was resistant to 120 nM of 1 alpha,25(OH)2D3 but sensitive to 10-1000 nM of dexamethasone. The other was resistant to 1000 nM of dexamethasone but sensitive to 12 nM of 1 alpha,25(OH)2D3. This suggests that the mechanism of action of 1 alpha,25(OH)2D3 in inducing differentiation of Ml cells is different at least in part from that of dexamethasone, and that combination therapy by both steroids may be useful in reducing leukemogenicity of Ml cells in vivo.
Animals↗