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Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of tumor-induced angiogenesis by the administration of recombinant interferon-gamma followed by a synthetic lipid-A subunit analogue (GLA-60).

The effect of the administration of recombinant interferon-gamma (rIFN-gamma) and a synthetic lipid A subunit analog (GLA-60) on angiogenesis induced by B16-BL6 melanoma was examined in syngeneic C57BL/6 mice. Intravenous administration of rIFN-gamma followed by GLA-60 (referred to as rIFN-gamma/GLA-60) induced endogenous production of tumor necrosis factor (TNF). This treatment on day 3 after tumor inoculation caused a marked decrease in the number of vessels oriented towards the tumor mass (angiogenic response) and tumor size over a period of 9 days. In contrast, neither rIFN-gamma nor GLA-60 alone, nor GLA-60/rIFN-gamma (reverse sequence of administration), which is unable to induce the production of TNF in the serum, had any effect. Sera induced by the treatment with rIFN-gamma/GLA-60, and recombinant TNF, inhibited the in vitro growth of lung endothelial cells which is considered to be one of the essential events in tumor neovascularization. Multiple i.v. treatments with rIFN-gamma/GLA-60 on days 5, 8 and 11 after s.c. implantation of tumor significantly inhibited primary tumor growth by the amputation time (day 20) and lung metastasis of B16-BL6 cells on day 34, while other treatment modalities had no such effect. Our results indicate that inhibition of lung-tumor metastasis by rIFN-gamma/GLA-60 treatment may be partly due to the inhibition of tumor-associated angiogenesis.

Animals↗
PubMed1992

Stimulation of host-defense mechanism with synthetic adjuvants and recombinant cytokines against viral infection in mice.

The efficacy of synthetic immunoadjuvants and recombinant cytokines for the potentiation of host-resistance against virus infection was investigated using mouse models infected with Sendai virus and herpes simplex type 1 virus (HSV). The synthetic MDP derivative, MDP-Lys(L18), and recombinant cytokines, IL-1 beta, IFN-gamma, G-CSF and GM-CSF were shown to be effective for the stimulation of nonspecific protection against Sendai virus infection in mice. Both MDP-Lys(L18) and GM-CSF were effective for the protection against HSV infection in cyclophosphamide (CY)-treated mice. B30-MDP was suggested to be useful as an immunoadjuvant for the potentiation of antigenicity of recombinant or component vaccines.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin).

We have investigated the effect of the immunomodulator ubenimex (hereafter referred to as bestatin) on the enzymatic degradation of the extracellular matrix by human renal cell carcinoma SN12M cells during the invasive process. The invasion of SN12M cells into reconstituted basement membrane (Matrigel) was inhibited by the presence of bestatin in a concentration-dependent manner. However, bestatin did not have any effect on tumor cell adhesion and migration to the extracellular matrices which may be involved in tumor cell invasion. Bestatin inhibited the degradation of type IV collagen by tumor cells, but not by tumor-conditioned medium (TCM), in a concentration-dependent manner. We also found that bestatin inhibited hydrolysing activities towards substrates of aminopeptidases in SN12M cells. Since bestatin was found to inhibit aminopeptidase activity, the inhibition of tumor invasion by bestatin is likely to be associated with its action as an enzyme inhibitor. Bestatin only slightly inhibited tumor cell plasmin activity, which can lead to the conversion of the latent collagenase to the active form, but this slight effect was not significant. The zymography of TCM from SN12M cells showed that the treatment of tumor cells with bestatin resulted in the disappearance of the 68 kDa type IV collagenase-enzyme level (active form) and slight reduction of the 72 kDa type IV collagenase-enzyme level (latent form). These results indicated that bestatin may inhibit tumor cell invasion through a mechanism involving its inhibitory action on aminopeptidases in tumor cells, suggesting that the aminopeptidase may partly be associated with the conversion of a latent form of type IV procollagenase to an active form or the secretion of the collagenases from tumor cells.

Adult↗
PubMed1992

Argininosuccinate synthetase gene expression in leukemias: potential diagnostic marker for blastic crisis of chronic myelocytic leukemia.

Argininosuccinate synthetase (ASS) activity is hardly detected in human lymphocytes. In this study, we examined the ASS gene expression of various leukemia cells by a polymerase-chain-reaction method. We demonstrate here that (a) acute lymphocytic and acute myelocytic leukemia cells exhibit the highly elevated expression of the ASS gene and (b) chronic myelocytic leukemia (CML) in blastic crisis also exhibits the increase of ASS gene expression while CML in chronic phase, chronic lymphocytic leukemia and adult T leukemia cells show the similar level to that of normal lymphocytes. These results suggest that the ASS gene expression is of value as a diagnostic marker of acute type leukemia, particularly for blastic crisis of CML.

Adult↗
PubMed1992

Monoclonal antibodies to a CD4 peptide derivative which includes the region corresponding to an immunoglobulin CDR3: evidence of the involvement of pre-CDR3-related region in HIV-1 and host cell interaction.

A CD4 peptide of amino acid residues 68-130 [CD4(68-130)], which had the capacities to inhibit HIV-1 replication and HIV-1-induced syncytium formation, was used as an immunogen for the preparation of mAb. The mAbs prepared were classified into at least five types (I-V) in terms of their recognition sites by ELISA using various kinds of smaller CD4 peptides. Among them, the type I mAb no. 35 recognizing amino acid residues 72-84, which lies just before the region corresponding to an immunoglobulin third complementarity-determining region (CDR3), showed the strongest effects in reducing both HIV-1 infection and HIV-1-induced syncytium formation, although a large amount of no. 35 mAb was necessary to reduce such HIV-1 activities compared with those of anti-Leu-3a and OKT4A mAbs which recognize CD4 epitopes near a portion corresponding to an immunoglobulin CDR2. Western blot analysis showed that the reactivities of CD4 molecule in CD4-positive cells or sCD4 molecule with types I-V mAbs were stronger than that with anti-Leu-3a mAb. Flow cytometry showed that no. 35 mAb was faintly reactive with native CD4 molecule on cell surface at the concn showing the inhibitory effects on HIV-1 infection and syncytium formation. In addition, a smaller peptide CD4(66-92), one of the good epitope peptides for no. 35 mAb, also showed strong inhibitory effect on HIV-1 infection as well as a weaker inhibitory effect on syncytium formation. These results suggest that, in addition to the CD4 CDR2-related region, the pre-CDR3-related region is also involved in the early events of the interactions between the host cell and HIV-1.

Amino Acid Sequence↗
PubMed1992

Review: inducer of cytokines in vivo: overview of field and romurtide experience.

We have reported that the bacterial cell-wall skeletons, such as mycobacteria, nocardia, corynebacteria, propionibacteria and listeria, had potent adjuvant activity on immune responses. It was reported that N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) was the minimum structural requirement of adjuvant activity of the bacterial cell-wall skeleton and a variety of MDP derivatives and related compounds were synthesized. Among the synthetic MDP derivatives, we have selected MDP-Lys(L18)(romurtide) as the immunostimulant, by using experimental models for non-specific host resistance against Escherichia coli in mice. Romurtide was shown to have host-stimulating activity against bacterial, fungal and viral infections, cytokine producing activity and the capacity to increase the number of leukocytes and platelets in experimental models. It was also shown that the clinical effectiveness of romurtide on the restoration of the number of leukocytes and platelets of cancer patients treated with chemotherapy or radiation therapy. The mechanism of action of romurtide is discussed.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Synthetic immunoadjuvants: application to non-specific host stimulation and potentiation of vaccine immunogenicity.

It is well recognized that immunoadjuvants mainly play two roles; non-specific stimulation of host resistance against infections and cancer, and the potentiation of vaccine immunogenicity. This article reviews the recent results of the development of synthetic immunoadjuvants in our laboratory with special reference to muramyldipeptide (MDP), trehalose dimycolate (TDM), lipid A, chitin and their related compounds. The usefulness of MDP derivative MDP-Lys(L18), which has recently gone on the market as a haematopoietic agent for restoration of leukopenia in cancer patients treated with radiotherapy and chemotherapy, is reviewed. The various approaches to application of synthetic immunoadjuvants to the potentiation of vaccine immunogenicity, including adjuvant formulation, are also discussed.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Use of low toxicity adjuvants and killed virus to induce protective immunity against the Friend murine leukaemia retrovirus-induced disease.

Low toxic and synthetic adjuvants were investigated in the induction of protective immunity against Friend murine retrovirus-induced erythroleukaemia by immunization with inactivated Friend murine leukaemia helper virus (F-MuLV). 6-O-(2-tetradecyl-hexadecanoyl)-N-acetylmuramyl-L-alanyl-D-isoglutamine (B30-MDP) showed a significant enhancement of the protective immunity against Friend virus-induced erythroleukaemia not only in H-2a/b mice known to make good immune responses to F-MuLV envelope, but also in H-2a/a mice which are usually unable to respond to F-MuLV envelope protein. Another analogue of N-acetylmuramyl-D-isoglutamine (MDP), N alpha-acetylmuramyl-L-alanyl-D-isoglutaminyl-N epsilon-stearoyl-L-lysine [MDP-Lys(L18)], which has been shown to enhance non-specific protective activity against bacterial and viral infections, however, showed no adjuvant activity in the present system. A combined adjuvant of the synthesized mycobacterial cord factor, trehalose dimycolate (TDM) and detoxified bacterial endotoxin, monophosphoryl lipid A from Salmonella minnesota, gave good protection which was comparable to complete Freund's adjuvant in both H-2a/b and H-2a/a mice.

Adjuvants, Immunologic↗
PubMed1992

B30-MDP, a synthetic muramyl dipeptide derivative for tumour vaccination to enhance antitumour immunity and antimetastatic effect in mice.

The effect of a muramyl dipeptide derivative (B30-MDP) on the augmentation of antitumour immunity against highly metastatic L5178Y-ML25 mouse lymphoma cells was examined in CDF1 (Balb/c x DBA/2) mice. Mice immunized with a mixture of X-irradiated tumour cells (10(3)) and B30-MDP (100 micrograms) on 7 days prior to challenge by viable tumour cells displayed a significant decrease in metastasis towards the target organs, liver and spleen, compared with that of untreated mice. Immunization of mice with the mixture on day 5 or 7 after tumour challenge, when the level of glutamic-pyruvic transaminase (GPT) and glutamic-oxaloacetic transaminase (GOT) in sera of mice inoculated with viable tumour cells was observed to be normal, caused less metastasis than immunization with X-irradiated tumour cells alone. Sensitization with X-irradiated tumour cells admixed with B30-MDP induced almost two times higher cytotoxicity of spleen cells against L5178Y-ML25 lymphoma cells than sensitization with X-irradiated tumour cells without B30-MDP. In contrast, cytotoxic activity of spleen cells against another target, L1210 lymphoma cells derived from BDF1 mice, was not observed by immunization with X-irradiated L5178Y-ML25 cells with or without B30-MDP. Specific lysis by splenic cells of the immunized mice against L5178Y-ML25 cells decreased to the normal level when T cells were deleted from the immunized spleen cells by the treatment of rabbit anti-mouse Thy1.2 antibody and rabbit complement. These results indicate that B30-MDP is able to augment a specific tumour immunity due to the enhancement of cytotoxicity mediated by T lymphocytes, and is useful as an immunopotentiating agent for active immunization of inactivated tumour cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro.

Arginine deiminase (AD) is a potent growth inhibitor for some but not all tumour cell lines in vitro. As AD catalyses the direct conversion of L-arginine to L-citrulline, the AD-sensitivity of various tumour cells might be attributed to the levels of urea cycle enzymes involved in L-arginine biosynthesis. This study demonstrated that human melanoma cells were highly sensitive to the growth inhibitory activity of AD. Five melanoma cell lines tested also exhibited reduced argininosuccinate synthetase (ASS) gene expression--being almost absent in four cell lines and at low level in one cell line. This resulted in an inability of the cells to utilize L-citrulline for growth. Based on the tissue-specific regulation of ASS gene, the feature of melanomas suggests that it might be possible to develop agents with strong AD activity for chemotherapeutic use for human melanomas in vivo.

Antineoplastic Agents↗
PubMed1992

Human immunodeficiency virus type 1 (HIV-1) superinfection of a cell clone converting it from production of defective to infectious HIV-1 is mediated predominantly by CD4 regions other than the major binding site for HIV-1 glycoproteins.

A cell clone, L-2, which produces non-infectious doughnut-shaped human immunodeficiency virus type 1 (HIV-1) particles, was permissive for HIV-1 superinfection, which resulted in the production of infectious particles. The superinfection showed slow kinetics compared with primary HIV-1 infection of M10 cells, the parent of the L-2 cell clone. Inhibition studies on the superinfection of L-2 cells using several CD4-related reagents showed that the CD4 molecule was an essential component of the receptor for superinfection. Strong inhibitory effects were obtained using CD4 peptides such as CD4(68-130), which includes a portion homologous to the immunoglobulin third complementarity-determining region (CDR3), as well as recombinant soluble CD4. In contrast, a CD4(45-60) peptide, which includes most of the CDR2-related region, was not effective, although the Leu-3a monoclonal antibody (MAb), which recognizes a site near the CDR2-related region, did slightly, but significantly, delay the superinfection kinetics. Comparative flow cytometry of L-2 and M10 cells revealed that the cell surface of L-2 cells despite expressing HIV-1 env protein, reacted slightly with OKT4 or anti-CD4(68-130) MAb, but not with Leu-3a or OKT4A MAb. In contrast, no reaction was detected with any of these anti-CD4 MAbs on the surface of another HIV-1 superinfection-resistant cell clone, MOLT-#8IIIB-14, which expresses HIV-1 env proteins but does not produce infectious HIV-1 particles. These results strongly suggest that expression of the CD4 major receptor site for primary HIV-1 infection is preferentially decreased on the surface of L-2 cells, but that the OKT4 epitope and the nearby region corresponding to immunoglobulin CDR3 remain exposed on the cell surface. Consequently, the CD4 CDR3-related region could play a major role as the receptor for the superinfection reported here.

Binding Sites↗
PubMed1992

Arginine deiminase gene of an AIDS-associated mycoplasma, Mycoplasma incognitus.

Recently, we have demonstrated by molecular cloning that a strong immunosuppressive factor derived from Mycoplasma arginini is arginine deiminase. We show here that mycoplasma species identified in many of AIDS patients also bear the arginine deiminase gene. The implication of the arginine deiminase gene detected in AIDS-associated mycoplasma species is discussed.

Acquired Immunodeficiency Syndrome↗
PubMed1992

DT-5461, a new synthetic lipid A analogue, inhibits lung and liver metastasis of tumor in mice.

We have investigated the antimetastatic effect of a new synthetic lipid A analogue, of low endotoxicity, DT-5461, against two highly metastatic tumor cell lines, L5178Y-ML25 T-lymphoma and B16-BL6 melanoma cells in mice. Four intermittent i.v. administrations of DT-5461 at intervals of 4 days resulted in a significant inhibition of liver metastasis caused by i.v. injection of L5178Y-ML25 cells and lung metastasis of B16-BL6 cells in the experimental metastasis models. Intraperitoneal and intranasal administrations as well as i.v. administration of DT-5461 were also effective in preventing lung metastasis of the melanoma cells. Multiple administrations of DT-5461 before the surgical excision of primary tumors significantly reduced the number of lung colonies of melanoma cells and primary tumor size. Similarly, this treatment modality after the surgical excision of primary tumors showed a greater reduction of lung tumor colonies as compared with lipopolysaccharide, a synthetic lipid A (No. 506) and its analogue as well as untreated control in the spontaneous lung metastasis model. Furthermore, the group that received DT-5461 after the inoculation of lymphoma or melanoma cells showed significantly enhanced survival rate compared with the untreated control. These results suggested that DT-5461 may be therapeutically useful for the inhibition of tumor metastasis.

Animals↗
PubMed1992

Differences in chemotaxis to fibronectin in weakly and highly metastatic tumor cells.

We have examined the chemotactic ability of tumor cell lines with different metastatic potential to plasma fibronectin in Transwell chamber assay. Human renal carcinoma cells with highly metastatic potential, SN12 C-2, chemotactically migrated to fibronectin (10 micrograms/ml) about three-fold more strongly than weakly metastatic SN12 C-4 cells. Similarly, murine melanoma B16-BL6 cells (highly metastatic) showed higher motility to soluble fibronectin in comparison with weakly metastatic B16-F1 cells. Anti-VLA-alpha 3 and beta 1 antibodies potently blocked the chemotaxis of both highly and weakly metastatic cells (SN12 C-2 and C-4) to fibronectin. This implies that the migration of both C-2 and C-4 cells to fibronectin is basically mediated by VLA-3 receptor. In contrast, the anti-VLA-alpha 5 antibody and RGDS peptide significantly inhibited the chemotaxis of SN12 C-2 cells to fibronectin, but did not affect weakly metastatic SN12 C-4 cells. These results suggest that the chemotactic ability to fibronectin positively correlates with the metastatic potential in SN12 and B16 cell lines, and that VLA-5 receptor is concerned in the motility of highly metastatic SN12 C-2 cells to soluble fibronectin.

Antibodies, Monoclonal↗
PubMed1992

Elevated gene expression of argininosuccinate synthetase in peripheral lymphocytes from systemic lupus erythematosus (SLE) patients.

Argininosuccinate synthetase (ASS) is a rate-limiting enzyme of urea cycle and functions primarily in the liver, whereas ASS activity is hardly detected in normal lymphocytes. In this study, we examined the level of ASS gene expression in peripheral blood lymphocytes (PBL) from human SLE patients by amplification of reverse-transcribed mRNA using the polymerase chain reaction. We have demonstrated that (a) approximately 40% of SLE patients exhibited 2.5 to 5 times higher expression of ASS gene in PBL than those of healthy PBL and (b) the elevation of ASS gene expression of PBL significantly correlates with the active pathogenesis of SLE patients according to the criteria of Japanese Ministry of Health and Welfare (p < 0.001 by student's two-tailed t-test). Thus, it is suggested that ASS gene expression is a promising marker of hyperactivated lymphocytes uniquely generated in patients with systemic autoimmune disease.

Animals↗
PubMed1992

Theileria sergenti proliferates in SCID mice with bovine erythrocyte transfusion.

The unavailability of in vitro or in vivo experimental systems has been the major factor hampering the progress of research studies on Theileria sergenti, causative agent of theileriosis, a major disease of cattle in Japan. We report the first successful propagation of T. sergenti in SCID mice into which uninfected bovine erythrocytes (Bo-RBC) were supplied periodically. The infectivity of T. sergenti proliferated in an SCID mouse was ascertained by successful transfer of infection into another SCID mouse into which uninfected Bo-RBC were supplied periodically.

Animals↗
PubMed1991

Recombinant human granulocyte colony-stimulating factor inhibits the metastasis of hematogenous and non-hematogenous tumors in mice.

We studied the effects of in vivo administrations of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on the metastasis of murine hematogenous and non-hematogenous tumors in spontaneous and experimental metastasis models. Spontaneous lung metastasis caused by intra-footpad injections of B16-BL6 melanoma and Lewis-lung-carcinoma (3LL) cells were inhibited by intravenous (i.v.) and subcutaneous (s.c.) injections of rhG-CSF after excision of the primary tumors. Recombinant hG-CSF significantly inhibited liver metastasis when administered i.v. after i.v. injection of L5178Y-ML25 T-lymphoma cells. Multiple i.v. administration of rhG-CSF after the tumor inoculation prolonged the survival times of mice inoculated i.v. with L5178Y-ML25 lymphoma cells. Recombinant hG-CSF did not directly affect the growth of B16-BL6 and L5178Y-ML25 cells in vitro. During the administration periods, both i.v. and s.c. injections of rhG-CSF increased the number of total white blood cells (WBC) in peripheral blood to approximately 3 times the normal level in normal and tumor-bearing mice. We also found that the administration of rhG-CSF stimulates neutrophils to become cytostatic against these tumor cells. Our results indicate that the injection of rhG-CSF is effective in inhibiting lung and liver metastases by activating neutrophils and increasing cell number.

Animals↗