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Biomedical subjects

I Azuma

Publications and source records attributed to I Azuma.

At least 109 records · Page 6Linked to original sources
PubMed1993

Synthetic Arg-Gly-Asp-Ser analogues of the cell recognition site of fibronectin that retain antimetastatic and anti-cell adhesive properties.

Synthetic peptide analogues of the Arg-Gly-Asp-Ser (RGDS) sequence of fibronectin in which the amino acid of Gly was substituted with another one, named X, i.e. Arg-X-Asp-Ser (R-X-DS), and N-terminal modified R-X-DS have been synthesized to examine their antimetastatic effects in murine lung or liver metastasis models, as well as the inhibitory effect on tumor cell invasion, migration and adhesion in vitro. R-X-DS [X = Leu (L) or D-Leu (1)], as well as RGDS at a high dose of 3000 micrograms, significantly reduced the number of lung tumor colonies when they were co-injected with B16-BL6 melanoma. At a dose of 1000 micrograms/mouse, N-terminal modified R-X-DS, i.e. acetyl-D-R-X-DS [AcDR-X-DS: X = G, L or I], showed a more potent inhibitory effect on the lung or liver metastasis of B16-BL6 melanoma or L5178Y-ML25 lymphoma cells, respectively, as compared with RGDS or R-X-DS. AcDRLDS and AcDRIDS prevented the invasion of B16-BL6 cells into Matrigel/fibronectin- and Matrigel/laminin- coated filters, haptotactic migration, and the adhesion of the cells to both fibronectin- and laminin-coated substrates, whereas AcDRGDS inhibited only fibronectin-mediated cell functions. The intermittent i.v. administration of a water soluble vinylpolymer [poly(carboxyethylmethacrylamide), poly(CEMA)] containing R-X-DS (X = L or 1) or RGDS, following the subcutaneous inoculation of B16-BL6 cells, significantly inhibited spontaneous Jung metastasis as compared with multiple administrations of RGDS, R-X-DS or the untreated control.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

[Progress in medical treatment for glaucoma].

Recently, an epidemiological study was conducted in Japan by Shiose, et al, and the prevalence of open-angle glaucoma in Japanese aged 40 years or older was found to be 2.62% [primary open-angle glaucoma 0.58%, low-tension glaucoma (LTG) 2.04%]. Historically, treatment for glaucoma has been based on lowering intraocular pressure. It is also necessary to improve intraocular blood flow. In the beginning of the study, the effect of anti-glaucoma agents on choroidal blood flow was examined in rabbit eyes. An increase of choroidal blood flow was found following topical application of the prostaglandin-related compound isopropyl unoprostone (UF-021) and the adrenergic alpha-1 antagonist bunazosin hydrochloride (DE-070). Then, a new vasoconstrictor, endothelin, showed strong effects on intraocular pressure, intraocular circulation, and visual function in rabbit eyes. Endothelin-1 (ET-1) was found to be a marked vasoconstrictor with prolonged reduction of intraocular pressure and the blood flow in the choroid and optic nerve head. The effects were suppressed by Ca2+ channel blocker and adrenergic alpha-1 blocker. Plasma concentration of ET-1 was determined by radioimmunoassay in patients with glaucoma. A significantly high level of ET-1 concentration was seen in patients with LTG. Endothelin appears to be an important tool for studying the pathogenesis of LTG. Finally, a prospective clinical trial of the therapeutic effects of bunazosin hydrochloride was performed in patients with LTG for one year. Clinical usefulness was evaluated by changes in the mean deviation value of Humphrey perimetry. Satisfactory results were obtained in maintaining the visual field and in reducing intraocular pressure. In the light of our investigations, it is advisable to introduce an adrenergic alpha-1 blocker or prostaglandin-related compound for reduction of glaucomatous damages. We look forward to the development of the neuro-protective future glaucoma therapy.

Adrenergic alpha-Antagonists↗
PubMed1993

Double-masked comparative study of UF-021 and timolol ophthalmic solutions in patients with primary open-angle glaucoma or ocular hypertension.

A double-masked comparative clinical study of UF-021 (Rescula), a unique prostaglandin-related compound, was carried out at 18 centers with timolol maleate 0.5% ophthalmic solution as an active reference drug. After a wash-out period, UF-021 (0.12%) or timolol (0.5%) was given topically twice a day for 12 weeks to 158 patients with primary open-angle glaucoma or ocular hypertension, in a randomized double-masked manner. Both groups showed a significant reduction in intraocular pressure from the second week to the end of the study. In overall improvement rating, 91.4% of the cases (64/70) in the UF-021 group and 88.3% (68/77) in the timolol group were judged to be "Extremely improved" or "Improved". Five and 4 cases reported having side effects in the UF-021 and timolol groups, respectively, but none of the cases required any change or discontinuation of treatment. While UF-021 did not affect blood pressure, both systolic and diastolic blood pressures in the timolol group were significantly decreased. These results suggest that UF-021 (0.12%) has the potential to lower intraocular pressure equivalent to timolol (0.5%), while having no effect on cardiovascular functions.

Administration, Topical↗
PubMed1993

[Effects of intravitreal injection of endothelin on the visual system].

Endothelin, a novel, potent, and long-acting vasoconstrictor peptide, is thought to regulate retinal circulation and its autoregulation. A disturbance in the regulation of endothelin production might contribute to the pathogenesis of retinochoroidal or optic nerve diseases. We examined the effects of endothelin on the retina and the optic nerve using the electroretinogram (ERG) and visual evoked potential (VEP). Six male albino rabbits underwent intravitreal injection of 0.1 ml (10(-5) mol/l) endothelin-1 in the right eye. Six other male albino rabbits, which were injected intravitreally with 0.1 ml of Opeguard-MA in the right eye, were used as controls. Endothelin-1 caused marked constriction of retinal vessels and pallor of the optic nerve head. These findings persisted for 10 days after endothelin-1 injection. The amplitude of the b-wave and the latency of the oscillatory potential in the ERG were not significantly different from those in controls. On the other hand, prolongation of the VEP-N1 latency was observed for 14 days after the injection. These results indicate that endothelin acts on the circulation of the optic nerve head rather than that of the retina, and that effects persist for a relatively long period.

Animals↗
PubMed1993

[Effect of endothelin-1 on ocular circulation].

Endothelin (ET)-1, a potent vasoconstrictor which was discovered recently, might be involved in the regulation of ocular circulation. In this paper, we studied the effects of ET-1 on capillary blood flow of the optic nerve head and choroid in rabbits, using a hydrogen gas clearance flowmeter. Intravitreal injection of 0.1 ml of ET-1 at 10(-5) M and 10(-6) M caused a significant decrease in blood flow, which in the optic nerve head continued more than 3 hours, but in the choroid recovered at 3 hours after the injection (maximum decrease occurred at 75 minutes and at 30-60 minutes, respectively). Intraocular pressure was reduced as the time passed. Intravenous administration of 10(-10) mol/kg of ET-1 induced a reduction in blood flow, which in the optic nerve head continued more than 3 hours, but in the choroid recovered at 90 minutes after the administration. Intraocular pressure was reduced during 3 hours' observation. The decrease in blood flow in the optic nerve head was inhibited by previous administration of calcium antagonist (nicardipine), so the calcium channel was thought to be involved in this reaction.

Animals↗
PubMed1993

[Clinical evaluation of UF-021 ophthalmic solution in glaucoma patients refractory to maximum tolerable therapy].

UF-021 ophthalmic solution, a novel prostaglandin-related therapeutic agent for glaucoma, was additionally applied to the eyes in intractable cases of primary open angle glaucoma (14 cases, 21 eyes) and ocular hypertension (1 case, 2 eyes) in which intraocular pressure (IOP) had not been kept under satisfactory control even with combined drug therapy by conventional, existing anti-glaucoma agents including sympathetic beta-blockers. Decrease of IOP by UF-021 ophthalmic solution (0.12%) in the treated eyes was observed from not less than one month after the initial application by 3 mmHg and more in about 85%, and by 5 mmHg and more in about 76% of the enrolled patients, respectively. The IOP reduction induced by the additional application of UF-021 was sustained for more than 6 months, resulting in successful avoidance of surgical operations in many patients. When UF-021 ophthalmic solution was applied concurrently with various anti-glaucoma agents including carbonic anhydrase inhibitors, it caused no controversial side-effects and yielded therapeutic efficacy for a prolonged period. These findings suggest that UF-021 can yield IOP-reducing activity through a novel pharmacological mechanism different from other existing drugs. In conclusion, UF-021 ophthalmic solution is extremely useful for the treatment of glaucoma.

Dinoprost↗
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↗