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Biomedical subjects

T Kasukabe

Publications and source records attributed to T Kasukabe.

At least 55 records · Page 3Linked to original sources
PubMed1988

Purification of a novel growth inhibitory factor for partially differentiated myeloid leukemic cells.

A novel factor termed growth inhibitory (GI) factor, which specifically inhibits the growth of mouse monocytic leukemia cells including monocytic cell lines (Mm-A and J774.1) and other partially differentiated myeloid leukemic cells, has been purified from conditioned medium of some clones of mouse myeloblastic leukemia M1 cells. The procedure for purification of the GI factor included ammonium sulfate precipitation, CM-Sepharose CL-6B and Sephadex G-200 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 25,000 on sodium dodecyl sulfate-polyacrylamide gel. A concentration of 8 X 10(-10) M GI factor was required for 50% inhibition of growth of Mm-A cells. On chromatofocusing, the GI activity was eluted with Polybuffer 96/acetic acid at pH 8.2-8.4. The purified GI factor markedly inhibited growth of mouse bone marrow cells stimulated by macrophage colony-stimulating factor. The GI factor appeared to be a unique cytokine unrelated to known cytokines such as the tumor necrosis factor, interferons, and oncostatin M.

Animals↗
PubMed1987

Control of proliferating potential of myeloid leukemia cells during long-term treatment with vitamin D3 analogues and other differentiation inducers in combination with antileukemic drugs: in vitro and in vivo studies.

Growth inhibition of murine and human myeloid leukemia cells by differentiation inducers during long-term culture was examined to improve the strategy for therapy of myeloid leukemia by differentiation inducers. When the effect of 1 alpha,25-dihydroxyvitamin D3, a typical differentiation inducer, on proliferation of mouse myeloid leukemia M1 cells was examined at a constant product of time and concentration (480 nM in 20 days), the continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3 was the most effective for inhibition of cell proliferation. After 20 days, the cumulative cell number was reduced about 3 X 10(5) times by continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. Similar results were obtained when M1 cells were treated continuously with dexamethasone. M1 cells resistant to 1 alpha,25-dihydroxyvitamin D3 appeared about 25 days after the start of continuous treatment with 24 nM 1 alpha,25-dihydroxyvitamin D3. On the other hand, when M1 cells were treated continuously with 1 alpha,25-dihydroxyvitamin D3 and noncytotoxic doses of antileukemic drugs such as 1-beta-D-arabinofuranosylcytosine and daunomycin, resistant cells did not appear for at least 35 days. A similar effect of 1 alpha,25-dihydroxyvitamin D3 and antileukemic drugs on cell proliferation was observed with the human monoblast-like cell line U937. The survival of syngeneic SL mice inoculated with M1 cells was prolonged more by treatment with both 1 alpha-hydroxyvitamin D3 and daunomycin than by treatment with either drug alone. These results suggest that continuous treatment with both differentiation inducers and certain antileukemic drugs may be more effective therapeutically than treatment with a differentiation inducer alone.

Animals↗
PubMed1987

Production by undifferentiated myeloid leukemia cells of a novel growth-inhibitory factor(s) for partially differentiated myeloid leukemic cells.

Mouse monocytic Mm-A cell line is a highly leukemogenic variant cell line of the monocytic and non-leukemogenic Mm-1 cell line, which developed spontaneously from mouse myeloid leukemia M1 cells. Growth-inhibitory factor (GI factor) for Mm-A cells was found in conditioned medium (CM) of differentiation inducer-resistant myeloblastic M1 cells (clone R-1). The R-1 cells were cultured with or without 2% calf serum for 2 days, and the CM was fractionated with 50% ammonium sulfate and used as the GI factor preparation (termed R1CM). When Mm-A cells were cultured with 5% (v/v) R1CM for 3 days, their growth was inhibited about 80%. This inhibition of Mm-A cell growth by R1CM was irreversible. This GI factor also inhibited the growth of M1 cells that had been pretreated with inducer and had expressed some differentiation-associated properties but still retained a proliferative capacity. In contrast, it scarcely inhibited the growth of untreated M1 cells. The GI factor inhibited the growth of other mouse monomyeloblastic leukemic WEHI-3B D+ cells pretreated with a differentiation inducer, retinoic acid, and mouse monocytic leukemia J774.1 cells. However, it did not affect the growth of human monocytic (U937 and THP-1) or myeloid (KG-1, ML-1, and HL-60) cell lines. These results suggest that GI factor produced by parent myeloblastic and inducer-resistant M1 cells preferentially inhibits the growth of mouse monocytic leukemia cells in intermediate stages of differentiation from myeloblastic leukemia cells to mature macrophages.

Animals↗
PubMed1985

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↗
PubMed1985

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↗
PubMed1984

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↗
PubMed1984

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↗
PubMed1983

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↗
PubMed1983

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↗
PubMed1983

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↗
PubMed1983

Induction of differentiation of human acute non-lymphocytic leukemia cells in primary culture by inducers of differentiation of human myeloid leukemia cell line HL-60.

Leukemia cells from patients with acute non-lymphocytic leukemia were treated with various inducers of differentiation of the human promyelocytic leukemia cell line HL-60. All cells in 14 specimens tested underwent morphological, functional and histochemical changes after treatment with some inducers of differentiation of HL-60 cells, but the most effective inducer varied for different specimens. These results suggest that treatment with some inducers should be effective for inducing most acute myeloid leukemia cells to differentiate into morphologically and functionally mature granulocytes and macrophages.

Adult↗
PubMed1982

Modification of membrane phospholipid composition by choline analogues induces differentiation of cultured mouse myeloid leukemia cells.

Mouse myeloid leukemia M1 cells could be induced by various inducers to form Fc receptors, phagocytize, produce lysozyme, and change into forms that were morphologically similar to macrophages and granulocytes. Previous experiments showed that change in phospholipid metabolism was associated with cell differentiation. In the present experiment, culture of M1 cells with choline analogs such as N-monomethyl-ethanolamine and N,N'-dimethylethanolamine resulted in accumulation of phosphatidyl-N-monomethyl-ethanolamine and phosphatidyl-N,N'-dimethylethanolamine in the cell membranes. This change upon treatment with choline analogs was associated with morphological and functional differentiation of the M1 cells into macrophages and granulocytes. These results suggest that phospholipid metabolism is involved in the mechanism of differentiation of M1 cells.

Animals↗
PubMed1982

Differentiation of isotope-labeled myeloid leukemia cells free in the peritoneal cavity of syngeneic mice.

Ml cells were labeled in vitro with [3H]thymidine and injected into the peritoneal cavity of syngeneic mice. After several days the peritoneal cells were harvested and [3H]labeled cells were determined by autoradiography. The inoculated isotope-labeled Ml cells differentiated in the peritoneal cavity and lipopolysaccharide, an inducer of cell differentiation, significantly stimulated differentiation. These results provide direct evidence that Ml cells can be induced to differentiate in vivo under conditions in which leukemia can develop.

Animals↗
PubMed1982

Inhibition of differentiation of mouse myeloid leukemia cells by heat-stable calf serum components of very high molecular weight.

Mouse myeloid leukemia cells (Ml) were induced to differentiate into macrophages and granulocytes by various inducers including glucocorticoid. The tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited the induction of differentiation of Ml cells in medium containing calf serum, but enhanced the induction in medium containing fetal calf serum and several inducers. For elucidation of the factor(s) in serum affecting the response of Ml cells to tumour promoters, calf serum was fractionated by Sephadex G-200 gel filtration. Differentiation of Ml cells induced by dexamethasone was markedly inhibited by TPA and high mol. wt fractions of calf serum eluted in the void volume and low mol. wt fractions that co-migrated with bovine serum albumin. High mol. wt fractions alone inhibited the differentiation of Ml cells induced by dexamethasone, and also acted additively with TPA in inhibiting the differentiation. The inhibition by high mol. wt fractions was not related to cytotoxicity and was reversible. The differentiation of Ml cells induced by proteinous inducer or lipopolysaccharide was also inhibited by high mol. wt fractions. The inhibitory factor was heat stable (70 degrees C for 20 min or 90 degrees C for 10 min). These results suggest that the tumour promoter and calf serum components cooperate in inhibiting differentiation of mouse myeloid leukemia cells induced by various inducers.

Animals↗
PubMed1982

Modification of growth and differentiation of myeloid leukemia cells by tumor promoters.

The tumor promoter TPA inhibited both functional and morphological differentiation of mouse myeloid leukemia M1 cells cultured in medium containing calf serum or horse serum, but enhanced these inductions in medium containing fetal calf serum. The metabolic processes of prostaglandin E2 synthesis were associated with modification by TPA of differentiation of M1 cells. The factor(s) in the sera affecting the differentiation of M1 cells with TPA was nondialyzable and macromolecular. Upon Sephadex G-200 gel filtration, much more inhibitory activity was found in calf serum than in fetal calf serum, and stimulatory activity was found only in fetal calf serum.

Animals↗
PubMed1982

Modification by serum of differentiation of cultured human myeloid leukemia cells in response to 12-O-tetradecanoylphorbol-13-acetate.

In medium with serum, 12-O-tetradecanoylphorbol-13-acetate (TPA) induced alpha-naphthyl acetate esterase activity in human promyelocytic leukemia cells (HL-60), adherence of the cells to the culture dish, and their change into forms that were morphologically similar to macrophages. HL-60 cells grew in the absence of serum in synthetic medium supplemented with insulin, transferrin, and several trace elements, and could be maintained for more than 6 months in this medium. Induction of differentiation by TPA was observed with cells grown in serum-free medium. Human myeloid leukemia cells (K562-4) cultured in medium with serum could not be induced to differentiate even in the presence of TPA, but their differentiation into macrophages in the presence of TPA, arginase or actinomycin D was observed after they had been grown in serum-free medium for 4 months. Addition of serum inhibited the induction of differentiation of HL-60 and K562-4 cells that had been grown in serum-free medium. Calf serum was more inhibitory than fetal calf serum on TPA-induced differentiation, but there was no significant difference in the effects of the two sera on induction by actinomycin D or arginase. These results suggest that the different responses in media with different sera may be specific to TPA. Induction of adhesiveness of K562-4 cells by TPA required some unknown serum factor(s), although addition of serum inhibited the inductions of morphological and functional differentiation. The relation between the ability of K-562-4 cells to be induced to differentiate into macrophages and long-term cultivation in serum-free medium is discussed.

Animals↗
PubMed1981

Decrease in phospholipid methylation during differentiation of cultured mouse myeloid leukemia cells.

Mouse myeloid leukemia cells (M1) could be induced by various inducers to differentiate into macrophages and granulocytes. When M1 cells were cultured with inducer, the incorporation of methyl group into phosphatidylethanolamine was decreased while the incorporation of choline into phosphatidylcholine was slightly increased. The decrease of cellular phospholipid methylation may be partly due to the decrease of methyltransferase activity.

Animals↗