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Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 127 records · Page 7Linked to original sources
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

Macrophage activation and host augmentation against Sendai or herpes simplex virus (HSV) infections with synthetic polypeptides in mice.

Poly-L-Lys (mean mol. wt; 12,000), poly-L-Arg (5000) and poly-L-Orn were found to activate peritoneal macrophages effectively in vivo in 14 synthetic homo polypeptides. The ability of sequential poly(L-Arg-L-X) (5000) to activate macrophages was less than that of poly-L-Arg. Neither (L-Arg)12 nor (L-Arg)6 by themselves activated macrophages, but poly-D-Arg (5000) did, as also did poly-L-Arg; this suggests that the polycationic character of poly-L-Arg plays a role in the activation of macrophages. The intranasal administration of poly-L-Lys, -L-Arg, -L-Orn, -D-Arg, all of which activated macrophages, augmented host resistance against Sendai virus infection in mice. The protection afforded by poly-L-Arg seemed to depend on its mol. wt: the order of protection was poly-L-Arg greater than (L-Arg)12 greater than (L-Arg)6. The intranasal administration of poly-L-Arg 3 days before the infection was effective, while that 1 day before infection was not. There was no difference between the groups in the titer of interferon produced by the infection of Sendai virus given with poly-L-Arg either 3 days before or 1 day before the infection. The administration of poly-L-Arg 3 days before the infection caused a significant decrease of the virus titer in the lung 6 days after the infection when compared with the control or the mice given 1 day before. The intravenous administration of 2-chloroadenosine (2-Cl-Ade), which is a selective inhibitor of macrophages, into the mice which had received poly-L-Arg intranasally 3 days before the infection caused a significant decrease in the survival rate of the mice, indicating that the macrophages activated with poly-L-Arg are likely to be an important element in affording the protection. Subcutaneous administration of poly-L-Arg revealed protective activity against systematic infection with herpes virus-type 1.

2-Chloroadenosine↗
PubMed1989

Regression of bovine lymphosarcoma by treatment with cell-wall skeleton of Nocardia rubra.

Five bovine-leukaemia-virus-positive cattle with enlarged subcutaneous lymphatic nodules and having tumour-associated antigens (TAA) in their peripheral blood lymphocytes (PBL) were treated by injection of the cell-wall skeleton of Nocardia rubra (N-CWS) into the nodules. All treated animals received two or three injections of N-CWS (each 0.5-4 mg per nodule) at 2 or 4-week intervals. The effect of the treatment was evaluated by the size of the nodules. Complete regression of nodules was observed in seven out of ten nodules treated in five animals. Decrease of TAA-positive cells was also observed in their peripheral blood lymphocytes for all five treated animals. In one cow, the TAA-positive cells remained low for at least 280 days after treatment.

Adjuvants, Immunologic↗
PubMed1989

Effect of N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl- L-lysine on resistance to herpes simplex virus type-1 infection in cyclophosphamide-treated mice.

The restoration of resistance by N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine [MDP-Lys(L18)] on herpes simplex virus (HSV) type-1 infection was examined in cyclophosphamide (CY)-treated mice. MDP-Lys(L18) was shown to restore the resistance to HSV infection in CY-treated mice when it was injected either subcutaneously, intravenously, or intraperitoneally before infection. Treatment with MDP-Lys(L18) in CY-treated mice restored impaired activity for inhibiting HSV growth in the liver.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Prophylactic activity against Sendai virus infection and macrophage activation with lipophilic derivatives of N-acetylglucosaminylmuramyl tri- or tetrapeptides.

The efficacy of N-acetylglucosaminyl-beta (1----4)-N-acetylmuramyl tri- or tetrapeptides (GM) and the lipophilic derivatives for host augmentation against Sendai virus infection and for macrophage activation in vitro was examined. The anti-infectious activities of GM derivatives were shown to increase with the chain length of the fatty acid combined with the diaminopimelyl group. When the macrophages were activated with 1 U ml-1 murine interferon gamma (IFN-gamma) and 0.001 microgram ml-1 GM derivatives, the cytocidal ability of macrophages depended on the length of the side chain, and exhibited a positive relationship with the anti-infectious activity of GM derivatives against Sendai virus infection. These results indicated that the increment of lipophilicity of GM derivatives would play an important role in the anti-infectious activity and macrophage activation in vitro.

Adjuvants, Immunologic↗
PubMed1989

Protective activity of recombinant cytokines against Sendai virus and herpes simplex virus (HSV) infections in mice.

The efficacy of recombinant cytokines such as murine interferon-gamma (IFN-gamma), human granulocyte colony-stimulating factor (G-CSF), mouse granulocytic-macrophage colony-stimulating factor (GM-CSF) and human interleukin-1 beta (IL-1 beta) has been examined for augmentation of host resistance against Sendai virus and herpes simplex virus (HSV) infections. All four cytokines were found to protect mice against Sendai virus infection. IFN-gamma afforded protection when administered intranasally but not intravenously several days before the infection. Intranasal administration of G-CSF one day before the infection was the most effective administration route and timing. Intranasal administration of GM-CSF was found to afford protection 1 or 3 days before the infection. IL-1 beta demonstrated therapeutic activity against Sendai virus infection after intranasal administration on the same day as the infection. When each of the cytokines was administered subcutaneously four times daily into cyclophosphamide-treated mice before intravenous infection with HSV, only GM-CSF revealed any protective activity.

Administration, Intranasal↗
PubMed1989

Lethal toxicity and adjuvant activities of synthetic TDM and its related compounds in mice.

Trehalose-6,6'-dimycolate (TDM) and its monosaccharide-type analogues were synthesized, and their lethal and adjuvant activities were examined in mice. All the monosaccharide-type analogues with a glucose or N-acetylglucosamine moiety were devoid of lethal toxicity to mice; in particular, D-GlcNAcM(1-deoxy) and D-GlcNM did not cause any loss of body weight at an early stage after intravenous administration as a 9% oil-in-water emulsion. Intraperitoneal administration of D-GlcNAcM(1-deoxy) in aqueous suspension, as well as TDM, could activate macrophages to become tumoricidal against tumour cells, whereas D-GlcNAcM(1-deoxy) in oil emulsion, unlike TDM, caused no granulomatous formation in the lung after intravenous injection. Squalane-treated D-GlcNAcM(1-deoxy) showed significant inhibition of spontaneous lung metastases by B16-BL6 melanoma cells when it was administered twice intratumorally. The non-toxic monosaccharide-type analogue of TDM [D-GlcNAcM(1-deoxy)] was a beneficial adjuvant for the activation of macrophages and the prevention of cancer metastasis.

Adjuvants, Immunologic↗
PubMed1989

Adjuvant activities of synthetic lipid A subunit analogues and its conjugates with muramyl dipeptide derivatives.

We investigated the effects of the active principle of lipopolysaccharide (LPS), synthetic lipid A (compound 506), and of its related compounds GLA-60, -59 and -27, on murine macrophage activation and cytokine induction. GLA-60, which is devoid of endotoxic activity, showed interleukin-1 (IL-1)-inducing activity and activation of murine macrophages comparable to those of LPS or compound 506. The biological activities of six conjugates of GLA-60 with MDP derivatives GMD-323 to -328 were investigated in this study. All the GMD compounds except GMD-323 showed potent inducing activities for IL-1 and tumoricidal macrophages, especially GMD-324 and -326, which exhibited much higher activity than GLA-60. However, TNF- and CSF-inducing activities of these conjugates were lower than those of GLA-60. IL-1-inducing activity of the mixture of MDP derivative (GMD-267) and GLA-60 was higher than that of the conjugates (GMD-324) or that of GLA-60 and GMD-267 alone.

Acetylmuramyl-Alanyl-Isoglutamine↗
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↗
PubMed1989

[Effects of combined instillation of dapiprazole and epinephrine on human anterior chamber depth, intraocular pressure and pupil diameter].

Pilocarpine, a first choice drug for primary angle closure glaucoma (PACG), is reported to produce shallow anterior chamber and posterior synechia and consequently a small immobile pupil. In this paper, dapiprazole, a newly synthesized alpha 1 blocker, was given topically in combination with epinephrine eye drops to 15 healthy volunteers and 10 patients with PACG. In both volunteers and patients, the treated eyes revealed deeper anterior chambers, thinner lenses and significant IOP reduction after the combined instillation of dapiprazole and epinephrine. Though light reaction was preserved, mild miosis was observed in volunteers, but no pupillary change in patients. The conjunctival hyperemia induced by dapiprazole was reversed by additional instillation of epinephrine. Burning sensation was the only side effect observed after instillation of dapiprazole. In conclusion, the combined instillation of dapiprazole and epinephrine appears to be a good choice for the therapy of PACG.

Adrenergic alpha-Antagonists↗
PubMed1988

Functional analysis of mononuclear cells infiltrating into tumors. IV. Purification and functional characterization of cytotoxic cell-generating factor.

Rat cytotoxic cell-generating factor (CGF) was purified from cell-free supernatants of a T cell hybridoma (6B2-B8) that constitutively produces CGF. CGF activity was assessed by its ability to generate cytotoxic cells against 51Cr-labeled T-9 cells from spleen cells of T-9-immunized rats. The purification scheme consisted of ammonium sulfate precipitation, AcA 54 gel permeation, Mono Q anion exchange chromatography, Superose 12HR 10/30 gel permeation, SDS-PAGE with subsequent electroelution, and ProRPC HR5/10 reverse phase column chromatography. Overall, CGF was purified approximately 13,000-fold, with a maximum 2.5% recovery of activity, and the sp. act. of the purified CGF was approximately 19,000 U/mg. The purified CGF is distinct from the other lymphokines such as IL-1, IL-2, IL-3, IL-4, T cell-replacing factor/IL-5, IL-6, and IFN-gamma. It is capable of promoting the generation of cytotoxic T cells from R1-10B5 (+) spleen cells of T-9-immunized rats and also stimulates a W3/25 (+) T cell hybridoma to express the IL-2R. The CGF has an apparent m.w. of 28,000 under non-reducing and 14,000 and 16,000 under reducing conditions. 125I-labeled CGF binds to normal thymocytes as well as splenic T cells. The highest level of binding of CGF was detected on splenic T cells derived from T-9-immunized rats that were previously shown to contain CTL precursors. The binding analysis with 125I-labeled CGF demonstrated that CGF binds to a specific cell surface molecule with an approximate m.w. of 60,000 to 70,000.

Animals↗
PubMed1988

Fast protein liquid chromatography of lymphocyte blastogenesis inhibitory factor produced by the human macrophage-like cell line U937.

The human macrophage-like cell line U937 constitutively produces a lymphocyte blastogenesis inhibitory factor (LBIF). Using fast protein liquid chromatography (FPLC)-chromatofocusing, FPLC-anion-exchange chromatography and high-performance liquid chromatography-gel permeation chromatography, LBIF has been purified to homogeneity. It is a single polypeptide chain and has a molecular weight of 57,000 daltons according to sodium dodecyl sulphate polyacrylamide gel electrophoresis under reducing conditions. LBIF shows pI 4.28-4.56 upon chromatofocusing on Mono P.

Animals↗
PubMed1988

Regression of line-10 hepatocellular carcinoma by a less toxic cord factor analogue combined with L18-MDP or synthetic lipid A analogues.

A transplantable hepatocarcinoma of strain 2 guinea pigs was used as an experimental model for immunotherapy of cancer. 6,6'-Dideoxy-6,6'-bis-mycoloylamino-alpha,alpha- trehalose (TDNM) was found to be more effective in producing regression of transplantable line-10 tumours than 6,6'-di-O-mycoloyl-alpha,alpha-trehalose (TDM) when combined with 6-O-stearoyl muramyldipeptide (L18-MDP). TDNM showed potent antitumour activity in combination with synthetic lipid A of Escherichia coli (compound 506), but not with the lipid A analogues (GLA-59 and 60). As with the combination of MDP derivative and lipid A analogue, MDP derivatives conjugated with GLA-60 (GMD compounds) showed no tumour regression activity of line-10 cells in guinea-pigs.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Immunological activities of multiprenylacetyl derivatives of muramyldipeptides.

The immunological properties of six kinds of multiprenylacetic acids and six kinds of multiprenylacetyl muramyldipeptide (MDP) derivatives were examined by using experimental models in mice and guinea-pigs. All the multiprenylacetyl MDP derivatives, particularly TMD-232, showed potent adjuvant activity on the circulating antibody formation against bacterial alpha-amylase in mice, and induction of delayed-type hypersensitivity to monoazobenzenearsonate N-acetyl-L-tyrosine in guinea-pigs. All multiprenylacetic acid preparations tested in this study, however, showed no adjuvant activity in these immune systems. Both TMD-17 and TMD-232 entrapped into multilamellar vesicles showed potent host stimulation activity against Sendai virus infection in mice.

Acetylmuramyl-Alanyl-Isoglutamine↗