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Biomedical subjects

M Hozumi

Publications and source records attributed to M Hozumi.

At least 55 records · Page 3Linked to original sources
PubMed1992

Interleukin 4 potentiates the antiproliferative effect of 1 alpha, 25-dihydroxyvitamin D3 on mouse monocytic leukemia cells but antagonizes the antiproliferative effects of interferon alpha, beta and interleukin 6.

Mouse monocytic leukemia Mm cells are a line of spontaneously differentiated cells obtained from mouse myeloblastic leukemia M1 cells. The effect of interleukin 4(IL-4) on the proliferation of Mm cells in the presence or absence of growth inhibitory substances was investigated. In semi-solid agar culture, IL-4 markedly inhibited colony formation by Mm cells, reducing the number of colonies to 50% of that in control cultures at concentration of 3 U/ml. In contrast, IL-4 did not inhibit colony formation by the parent M1 cells. In liquid culture, IL-4 alone inhibited the proliferation of Mm cells only slightly. However, a combination of IL-4 and 1 alpha,25-dihydroxyvitamin D3 (VD3), which alone did not inhibit growth significantly, markedly inhibited the growth of Mm cells. This combination also increased the lysozyme activity of Mm cells significantly. On the other hand, IL-4 suppressed the antiproliferative effects of interferon alpha, beta and IL-6, which are growth inhibitory cytokines for these Mm cells. These results indicate that IL-4 can modulate the growth of monocytic leukemia Mm cells and that its modulatory effects depend on growth inhibitory substances.

Animals↗
PubMed1992

Characterization of growth inhibitory factors for mouse monocytic leukemia cells.

Growth inhibitory (GI) factors for mouse monocytic leukemia cells were previously found in conditioned medium (CM) of a clone of mouse myeloblastic leukemia Ml cells (R1-GI factor) and in CM of mouse lung tissue (L-GI factor). In the present study, the effects of these GI factors on the growth of variant cell lines (Mm-A, Mm-P and Mm-S2) of mouse monocytic line Mm-1 cells were examined. Mm-A are highly leukemogenic to syngeneic SL mice, Mm-P cells are moderately leukemogenic, while Mm-S2 cells have little or no leukemogenicity. The R1-GI factor markedly suppressed the growth of Mm-A cells, whereas it inhibited the growth of Mm-P and Mm-S2 cells only moderately. Recombinant mouse interferon beta (IFN beta) had similar target specificities to those of the R1-GI factor on these variant cells. Moreover, anti-mouse IFN beta antibody completely neutralized the GI activity of the R1-GI factor on Mm-A cells. These results show that the R1-GI factor and mouse IFN beta are very similar and probably identical proteins. The L-GI factor had different target specificities from the R1-GI factor: it showed strongest GI activity on Mm-P cells, moderate GI activity on Mm-S2 cells and weak GI activity on Mm-A cells. Recombinant human interleukin 6 (IL-6) had similar target specificities to the L-GI factor on these Mm-1 variant cells. Furthermore, the L-GI factor could support the proliferation of IL-6-dependent MH60.BSF2 cells. Anti-mouse IL-6 antiserum neutralized the GI activity of the L-GI factor on Mm-P cells. Thus the L-GI factor and mouse IL-6 seem to be closely related and possibly to be identical proteins.

Animals↗
PubMed1992

Effect of recombinant human D-factor on the growth of leukemic blast progenitors from acute myeloblastic leukemia patients.

We studied the effects of D-factor on the growth of leukemic blast progenitors from 15 patients with acute myeloblastic leukemia and two leukemia cell lines in methylcellulose and suspension cultures. When stimulated by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor or interleukin-3, leukemic blast progenitors undergo terminal division with limited differentiation in methylcellulose culture, forming blast colonies. Leukemic blast progenitors can renew themselves. The self-renewal can be detected as secondary colony formation after replating primary blast colonies in fresh methylcellulose media and by the growth of clonogenic cells in suspension culture. D-Factor suppressed primary and secondary colony formation in methylcellulose culture. Furthermore, D-factor suppressed clonogenic cell recovery in suspension culture. The suppression by D-factor of the growth of leukemic blast progenitors was not significantly dependent upon the colony-stimulating factors used as growth-stimulating factors. High concentration of G-CSF did not overcome the suppressive effect of D-factor. The results indicate that D-factor is effective in suppressing not only terminal division but also self-renewal of leukemic blast progenitors.

Adult↗
PubMed1992

[Pharmacological studies of nutritive and tonic crude drugs on fatigue in mice].

The aim of the present study was to clarify acute anti-fatiguing effects of three crude liquid drug preparations (S1-S3), containing almost the same amounts of Ginseng Radix, Epimedii Herba and Agkistrodon Japonicae, with each differentially containing an additional 11, 13 or 15 crude drugs. After preloading forced swimming or tetrabenazine (TBZ: 50, 100 mg/kg, i.p.), each of the S1-S3 preparations applied orally (0.1 ml/10 g) significantly increased the duration times of swimming together with decreased total duration times of immobility during swimming. These effects peaked 60 min postinjection with the following decreasing order of effectiveness: S3 > S2 > S1. The same order of efficacy was also found for increased locomotor activity and decreased durations of swimming immobility after TBZ. After pretreatment with 200 mg/kg TBZ preparations S1-S3 also increased the numbers of jumping on a hot plate with greatly reduced latency. Without preloading the forced swimming, S1-S3 did not have any effect on jumping and its latency, but both S2 and S3 significantly, but more weakly, as compared to those after its preloading, decreased the immobility times. These results indicate that these crude preparations may cause tonic effects and so far tested, these effects seem to be more effective on subjects fatigued with physical and/or mental works than an normal subjects.

Administration, Oral↗
PubMed1992

Control of growth and differentiation of Philadelphia chromosome-positive leukemia cells by tyrosine kinase inhibitors.

Herbimycin A, a selective inhibitor of tyrosine kinase activity, induced differentiation of leukemia cells isolated from Philadelphia chromosome-positive chronic myelogenous leukemia patients. However, it did not induce differentiation of leukemia cells from acute myelogenous leukemia patients, although these cells could be induced to differentiate by treatment with appropriate compounds. A selective inhibitor of tyrosine kinase might be useful in chemotherapy of Philadelphia chromosome-positive leukemia.

Antibiotics, Antineoplastic↗
PubMed1992

Effects of novel uracil analogs on proliferation and differentiation of human myeloid leukemia cells.

Twenty-seven novel nucleobases and nucleosides were synthesized by structural modification of uracil, and their effects on growth and differentiation of human myeloid leukemia HL-60 cells were examined. Some of the compounds inhibited the growth of HL-60 effectively. The nitroblue tetrazolium (NBT)-reducing activities of cells treated with the concentrations of these compounds for 50% inhibition of growth were compared. TI-66 (2,4-dibenzyl-6-fluoro-7,7,8,8-tetramethyl-cis-2,4-diazabicyclo-[4.2.0] octane-3,5-dione) was the most effective inducer of NBT-reducing activity and morphological differentiation of HL-60 cells into cells of the myelomonocytic lineage. TI-66 was also effective for induction of differentiation of another human myelogenous leukemia cell line, ML-1 cells, but not for differentiation of human erythroid leukemia K562 or HEL cells, or monocytic U937 cells. The effect of TI-66 in inducing differentiation of HL-60 cells was additive or more than additive in combination with retinoic acid or vitamin D3. Adenine or hypoxanthine alone induced NBT-reducing activity of the cells, and at suboptimal concentrations these compounds enhanced the effect of TI-66, but the enhanced NBT-reducing activities did not exceed the maximal activity induced by TI-66 alone. Simultaneous treatment of HL-60 cells with hypoxanthine reduced the growth inhibition by TI-66 alone. TI-66 was about 150 times more potent on a molar basis than adenine in inducing differentiation of HL-60 cells. These results suggest that nucleobase analogs such as TI-66 should be useful for differentiation therapy of some types of myelogenous leukemia.

Cell Differentiation↗
PubMed1992

[Differentiation therapy of hematologic malignancies: principles, current status and perspectives].

There is increasing evidence that various tumor cells can be induced by differentiation inducers including biological response modifiers, synthetic chemicals and conventional anticancer drugs to differentiate terminally both in vitro and in vivo into cells with normal characteristics. The differentiated cells lose their abilities for proliferation and transplantation in animals. Furthermore, survival times of the animals inoculated with various tumors were found to prolong by administration with the differentiation inducers. These basic findings suggest that induction of terminal tumor cell differentiation is another strategy for cancer therapy: differentiation therapy of cancer. Principles, current status and perspectives of the differentiation therapy of leukemia are reviewed in this article.

Animals↗
PubMed1991

Interleukin-4 inhibits the differentiation of mouse myeloid leukemia M1 cells induced by dexamethasone, D-factor/leukemia inhibitory factor and interleukin-6, but not by 1 alpha,25-dihydroxyvitamin D3.

The effects of interleukin-4(IL-4) on the growth and differentiation of mouse myeloid leukemia M1 cells induced by various differentiation inducers were investigated. IL-4 alone did not have any significant effect on the growth or differentiation of M1 cells, but inhibited their differentiation induced by dexamethasone, D-factor/leukemia inhibitory factor, or interleukin 6. IL-4 also restored the proliferation of M1 cells after growth inhibition during their induction of differentiation by inducers. In contrast, IL-4 enhanced inhibition of growth and induction of differentiation of M1 cells by 1 alpha,25-dihydroxyvitamin D3. These results indicate that modulation of differentiation of M1 cells by IL-4 depends on the differentiation inducer.

Animals↗
PubMed1991

Induction by some protein kinase inhibitors of differentiation of a mouse megakaryoblastic cell line established by coinfection with Abelson murine leukemia virus and recombinant SV40 retrovirus.

Mouse C1 line cells are megakaryoblastic cells established by coinfection of Abelson murine leukemia virus and recombinant simian virus 40. We examined the effects of various compounds on growth and differentiation of these cells. Megakaryocytic differentiation of C1 cells was not induced by cytokines that stimulate megakaryocytic maturation of normal progenitor cells, such as interleukin 3 and 6 and granulocyte-macrophage colony-stimulating factor. However, the cells were induced to differentiate into megakaryocytes by treatment with some protein kinase inhibitors. The inhibition of v-abl tyrosine kinase activity preceded induction of differentiation of the cells treated with tyrosine kinase inhibitors such as genistein, herbimycin A, and erbstatin. Treatment of C1 cells with a v-abl antisense oligomer inhibited their proliferation and induced acetylcholinesterase activity, a typical marker of megakaryocytic differentiation. These results suggest that inhibition of v-abl function is associated with induction of megakaryocytic differentiation of C1 cells. Among the compounds tested, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of cyclic nucleotide-dependent and Ca(2+)-phospholipid-dependent (protein kinase C) protein kinases, was the most potent inducer of differentiation of C1 cells. However, the differentiation-inducing effect of H-7 was unlikely to be mediated through inhibition of protein kinase C or cyclic nucleotide-dependent kinases, because other types of inhibitors of these kinases were not effective, and a protein kinase activator (phorbol ester) induced differentiation of C1 cells. Moreover, neither v-abl mRNA expression nor v-abl kinase activity in C1 cells was affected by treatment with H-7. These findings indicate that induction of megakaryocytic differentiation by H-7 is not related to inhibition of v-abl kinase, but rather to some novel function of H-7.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Hemin enhances the sensitivity of erythroleukemia cells to 1-beta-D-arabinofuranosylcytosine by both activation of deoxycytidine kinase and reduction of cytidine deaminase activity.

The sensitivity of human myelogenous leukemia cells to 1-beta-D-arabinofuranosylcytosine (ara-C) during induction of differentiation was examined. Treatment with hemin greatly increased the sensitivity of erythroid leukemia cells to ara-C. The enhancement of ara-C sensitivity by hemin was not as remarkable in nonerythroid leukemia cells. Hemin altered the metabolism of ara-C in human erythroleukemia K562 cells by reducing ara-C deaminase activity, increasing intracellular accumulation of ara-C, and activating the nucleoside kinases. These alterations may be involved in the enhancing effect of hemin on sensitivity of ara-C. These results suggest that some inducers of differentiation potentiate the antileukemic effect of ara-C on human erythroleukemia cells.

Cell Differentiation↗
PubMed1991

Induction of differentiation of human myeloid leukemia HL-60 cells by novel pyrimidine nucleoside analogs.

New pyrimidine nucleoside analogs (18 compounds) were synthesized and their growth-inhibiting and differentiation-inducing activities on human myeloid leukemia HL-60 cells were examined. Some of the analogs were found to induce nitroblue tetrazolium (NBT) reducing activity in the HL-60 cells. The inducing activities of these compounds were compared at their concentrations for 50% inhibition of cell growth. TI-79 (3-benzyl-5-methyl-3-(beta-D-ribofuranosyl)pyrido[2,3-d]pyrimidine- 2,4(1H,3H)-dione) was a very effective inducer of NBT-reduction and of differentiation of the cells into mature granulocytes. The induction of NBT-reducing activity by TI-79 was inhibited by high concentrations of the natural nucleoside, adenosine. Other differentiation inducers, such as retinoic acid, 1 alpha,25-dihydroxyvitamin D-3 and staurosporin markedly enhanced the induction of differentiation of HL-60 cells by TI-79. Nucleoside analogs such as TI-79 should be useful for differentiation therapy of some types of myelogenous leukemia.

Adenosine↗
PubMed1991

Induction of differentiation of human leukemia cells by inhibitors of myosin light chain kinase.

Inhibitors of myosin light chain kinase, 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-9) and 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-7), induced Nitroblue tetrazolium reducing activity, lysozyme activity and morphological maturation of human monoblastic U937, THP-1 and promyelocytic HL-60 cells, but not of erythroblastic K562 cells. However, three analogs of ML-9, which are an inhibitor and an activator of protein kinase C, and a calmodulin antagonist, respectively, did not induce differentiation of the cells.

Azepines↗
PubMed1991

Inhibition by erythroid differentiation factor (activin A) of P-glycoprotein expression in multidrug-resistant human K562 erythroleukemia cells.

The K562/VCR cell line, exhibiting acquired multidrug resistance (MDR) with increased expression of a cell surface glycoprotein (P-glycoprotein), was isolated from human erythroleukemia K562 cells. Various compounds that induced erythroid differentiation of K562 cells were tested for their effects on growth and differentiation of these K562/VCR cells. Sodium butyrate, hemin, 1-beta-D-arabinofuranosylcytosine, and erythroid differentiation factor (EDF) induced erythroid differentiation of K562/VCR cells as well as K562 cells. The MDR of K562/VCR cells was partly overcome by treatment with EDF but not with the other inducers. Expression of P-glycoprotein by K562/VCR cells was measured by radioimmunoassay using MRK16 monoclonal antibody. Results showed that EDF caused down-regulation of P-glycoprotein in K562/VCR cells, whereas the other inducers did not cause its down-regulation. Thus, in addition to inducing erythroid differentiation, EDF enhanced the sensitivity of K562/VCR cells to multidrugs and suppressed expression of P-glycoprotein. These results suggest that differentiation inducers may be useful in chemotherapy of leukemic MDR cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Both D factor/LIF and IL-6 inhibit the differentiation of mouse teratocarcinoma F9 cells.

Differentiation-stimulating factor (D factor)/leukemia inhibitory factor (LIF) and IL-6 are reported to be cytokines having multifaced functions including the induction of differentiation in mouse myeloid leukemia M1 cells. We here report that both D factor/LIF and IL-6 inhibit the differentiation of mouse teratocarcinoma F9 cells induced by retinoic acid alone or combined with dibutyryl cAMP. From the microscopic observation as well as Northern blot analysis using cDNA probes encoding several marker proteins for differentiation of F9 cells, we concluded that D factor/LIF and IL-6 are functionally closely related in the induction of differentiation in M1 cells and in the inhibition of F9 differentiation.

Alkaline Phosphatase↗
PubMed1991

Induction of differentiation of human myeloid leukemia HL-60 cells by novel nonphosphorus alkyl ether lipids.

We synthesized a new series of nonphosphorus alkyl ether glycerolipids, in which the 2-acetyl group of platelet-activating factor was replaced by a pyrimidin-2-yl group and the 3-phosphocholine portion by an omega-(substituted ammonio)ethoxyethyl side-chain including omega-thiazolio-, imidazolio- and pyridinio groups with or without a carboxyl substituent, respectively (compound I-XI). Their effects on cell proliferation and differentiation of human myeloid leukemia HL-60 cells were examined. Incubation of HL-60 cells with these cationic and zwitterionic alkyl ether lipids inhibited proliferation of HL-60 cells with IC50 values ranging from 10 to 500 ng/mL. The cells were induced by the lipids to differentiate into morphologically and functionally mature granulocytes. Among the compounds we tested, 1-octadecyl-2-pyrimidinyl-3-[3-(5- carboxylatepentyl)imidazolioethoxyethyl]glycerol (compound I) was the most effective in inducing differentiation of HL-60 cells. Compound I showed on a molar basis, an inhibitory effect on the leukemic cells over 50 times greater than did 2-(2-dodecyloxyethoxy)ethyl 2-pyridinio-ethyl phosphate, the antileukemic alkyl ether phospholipid.

Antineoplastic Agents↗
PubMed1991

Effects of inhibitors of protein tyrosine kinase activity and/or phosphatidylinositol turnover on differentiation of some human myelomonocytic leukemia cells.

The activities of protein tyrosine kinase and phosphatidylinositol turnover have been found to be associated with cell growth and differentiation. We examined the effects of some inhibitors for these biochemical activities in human myelogenous leukemia cells. Genistein, which is known to inhibit the activities of protein tyrosine kinase, phosphatidylinositol turnover and topoisomerase II, induced nitroblue tetrazolium (NBT) reduction and lysozyme activity in ML-1, HL-60 and U937 cells. Morphological studies showed that genistein-induced differentiation of myeloblastic ML-1 cells into promyelocytes and of promyelocytic HL-60 cells into mature granulocytes. The differentiation-inducing effect of genistein was augmented by addition of 1 alpha,25-dihydroxyvitamin D3 (VD3) or retinoic acid, VD3 being more effective than retinoic acid. Methyl 2,5-dihydroxycinamate, a protein tyrosine kinase inhibitor, had only a weak effect in inducing differentiation of ML-1 cells. On the other hand, psi-tectorigenin was more effective than genistein in inducing the differentiations of ML-1 and HL-60 cells. Psi-tectorigenin is reported to inhibit phosphatidylinositol turnover without inhibiting protein tyrosine kinase. Thus modulation of phosphatidylinositol turnover might be more important than that of protein tyrosine kinase activity for differentiation of some myelogenous leukemia cells.

Cell Differentiation↗