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Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 163 records · Page 9Linked to original sources
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↗
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↗
PubMed1988

Prostaglandin D2 reduces intraocular pressure.

When PGD2 was topically applied to the rabbit eye a reduction of intraocular pressure (IOP) was observed within 30 min. The IOP reduction lasted throughout the observation period of 7 hours. No increase of IOP was observed during the period. The effect of PGD2 was dose-dependent (0.4 microgram to 250 micrograms), and the minimum effective dose was estimated to be 2.0 micrograms. The application of PGD2 did not affect the pupil diameter. No sign of inflammatory response was observed by PGD2 application, that is, no hyperaemia, no flare, no irritation, and no increase of protein content in the aqueous humour. These results suggest that PGD2 or its analogues may be useful for treating glaucoma.

Animals↗
PubMed1988

Effects of prostaglandin D2 and its analogues on intraocular pressure in rabbits.

Studies were carried out of the effects of topically applied prostaglandin (PG) D2 and its metabolites and analogues on the intraocular pressure (IOP) in rabbits, and the results were compared with those of studies using PGE2 and F2 alpha. The application of PGD2 (0.4-250 micrograms) reduced the IOP, in a dose-dependent manner without causing a hypertensive phase. The hypotensive effect was observed within 30 minutes after the application and lasted for over 7 hours. Higher doses of PGE2 (10, 50 micrograms) or PGF2 alpha (50 micrograms) caused initial IOP elevation followed by a prolonged hypotensive phase. Lower doses of PGF2 alpha (2, 10 micrograms) caused a prolonged (over 7 hours) reduction in the IOP following a latency of over 2 hours. The IOP reduction by 2 micrograms of PGE2 lasted for 5 hours. No miotic response followed the use of these PG's. Conjunctival and iridal hyperemia, aqueous flare, irritation (defined by lid-closing), and aqueous protein content were examined at equi-hypotensive doses of the three PG's (50 micrograms for PGD2, 2 micrograms for PGE2, and 10 micrograms for PGF2 alpha). PGE2 was the strongest in causing these side effects, followed by PGF2 alpha. PGD2 did not cause any of these responses except for some development of conjunctival hyperemia. All of the 4 PGD2 metabolites were ineffective in reducing IOP. Among 6 PGD2 analogues, BW245C, PGD3, and PGD2 methyl ester more effectively reduced IOP than did PGD2. PGD1 and 16,16-dimethyl PGD2 were not effective.

Administration, Topical↗
PubMed1987

Antimetastatic effect of Lactobacillus casei YIT9018 (LC 9018) on a highly metastatic variant of B16 melanoma in C57BL/6J mice.

The effect of Lactobacillus casei YIT9018 (LC 9018) on a highly metastatic variant of B16 melanoma, B16-BL6, was determined in C57BL/6 mice. Intralesional (i.l.) injection of LC 9018 inhibited tumor growth and prolonged the survival after s.c. inoculation of B16-BL6 into C57BL/6 mice. Injection of LC 9018 i.v. protected the mice against pulmonary metastasis after i.v. inoculation of B16-BL6. Injection of LC 9018 i.l. before surgical excision of the primary tumor inhibited axillary lymph node metastasis and i.v. injection of LC 9018 after surgical excision of the primary tumor inhibited both axillary lymph node and lung metastases. On the other hand, the combination of i.l. and i.v. injections of LC 9018 markedly inhibited both lymph node and lung metastases. Natural killer cell activity of axillary lymph node cells was augmented by the injection of LC 9018 into a front footpad, while the cytolytic activity of axillary lymph node cells was significantly enhanced. However, the cytolytic activity was diminished by depleting whole lymph node cells of the plastic adherent cells. Furthermore, alveolar macrophage-mediated cytotoxic activity was augmented by the i.v. injection of LC 9018.

Animals↗
PubMed1987

Effect of multiporous microspheres derived from chitin and partially deacetylated chitin on the activation of mouse peritoneal macrophages.

Multiporous microspheres were prepared from 80% deacetylated chitin (DAC-80) and chitin, and their effects on the activation of murine peritoneal macrophages in vivo and on the production of monokines such as colony-stimulating factor (CSF) and interleukin 1 (IL-1) were examined. Multiporous DAC-80 microspheres of mean diameter 2.5 microns [MS-DAC-80(2.5)] enhanced the cytolytic activity of peritoneal macrophages and the production of CSF in vitro by macrophages, spleen cells and bone marrow cells, and in vivo. MS-DAC-80(2.5) also stimulated the production of IL-1 by both resident and thioglycolate-induced peritoneal macrophages. Multiporous chitin microspheres [MS-chitin(2.5)] showed no effect on the activation of peritoneal macrophages in vivo and on the production of IL-1 in vitro, but slightly enhanced the production of CSF in serum in vivo.

Acetylation↗