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Biomedical subjects

J Murata

Publications and source records attributed to J Murata.

At least 109 records · Page 6Linked to original sources
PubMed1990

Inhibition of tumor cell arrest in lungs by antimetastatic chitin heparinoid.

We have investigated the effect of sulfated chitin derivatives on the intravascular events in the metastatic cascade. 6-O-Sulfated carboxymethyl chitin (SCM-chitin III), as well as heparin, significantly inhibited the arrest of B16-BL6 cells in lungs after co-injection with radiolabeled tumor cells, but carboxymethylated chitin (CM-chitin) had no effect. Heparin showed a potent inhibitory effect on tumor cell-elicited platelet aggregation and on blood coagulation, which can subsequently enhance the survival, arrest and invasiveness of tumor cells, whereas SCM-chitin III showed much weaker properties. In contrast, SCM-chitin III was found to inhibit the adhesion of tumor cells to subendothelial matrix, while heparin did not. SCM-chitin III was still active in inhibiting experimental lung metastasis even in mice which had been pretreated with anti-asialo GM1 serum or carrageenan to eliminate NK cells or macrophages. Thus, these results suggest that SCM-chitin-mediated inhibition of tumor metastases is distinct from that by heparin and may be due to interference with tumor cell arrest in the capillaries and consequently to the inhibition of tumor cell adhesion to subendothelial matrix.

Animals↗
PubMed1990

Inhibition of lung metastasis by synthetic and recombinant fragments of human fibronectin with functional domains.

We have investigated the antimetastatic effect of synthetic or recombinant peptides containing the functional domains of fibronectin on experimental and spontaneous lung metastases of murine tumor cells. CS1 peptide which is present within type III homology connecting segment (IIICS) as well as C-274 (cell-binding domain) were able to inhibit experimental lung metastasis when co-injected intravenously (iv) with B16-BL6 melanoma cells, while H-271 (heparin-binding domain) could not. In the spontaneous metastasis model, multiple iv administrations of CS1 or C-274 after surgical excision of primary tumors caused a significant reduction of metastatic colonies in the lung. Both CS1 and C-274 significantly inhibited cell adhesion and migration to fibronectin-coated substrates when added freely in solution. CS1 peptide also inhibited the cell adhesion and migration to laminin-coated substrates, but C-274 did not. H-271 did not have any inhibitory effect on cell adhesion or migration to either of the substrates. Similarly, CS1 inhibited tumor invasion to both Matrigel/fibronectin- and Matrigel/laminin-coated filters, whereas C-274 inhibited the invasion to only Matrigel/fibronectin-coated filter. These results indicate that CS1 peptide of fibronectin, lacking the Arg-Gly-Asp-containing domain, actively inhibits tumor metastases in spontaneous and experimental metastasis models. The use of such a peptide might offer a promising therapeutic approach for combatting or preventing cancer metastasis.

Amino Acid Sequence↗
PubMed1989

Inhibition of the metastasis of murine malignant melanoma by synthetic polymeric peptides containing core sequences of cell-adhesive molecules.

We investigated that the antimetastatic and antiadhesive activities of peptides based on Arg-Gly-Asp adhesive signal in fibronectin could be augmented by their polymerization. Poly(Arg-Gly-Asp), which consists of a repetitive sequence of Arg-Gly-Asp, inhibited lung metastases in C57BL/6 mice more effectively than Arg-Gly-Asp tripeptide was able to do, when coinjected or separately injected with B16-BL6 cells. The adhesion of tumor cells to fibronectin was specifically inhibited by adding poly(Arg-Gly-Asp) but not unrelated peptides. In contrast, poly(Arg, Gly, Asp), in which three amino acids are randomly arranged, showed neither inhibition of lung metastases nor any adhesive ability to attach to tumor cells. The inhibitory effect of polymeric peptides containing the Arg-Gly-Asp sequence on lung metastases decreased according to the decreasing repeat units of the Arg-Gly-Asp core sequence. Polymeric peptides with Arg-Gly-Asp entrapped within the liposome membranes also caused a remarkable reduction of metastatic colonies. In a spontaneous metastasis model, multiple i.v. administrations of poly(Arg-Gly-Asp) after tumor inoculation caused the significant reduction of metastatic colonies in the lung but did not affect the growth (size) of primary tumor. We found that the polymerization (multivalency) of the Arg-Gly-Asp core sequence was able to augment the inhibition of tumor lung metastases in experimental and spontaneous metastasis models as well as the cell-adhesive property more effectively than a monovalent unit of Arg-Gly-Asp peptide.

Amino Acid Sequence↗
PubMed1989

Induction of an endogenous tumor necrosis factor in mice by murine recombinant interferon-gamma combined with a lipid A subunit analog (GLA-60) of low toxicity.

We have investigated the endogenous production of a serum cytotoxic factor when recombinant interferon-gamma (rIFN-gamma) is combined with synthetic lipid A subunit analogs of low toxicity (GLA compounds). The cytotoxic activity of the serum was measured by the crystal violet staining method with L929 cells as a target. Intravenous administration of rIFN-gamma followed by intravenous administration of lipopolysaccharide induced the endogenous production of a cytotoxic factor in the serum. The priming effect of rIFN-gamma appeared immediately and persisted for approximately 20 h after the injection. Administration of lipopolysaccharide as a trigger enhanced the production of the cytotoxic factor in the serum maximally 2 h after the injection. The cytotoxic activity in the serum was completely inhibited by anti-(mouse tumor necrosis factor) (TNF) antibody. A synthetic lipid A subunit analog (GLA-60), which is much less toxic in its endotoxin activities than lipopolysaccharide or synthetic lipid A (compound 506), induced the endogenous production of serum TNF in rIFN-gamma-primed mice. GLA-60 entrapped within liposomes induced the production of serum TNF in rIFN-gamma-primed mice more effectively than GLA-60 solubilized in phosphate-buffered saline. Intravenous or intranasal administrations of rIFN-gamma followed by intranasal administration of GLA-60 produced TNF in the lung washing fluid but not in the serum, indicating that TNF production can be induced locally rather than systemically by the alteration of the administration route of the primer and trigger. These results indicate that GLA-60, a lipid A subunit analog of low toxicity, is a beneficial triggering agent in the production of endogenous TNF, as well as having other immunopharmacological properties, and may provide a basis for cancer (metastases) treatment as a result of its ability to induce endogenous TNF.

Animals↗
PubMed1989

Antimetastatic effect of endogenous tumor necrosis factor induced by the treatment of recombinant interferon gamma followed by an analogue (GLA-60) to synthetic lipid A subunit.

We have investigated the effect of endogenous production of tumor necrosis factor (TNF) induced by the combination of recombinant interferon gamma (rIFN gamma) as a primer followed by GLA-60 as a trigger (rIFN gamma/GLA-60) on murine lung metastases caused by B16-BL6 melanoma. In order to examine the therapeutic effect of endogenous TNF on tumor metastasis, the ability of multiple administrations of rIFN gamma/GLA-60 to induce TNF production was also tested. The multiple administrations of rIFN gamma/GLA-60 at intervals of 2 days were effective for the induction of endogenous TNF in mice but continuous multiple administrations of them for 2-4 days were not. In tumor-bearing mice, the production of endogenous TNF by rIFN gamma/GLA-60 was less than that of normal mice, but treatment 3 days after the surgical excision of primary tumors showed the endogenous TNF production to be similar to that in normal mice. In the experimental lung metastasis model, intravenous administration of rIFN gamma followed by intravenous or intranasal administration of GLA-60 showed potent inhibition of lung metastases of B16-BL6 melanoma, whereas the reverse sequence of administration (GLA-60/rIFN gamma) or administration of a mixture of rIFN gamma and GLA-60, which cannot induce the production of TNF, caused no inhibition of lung metastases. These results indicated that the regression of tumor metastases by rIFN gamma/GLA-60 was mediated by the production of endogenous TNF in addition to the direct effects of both immunostimulants. Furthermore, the administration of rIFN gamma and GLA-60 significantly inhibited the tumor metastases in spontaneous lung metastasis model. These results may provide a promising approach for the treatment of cancer metastasis as a result of its ability to induce endogenous TNF.

Adjuvants, Immunologic↗
PubMed1989

Inhibitory effect of a synthetic polypeptide, poly(Tyr-Ile-Gly-Ser-Arg), on the metastatic formation of malignant tumour cells.

A new type of polypeptide containing the repeating sequence of cell attachment site in laminin, poly(Tyr-Ile-Gly-Ser-Arg), was synthesized by the polymerization procedure with diphenylphosphoryl azide (DPPA). We found that this polypeptide inhibited the metastatic formation in the lung of malignant tumour cells far more effectively than pentapeptide.

Amino Acid Sequence↗
PubMed1989

Inhibition of tumour cell adhesion by anti-metastatic polypeptide containing a repetitive Arg-Gly-Asp sequence.

Anti-cell adhesive activity was examined by the synthetic polypeptide, containing repetitive Arg-Gly-Asp sequence of cell attachment site from fibronectin, poly (Arg-Gly-Asp). The attachment of tumour cells to fibronectin substrate was specifically inhibited by adding poly (Arg-Gly-Asp) in cell surface receptor-mediated and divalent cation-dependent manners, but not by unrelated peptides. In our previous study, the lung metastatic formation of tumour cells was dramatically reduced by intravenous co-injection of anti-cell adhesive poly (Arg-Gly-Asp) with B16-BL6 melanoma cells. These findings suggest that polypeptide-mediated inhibition of pulmonary metastasis is partly due to interference with tumour cell adhesion to the substrates including fibronectin in target organs or tissues.

Amino Acid Sequence↗
PubMed1989

Antimetastatic effects of synthetic polypeptides containing repeated structures of the cell adhesive Arg-Gly-Asp (RGD) and Tyr-Ile-Gly-Ser-Arg (YIGSR) sequences.

We have investigated the inhibitory effect on experimental or spontaneous lung metastases of polypeptides which contain repetitive structures of the Arg-Gly-Asp (RGD) or Tyr-Ile-Gly-Ser-Arg (YIGSR) sequence derived from adhesion molecules, and studied their biological characterisation after administration. In the spontaneous metastasis model, multiple intravenous (i.v.) administrations of poly (RGD) and poly (YIGSR) resulted in a reduction of lung tumour colonies, although the monomer peptides, RGD or YIGSR, had no effect under these conditions. The treatment with poly(RGD) substantially prolonged the survival time for mice injected i.v. with B16-BL6 cells as compared to the treatment with RGD and random poly(R, G, D). Tumour cell adhesion to the fibronectin-substrates was remarkably inhibited by adding poly(RGD) freely in solution. Poly(RGD) was found to inhibit completely the ability of platelets to enhance tumour cell adhesion to fibronectin-substrate and tumour cell-elicited platelet aggregation in vitro, but poly(R, G, D) had no such effect. We also found that poly(RGD) led to a decrease in the arrest and retention of tumour cells after its co-injection with radiolabelled tumour cells and that the radiolabelled polypeptide can be at least decomposed into small fragments during circulation. Poly(RGD) was found to be still active in inhibiting experimental lung metastasis even when the contributions of NK cells or macrophages were removed from this system after pretreatment with anti-asialo GM1 serum, 2-chloroadenosine or carrageenan. The results indicate that the poly(RGD)-mediated inhibition of tumour metastasis may be due to the interference of the adhesive interaction of tumour cells with a specific site in the target organs. Derivatives of polypeptides which contain RGD and/or YIGSR sequences derived from cell adhesion proteins may thus provide a promising approach for the control and prevention of cancer metastasis.

Amino Acid Sequence↗
PubMed1989

Inhibitory effect of chitin heparinoids on the lung metastasis of B16-BL6 melanoma.

Structure-function studies for the antimetastatic activity of chemically modified chitin heparinoids composed of N-acetyl glucosamine units were performed in an experimental lung metastasis model. 6-O-Sulfated chitin (S-chitin) significantly inhibited the lung tumor colonization in proportion to the degree of sulfation. However, 6-O- and N-sulfated but partially N-deacetylated chitin (S-chitosan), and 6-O-carboxymethylated chitin (CM-chitin) had no effect. 6-O-Sulfated CM-chitin (SCM-chitin), which exhibited fairly low levels of anticoagulant activity, was also more effective than intact heparin. Furthermore, SCM-chitin with a high degree of sulfation (SCM-chitin III) caused a marked decrease of the number of lung tumor colonies in the spontaneous lung metastasis model. These results strongly suggest that 6-O-sulfate and N-acetyl groups in the glucosamine unit were required for the anti-metastatic effect of chitin heparinoids as well as heparin, and SCM-chitin III may be of therapeutic benefit for the prevention of tumor metastasis.

Animals↗
PubMed1989

Inhibition of tumor cell invasion by ubenimex (bestatin) in vitro.

We have investigated the effect of the immunomodulator ubenimex (bestatin) on tumor cell invasion of reconstituted basement membrane (Matrigel). The invasion of B16-BL6 melanoma cells and Lewis lung carcinoma (3LL) cells into Matrigel-coated filters was inhibited by the presence of bestatin in a concentration-dependent manner. The pretreatment of either tumor cells or Matrigel with bestatin, however, had little effect on the invasion of tumor cells. Since bestatin was found to inhibit amino-peptidase in addition to its immunomodulating activities, the inhibition of tumor invasion by bestatin is likely to be associated with the action as an enzyme inhibitor. Other aminopeptidase inhibitors, arphamenine B and amastatin A, could also inhibit tumor cell invasion into Matrigel. Bestatin inhibited hydrolyzing activities towards substrates of aminopeptidases in B16-BL6 melanoma cells. However, bestatin did not have any effect on the haptotactic migration and adhesion of tumor cells to the substrates. These results indicated that bestatin may inhibit tumor cell invasion through a mechanism involving its inhibitory action on aminopeptidases in tumor cells.

Aminopeptidases↗
PubMed1989

Effect of systemic administration of mouse recombinant interferon-gamma on the lung tumor metastases in mice.

The purpose of this study was to examine the effective anti-metastatic activity by multiple i.v. administrations of mouse recombinant interferon-gamma (IFN-gamma) against pulmonary metastases of 3LL or B16-BL6 melanoma cells after surgical excision of primary tumors. Multiple treatments with IFN-gamma reduced effectively the incidence of pulmonary tumor metastases. Repeated 4 consecutive treatment modalities with IFN-gamma showed remarkable reduction of lung tumor colonies, and also rendered alveolar macrophages (AM) cytotoxic against B16-BL6 cells. In contrast, 14 consecutive administrations of IFN-gamma at any doses (10(2) and 10(3) U/mouse) could not activate macrophages to become cytotoxic, but were effective in regressing metastases. Thus, antimetastatic activity of IFN-gamma may be due to the stimulation of host immune defense systems such as induction of tumoricidal macrophages, presumably the direct antiproliferative action to tumor cells, or both actions under the appropriate administration conditions. We found that the systemic administration of IFN-gamma under appropriate multiple treatment modalities results in the reduction of the lung metastases and can activate AM to become tumor cytotoxic at relatively low doses (10(2) U). High-dose IFN-gamma in the multiple administration schedule was also effective for the reduction of lung tumor colonies, but strongly suppressed the nonspecific immune function and could not activate tumoricidal properties of AM.

Animals↗
PubMed1988

Induction of tumoricidal macrophages and production of cytokines by synthetic muramyl dipeptide analogues.

The ability of various synthetic muramyl dipeptide (MDP) derivatives to induce the production of interleukin-1 (IL-1) and colony stimulating factor (CSF) in vitro and in vivo and to induce cytotoxic macrophages was studied. 6-O-L18-MDP(Me) and MDP-Lys(L18), which were potent inducers of IL-1 and CSF production and of cytotoxic macrophages, had protective activity against Sendai virus infection in mice. In contrast, 1-O-L18-(6-O-P)-MDP(Me) and 2-N-L18-MDP exhibited weak or no ability to induce IL-1 and CSF production and no induction of tumoricidal macrophages, and did not protect against infection of Sendai virus. MDP derivatives, except 2-N-L18-MDP, efficiently rendered macrophages cytotoxic against target cells in the presence of murine recombinant interferon-gamma in vitro. The derivatives that induced cytokines and cytotoxic macrophages appeared to produce anti-viral activity.

Acetylmuramyl-Alanyl-Isoglutamine↗