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Biomedical subjects

D Mizuno

Publications and source records attributed to D Mizuno.

At least 91 records · Page 5Linked to original sources
PubMed1984

Host-mediated antitumor effect of DMG, a degraded D-manno-D-glucan from Microellobosporia grisea culture fluid.

DMG, a new polysaccharide with a well-characterized structure, isolated from the culture filtrate of an actinomycetes and then degraded by acid treatment, was tested for antitumor activity on allogeneic and syngeneic tumors in mice. In the allogeneic Ehrlich solid tumor system, DMG showed antitumor activity over a wide dose range, its optimal dose being 10-100 mg/kg. The optimal time of DMG administration was 1-2 weeks after tumor inoculation, but DMG was also effective when given before tumor inoculation. DMG was effective when given ip, sc, it (intratumorally) or iv. DMG also had antitumor effects on syngeneic tumors. It rapidly inhibited the growth of MM46 mammary carcinoma, MH134 hepatoma, and Meth A fibrosarcoma, and also inhibited spontaneous pulmonary metastases of B16-BL6 melanoma. However, it had no direct cytocidal action on tumor cells in vitro. Its antitumor activity was much less in athymic nude mice and in mice immunosuppressed by whole-body X-irradiation than in normal hosts.Thus, DMG was shown to exert antitumor activity via host-mediated mechanisms. Its antitumor activity is discussed in comparison with those of other antitumor polysaccharides.

Animals↗
PubMed1984

Immunopotentiation by a new antitumor polysaccharide, DMG, a degraded D-manno-D-glucan from Microellobosporia grisea culture fluid.

The immunopharmacological behavior of DMG, an antitumor polysaccharide, was studied in mice. DMG administered ip or sc stimulated peritoneal macrophages to produce high levels of interleukin-1 activity, which can amplify successive immune responses. DMG dose-dependently and schedule-dependently increased the cellular immune response against allogeneic tumor cells and the humoral immune response to sheep erythrocytes. DMG also enhanced nonspecific antitumor effector functions, such as natural killer activity of spleen and peritoneal cells, and the cytostatic activity of peritoneal macrophages. Peritoneal macrophages activated by ip or sc injection of DMG exhibited high cytostatic activity, especially after exposure in vitro to lymphokine supernatants containing macrophage activation factor. Moreover, granulocyte/macrophage colony-stimulating activity in the serum increased 2-10 hr after DMG administration. Thus, DMG potentiated antigen-specific immunological functions and nonspecific functions of host defense systems against cancer both qualitatively and quantitatively.

Adjuvants, Immunologic↗
PubMed1984

Induction of macrophage growth by heat-stable factor in tumorous ascitic fluid.

Peritoneal macrophages from mice synthesized DNA and proliferated in vitro in the presence of cell-free tumorous ascites. The growth stimulating activity of ascitic fluid was stable on heat treatment (100 degrees C, 30 min). In contrast, the macrophage growth stimulating activity of L cell-conditioned medium was inactivated by heat treatment. The growth factor(s) in heat-treated ascitic fluid was stable at pH 2 and 10, and on treatment with 2-mercaptoethanol or urea. Treatments, with enzymes such as trypsin, pronase, phospholipase and neuraminidase, and with sodium periodate oxidation partially inactivated the macrophage growth stimulating activity of the heat-stable factor(s). The adherent cultured cells that proliferated in heat-treated ascitic fluid were macrophages, as indicated by their nonspecific esterase staining, pinocytosis and phagocytosis. These macrophages showed cytolytic activity against a murine tumor in the presence of wheat germ agglutinin, but not antitumor antibody. These results indicate that tumorous ascitis fluid contains a heat-stable macrophage growth factor(s) distinct from the colony stimulating factor and that the proliferated macrophages killed tumor cells in cooperation with a lectin.

Animals↗
PubMed1984

Cytolytic factor in eggs of the sea hare Aplysia kurodai.

A cytolytic factor partially purified from eggs of the sea hare Aplysia kurodai was examined for cytolytic activity against various target cells. All kinds of tumor cells tested were lysed in vitro by the cytolytic factor in the range of 10-100 ng protein/ml. In contrast, normal spleen cells were lysed by 10 micrograms/ml of this factor and red cells were not lysed even at this higher concentration. Tumor lysis was time-dependent and was complete within 10 hr. This factor inhibited DNA and RNA syntheses of tumor cells but not protein synthesis. The cytolytic activity was lost on heat-treatment (60 degrees) and at pH 2, and was partially inhibited by treatment with 8M urea and at pH 12, but the factor was resistant to treatments with trypsin, periodate and 2-mercaptoethanol. Neutralizing activity was observed in vivo on pretreatment of MM46 and L1210 cells with the factor. This cytolytic factor also inhibited the growth of solid-type MH134 tumor and ascitic-type MM46 tumor. These results indicate that Aplysia eggs contain a novel cytolytic factor that lyses tumor cells in vitro and inhibits tumor growth in vivo.

Animals↗
PubMed1984

Early cellular responses in the peritoneal cavity of mice to antitumor immunomodulators.

The early cellular responses to antitumor immunomodulators and conventional inducers, especially the polymorphonuclear leukocyte (PMN) responses, were examined in the peritoneal cavity of mice to investigate their effect on primary defense mechanisms. Immunomodulators were classified into 5 groups in terms of PMN response on the basis of its duration (declining or persistent) and extent (high or low induction): 1) TAK (beta-1,3-glucan)-type (high, persistent), 2) lentinan-type (high, declining), 3) yeast mannan-type (low, declining), 4) LPS (lipopolysaccharide)-type (low, persistent), 5) others (no effect). Since the general PMN response is of the declining type, the persistence of PMN with TAK- and LPS-type immunomodulators is a characteristic of the PMN-inducing activity. With respect to the extent, TAK- and lentinan-type immunomodulators induced larger numbers of PMN and macrophages than conventional inducers. These results suggest that some types of immunomodulators have effects on the early host-defense mechanism. From the viewpoint of the general self-defense mechanism we also compared these PMN responses with those to bacteria and to tumor inoculation, and the properties of substances inducing high PMN response, i.e., those with the quality of "foreignness," are discussed.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Assembly of transferred normal spleen cells in situ at sites eliciting the delayed hypersensitivity reaction to tumor antigens in mice.

Cell assembly at sites eliciting the delayed hypersensitivity reaction (DHR) to tumor antigens was studied using 51Cr-labeled cells. C3H/He mice were strongly immunized with syngeneic MM46 tumors. The MM46 antigen fraction elicited tumor-specific DHR when injected into the footpad of MM46-immunized mice. The test mice were then injected iv with 51Cr-labeled spleen cells from normal mice, their feet were cut off, and radioactivity in the feet was counted in a gamma-scintillation counter as a measure of the assembly of 51Cr-spleen cells at the site of the antitumor DHR. Assembly of spleen cells persisted for 48 hr after injection of the antigen fraction. Local passive transfer of the DHR also induced assembly of spleen cells, indicating that it is a cell-mediated immune reaction. On the basis of these results, the role of cell movement in host defense systems against tumors is discussed.

Animals↗
PubMed1984

Different local therapeutic effects of various polysaccharides on MH134 hepatoma in mice and its relation to inflammation induced by the polysaccharides.

The local antitumor activities and inflammation-inducing activities of various antitumor polysaccharides were examined and the relation between the two types of activity was studied. The tested antitumor polysaccharides included MG (a mannoglucan prepared from the culture fluid of Microellobosporia grisea), lentinan, bacterial lipopolysaccharide, TAK (a glucan from Alcaligenes faecalis) and their derivatives. Local antitumor activity was tested by intratumoral administration of the polysaccharides 4, 7 and 10 days after inoculation of MH134 hepatoma intradermally (id) into the abdomen of C3H/He mice. MG and its derivatives showed strong local antitumor activity. Inflammation-inducing activity was assayed by measuring foot-pad swelling and accumulation of iv-injected 51Cr-labeled spleen cells after injection of the test materials into the footpads of C3H/He mice. TAK had the strongest inflammation-inducing activity among the polysaccharides tested. No close correlation was found between the local antitumor activity and the inflammation-inducing activity.

Animals↗
PubMed1983

Measurement of Sarcophaga peregrina lectin under various physiological conditions by radioimmunoassay.

Lectin induced in the hemolymph of Sarcophaga peregrina (flesh fly) larvae on injury of the body wall or on pupation was studied further by radioimmunoassay, focusing on the interaction between the lectin and hemocytes. It was found that the amount of lectin on the surface of hemocytes prepared from injured larvae increased with time after injury of the body wall. Radioiodinated lectin could bind to hemocytes prepared from injured larvae more effectively than those from normal larvae, indicating a difference in the affinities to lectin of hemocytes from these two sources. The lectin was found to be synthesized in the fat-body and then secreted into the hemolymph both on injury of the body wall and on pupation. A significant level of lectin was maintained in pupae during the entire pupal stage, but it decreased rapidly before emergence, and no lectin was found in newly emerged flies. Since the lectin greatly activated the activity of mouse bone marrow cells to kill Candida parapsilosis cells, the biological significance of humoral lectin in the defense mechanism was discussed from the ontogenic viewpoint.

Animals↗
PubMed1983

Combination therapy of murine tumors with a degraded D-manno-D-glucan (DMG) from Microellobosporia grisea, and cyclophosphamide.

DMG, a degraded D-manno-D-glucan with a host-mediated antitumor activity did not significantly enhance nor inhibit the development of suppressor cells for either the antibody-forming response or the delayed hypersensitivity reaction to sheep red blood cells. Cyclophosphamide (CY), which inhibited the generation of suppressor cells, was combined with DMG in treatment of murine syngeneic tumors to obtain a higher antitumor activity. The antitumor activity of the combination against MH134 hepatoma was synergistically higher than that of either component alone. A marked antitumor effect of the combination treatment against MM46 mammary carcinoma was also shown. High levels of antitumor delayed hypersensitivity reactions were observed with this combination therapy. The possible roles of DMG and CY in this combination therapy are discussed.

Animals↗
PubMed1983

Comparative studies on antibody and lectin-dependent macrophage-mediated tumor lysis.

Three characteristics of the mechanisms of antibody-dependent macrophage-mediated cytolysis (ADMC) and lectin-dependent macrophage-mediated cytolysis (LDMC) in a C3H/He mouse-MM46 syngeneic tumor system were compared: the role of divalent cations, the effect of cyclic nucleotides, and the role of protease and oxygen compounds as lytic substances. Mg++, but not Ca++, was required for ADMC but neither was required for LDMC. Ca++ inhibited both LDMC and ADMC. Dibutyryl cyclic adenosine 3',5'-monophosphate (cAMP) and its agonists, such as cholera toxin, prostaglandin E1 (PGE1) and E2 (PGE2), inhibited ADMC, but had no effect on LDMC. Dibutyryl cyclic guanosine 3',5'-monophosphate (cGMP) had no effect on either ADMC or LDMC. Isoproterenol and isobutylmethylxanthine had no effect on either ADMC or LDMC. Protease inhibitors, such as pepstatin, bestatin, chymostatin, elastatinal, leupeptin, and bovine pancreatic trypsin inhibitor, did not affect either ADMC or LDMC. Tosylphenylalanyl-chloromethylketone inhibited both ADMC and LDMC, and also inhibited macrophage-tumor cell contact in both systems. Neither catalase nor superoxide dismutase clearly inhibited either ADMC or LDMC. The different sensitivities of ADMC and LDMC to pharmacological agents suggest that these two types of mediator-dependent macrophage-mediated cytolysis have partly different cytolytic processes as well as different recognition sites.

Animals↗
PubMed1983

Polymorphonuclear leukocyte-mediated cytolysis induced by animal lectin.

Nine animal lectins, i.e., Sarcophaga peregrina agglutinin, Balanus roseus agglutinin, Aplysia kurodai agglutinin, Balanus balanoides agglutinin, Tetraclita squamosa japonica agglutinin, Misgurnus anguillicaudatus lectin, Asterina pectinifera agglutinin, Helix aspersa agglutinin and Helix pomatia agglutinin, were tested for induction of cytolysis mediated by polymorphonuclear leukocytes. Among them, S. peregrina agglutinin and B. roseus agglutinin lysed murine target cells in co-operation with polymorphonuclear leukocytes (PMNs) from the peritoneal cavity of mice. PMNs can lyse various tumor cells in the presence of S. peregrina agglutinin, although normal spleen cells were also lysed. This lectin-dependent cytolysis by PMNs was inhibited by galactose, a sugar which is specifically recognized by S. peregrina agglutinin. S. peregrina and B. roseus agglutinins were inhibitory to in vivo development of MM46 tumor cells. These results suggest that PMNs can lyse various target cells in the presence of appropriate animal lectins and that some animal lectins participate in tumor rejection.

Acetylgalactosamine↗
PubMed1983

Potentiation of antitumor immunity in tumor-bearing mice by a degraded D-manno-D-glucan (DMG), a new antitumor polysaccharide.

DMG, a degraded D-manno-D-glucan from the culture fluid of Microellobosporia grisea, inhibited the growth of murine syngeneic MM46 mammary carcinoma. Mice in which the tumor had completely regressed by DMG treatment showed tumor-specific antitumor resistance. The antitumor action of DMG was studied by examining the influences of DMG on tumor-specific and non-specific immune responses in tumor-bearing hosts. The tumor-specific delayed hypersensitivity reaction appeared transiently on day 7 after tumor inoculation but had decreased by day 15 in untreated tumor-bearing mice. In contrast, the reaction was retained and augmented in DMG-treated tumor-bearing mice. The tumor-neutralizing activity of spleen cells from DMG-treated tumor-bearing mice, tested by a Winn assay, was tumor-specific and significantly higher than that of untreated tumor-bearing mice. The tumor-neutralizing activity of peritoneal cells and the in vitro cytostatic activity of peritoneal macrophages in response to lymphokine supernatants containing macrophage activation factor were also augmented by DMG treatment. In contrast, the level of antitumor antibody in the serum increased with time, irrespective of DMG administration. Thus, DMG potentiated cellular antitumor effector mechanisms.

Animals↗
PubMed1983

Inhibition of murine tumor development by the lectin wheat germ agglutinin.

The antitumor activity of lectins were examined by studying the effect of lectins on the in vivo growth of murine tumors. The lectin wheat germ agglutinin (WGA) inhibited the growth of MM46 ascites tumors in vivo as effectively as syngeneic antitumor antiserum, but other lectins were not effective in vivo. WGA also had an inhibitory effect on other syngeneic and allogeneic ascites tumors, a fact which is consistent with its wide range of target tumor cells demonstrated in the in vitro cytolysis system. These results suggest that WGA is a better antitumor agent than other plant lectins. The therapeutic effect of WGA might be, in part, due to its ligand activity between tumor cells and macrophages that induces lectin-dependent macrophage-mediated cytolysis, in addition to its direct cytostatic activity.

Animals↗
PubMed1983

Presence in mouse bone marrow of mediator-dependent cytotoxic effector cells against tumors.

The role of bone marrow cells as cytotoxic effector cells against tumor cells was examined in vitro. Bone marrow cells from normal C3H/He mice could lyse murine MM46 tumor cells in the presence of wheat germ agglutinin or syngeneic antitumor antibody. Bone marrow cells alone did not cause lysis. Eleven other lectins (concanavalin A, phytohemagglutinin, pokeweek mitogen, Lens culinaris hemagglutinin, Ulex europaeus agglutinin, peanut agglutinin, Bandeiraea simplicifolia agglutinin, Bauhinia purpurea agglutinin, soybean agglutinin, Limulus polyphemus agglutinin and Helix aspersa agglutinin) did not induce cytolysis. Enrichment of polymorphonuclear leukocytes (PMNs) by the method of free flow electrophoresis enhanced the activity of WGA-dependent cytolysis. These results suggest that PMNs series in the bone marrow of normal mice can lyse tumor cells with appropriate mediators.

Animals↗
PubMed1983

Antitumor activity of macrophages grown in tumorous ascitic fluid.

Peritoneal macrophages from mice injected with glycogen proliferated in vitro in the presence of cell-free tumorous ascites. DNA synthesis of macrophages was also induced by ascitic fluid, but did not occur in the absence of the fluid. However, macrophage growth was inhibited at a higher concentration of ascitic fluid (greater than 20%). The growth stimulating activity of this fluid was stable on heat treatment. The adherent cultured cells that proliferated were typical macrophages, as indicated by nonspecific esterase staining, pinocytosis and phagocytosis. These macrophages showed cytolytic activity against a murine tumor in the presence of wheat germ agglutinin. However, their cytotoxicity with antitumor antibody decreased during the culture period. These results indicate that tumorous ascitic fluid contains a macrophage growth factor(s) and that macrophages cultured with, and induced to proliferate by, ascitic fluid can kill tumor cells in cooperation with lectin but not antibody.

Animals↗
PubMed1983

Induction of polymorphonuclear leukocyte-mediated cytolysis by wheat germ agglutinin and antitumor antibody.

The role of polymorphonuclear leukocytes (PMNs) as effector cells in tumor lysis was investigated in vitro. PMNs were obtained from the peritoneal cavity of C3H/He Mice injected ip with 2 ml of 12% casein sodium. These PMNs could lyse murine MM46 tumor cells in the presence of the plant lectin, wheat germ agglutinin (lectin-dependent PMN-mediated cytolysis). PMNs alone did not cause cytolysis. PMNs obtained 6 hr after casein injection were effective against tumor target cells but those obtained 3 hr after the injection were not. Other lectins, such as concanavalin A, phytohemagglutinin, pokeweed mitogen, soybean agglutinin, Ulex europaeus agglutinin, Lens culinaris hemagglutinin and Bauhinia purpurea agglutinin, did not cooperate with PMNs in tumor lysis. Antitumor antibody was another mediator that induced tumor lysis in cooperation with PMNs (antibody-dependent PMN-mediated cytolysis). These results indicate that PMNs can lyse tumor cells in the presence of appropriate mediators.

Animals↗
PubMed1983

Mechanisms of lectin and antibody-dependent polymorphonuclear leukocyte-mediated cytolysis.

The mechanisms of tumor lysis by polymorphonuclear leukocytes (PMNs) were investigated. In antibody-dependent PMN-mediated cytolysis (ADPC), sensitized tumor cells were specifically lysed via Fc receptors on PMNs. On the other hand, lectin-dependent PMN-mediated cytolysis (LDPC) caused nonspecific lysis of several murine tumors after recognition of carbohydrate moieties on the cell membrane of both PMNs and tumor cells. Both ADPC and LDPC depended on glycolysis, and cytotoxicity was mediated by reactive oxygen species; LDPC was dependent on superoxide and ADPC on the myeloperoxidase system. The participation of reactive oxygen species in PMN cytotoxicity was also demonstrated by pharmacological triggering with phorbol myristate acetate. These results indicate that reactive oxygen species have an important role In tumor killing by PMNs and that ADPC and LDPC have partly different cytolytic processes as well as different recognition steps.

Animals↗