Potentiation of host defense mechanism against infection by a cytokine inducer, an acyl-MDP derivative, MDP-Lys(L18) (romurtide) in mice and humans.
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Acetylmuramyl-Alanyl-Isoglutamine↗
Biomedical subjects
I Azuma
Publications and source records attributed to I Azuma.
MDP-Lys(L18), a lipophilic derivative of muramyl dipeptide, inhibits the metastasis of haematogenous and non-haematogenous tumours in mice.
The antimetastatic effects of MDP-Lys(L18), a lipophilic derivative of muramyl dipeptide (MDP), against three different types of highly metastatic murine tumour cells, B16-BL6 melanoma, colon 26-M3.1 carcinoma and L5178Y-ML25 T lymphoma, were examined in C57BL/6, Balb/c and CDF1 mice, respectively. The administration of 100 micrograms of MDP-Lys(L18) 2 or 4 days before tumour inoculation led to a significant decrease in lung metastasis of B16-BL6 melanoma or colon 26-M3.1 carcinoma cells. MDP-Lys(L18) was also effective in the inhibition of liver metastasis of L5178Y-ML25 lymphoma cells by administration 2 or 4 days before tumour inoculation. The prophylactic effect of 100 micrograms of MDP-Lys(L18) on tumour metastasis was evident for the different administration routes, i.e. subcutaneous, intravenous or intranasal injection, or oral administration. It is of prime interest that oral administration of 1 mg of MDP-Lys(L18) induced a significant decrease in lung metastasis of B16-BL6 melanoma cells. Administration of MDP-Lys(L18) 4 days before assay led to induction of tumoricidal activity by peritoneal macrophages and growth inhibition by the sera against B16-BL6 or L929 cells. When MDP-Lys(L18) was subcutaneously administered five times after tumour inoculation to test therapeutic effect in an experimental and spontaneous metastasis model using B16-BL6 melanoma, the consecutive administrations of MDP-Lys(L18) significantly inhibited lung metastasis in tumour-bearing mice. These results suggest that MDP-Lys(L18) is able to enhance host resistance to reduce tumour metastasis and is a potent immunomodulating agent which may be applied prophylactically or therapeutically for the treatment of cancer metastasis.
Acetylmuramyl-Alanyl-Isoglutamine↗
In vivo induction of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes and delayed-type hypersensitivity by a 23-amino acid peptide from the highly conserved region in major core protein p24.
Cell-mediated immune responses are a major immune defence mechanism against the spread of human immunodeficiency virus type 1 (HIV-1) which may lead to acquired immune deficiency syndrome (AIDS). Therefore, the best candidate for a peptide vaccine preventive from the onset of the disease might be a chain section containing both B- and T-cell epitopes in regions of conserved sequences between the different HIV-1 isolates. We previously identified the highly conserved linear B-cell epitope (23 amino acids in the major core protein p24). Since the epitopes of cytotoxic T lymphocytes (CTLs) can be defined by short synthetic peptides, we examined whether this highly conserved region can elicit viral-specific, cell-mediated immune responses. The results showed specific induction of CD8+ CTLs in mice by immunization with the Gag 13-mer peptide. Lysis of targets is specific since unpulsed cells with the same MHC haplotype or cells with a different MHC haplotype pulsed with the peptide were resistant to lysis. This in vivo response induced by the Gag 23-mer peptide was almost the same as that induced by the 15-amino acid peptide from the HIV-1 Env gp120 which is an immunodominant domain in the V3 loop. Lymphocyte proliferation of T-cell fraction from immune spleen cells was observed after in vitro stimulation with the Gag 23-mer peptide, whereas there was no apparent lymphocyte proliferation with the Env 15-mer peptide. In addition, specific antibodies were raised against Gag p24 in mice immunized with the Gag 23-mer peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Persistent infection of MT-4 cells by human immunodeficiency virus type 1 becomes increasingly likely with in vitro serial passage of wild-type but not nef mutant virus.
Our previous studies have shown that human immunodeficiency virus type 1 (HIV-1), with mutations in accessory genes such as vif, vpr or vpu, can generate persistent infection of MT-4 cells, whereas infection by wild-type or nef mutant HIV-1 causes extensive cell death. The possibility of generating a naturally attenuated form of HIV-1 with reduced cytopathogenicity in MT-4 cells was examined by in vitro serial passage of the wild-type and a nef mutant form of HIV-1, each derived from the infectious molecular clone pNL432. The ability to cause persistent infection was observed after four passages of wild-type HIV-1 with the frequency of persistence becoming progressively higher with serial passage. In contrast, persistent infection was not observed even after 50 passages of the nef mutant virus. Sequence analysis of the accessory gene loci in genomes recovered from the persistent infections caused by passaged virus revealed mutations in vif and vpr, but not in vpu. The processing of the Env precursor to mature forms was not modified in any of the passages of either wild-type or nef mutant HIV-1. However, when compared with acute infections caused by similarly passaged virus of both wild-type and nef mutant HIV-1, persistent infections by passaged wild-type HIV-1 showed a significant decrease in the cell surface expression and function of Env. Cell surface CD4 was only partially down-regulated on cells acutely infected with the passaged viruses, whereas on cells persistently infected with passaged wild-type HIV-1 it was completely down-regulated. These results suggest that, during serial passage of HIV-1, mutations accumulate at least in the accessory genes vif and vpr in parallel with a lesser interaction between cell surface Env and CD4 molecules, and lead to the generation of less cytopathogenic viruses capable of persistent infection. Our results also suggest an important role for the nef gene product in the generation of HIV-1 strains that are less cytopathogenic.
Amino Acid Sequence↗
Inhibitory effect of recombinant fibronectin polypeptides on the adhesion of liver-metastatic lymphoma cells to hepatic sinusoidal endothelial cells and tumor invasion.
We have investigated the inhibitory mechanism of the initial arrest of L5178Y-ML25 lymphoma cells in a target organ (liver) by using recombinant fibronectin fragments with cell- and/or heparin-binding domains (C-274, H-271 or the fusion fragment CH-271). Pretreatment of hepatic sinusoidal endothelial (HSE) cell monolayers with lymphoma cells or their conditioned medium for 4 to 6 h resulted in the enhancement of lymphoma cell adhesion to HSE cell monolayer. The increased tumor adhesiveness was completely abolished by preincubation of the conditioned medium with anti interleukin-1 beta monoclonal antibody (mAb). Synthetic sialyl Le(x) (SLe(x)) as a ligand for endothelial cell leukocyte adhesion molecule-1 (ELAM-1) adhesion receptor and anti ELAM-1 mAb blocked the conditioned medium-induced enhancement of tumor-endothelial cell interaction, while pretreatment of the activated HSE cell monolayer with anti vascular cell adhesion molecule-1 (VCAM-1) mAb did not affect the enhanced tumor cell adhesion. These results indicate that tumor cell interaction with the stimulated HSE cells is mediated by ELAM-1 molecules on HSE cells. However, the expression of SLe(x) and SLe(a) on the tumor surface was not observed by flow cytometric analysis. ELAM-1-mediated enhancement of tumor cell adhesion to HSE monolayer was also inhibited in a concentration-dependent manner by CH-271 fusion polypeptide or the sulfated chitin derivative sulfated carboxymethyl-chitin, which can bind to the heparin-binding domain of CH-271. In addition, CH-271 inhibited not only tumor-endothelium interaction but also tumor cell invasion into reconstituted basement membrane Matrigel in vitro.
Animals↗
Inhibition of tumor angiogenesis and metastasis by a saponin of Panax ginseng, ginsenoside-Rb2.
We studied the effect of ginsenoside-Rb2 extracted from Panax ginseng on angiogenesis and metastasis produced by B16-BL6 melanoma cells in syngeneic mice. Intravenous administration of ginsenoside-Rb2 on day 1, 3 or 7 after tumor inoculation achieved a remarkable reduction in the number of vessels oriented toward the tumor mass, but did not cause a significant inhibition of tumor growth. The anti-angiogenic effect was dose-dependent ranging from 10 to 500 micrograms/mouse. In contrast, intra-tumoral or oral administration of ginsenoside-Rb2 caused a marked inhibition of both neovascularization and tumor growth. Ginsenoside-Rb2 did not affect the growth of rat lung endothelial (RLE) cells, B16-BL6 melanoma cells or various types of murine normal cells in vitro. The invasion of RLE cells into the reconstituted basement membrane (Matrigel), which is considered to be an essential event in tumor neovascularization, was inhibited by ginsenoside-Rb2 in a concentration-dependent fashion, while ginsenoside-Rb2 did not inhibit the haptotactic migration of endothelial cells to fibronectin-substrate. Multiple administrations of ginsenoside-Rb2 after the intravenous inoculation of B16-BL6 melanoma cells resulted in a significant inhibition of lung metastasis as compared with the untreated control. These results suggest that the inhibition of tumor-associated angiogenesis by ginsenoside-Rb2 may partly contribute to the inhibition of lung tumor metastasis.
Animals↗
Transfusion with xenogeneic erythrocytes into SCID mice and their clearance from the circulation.
We have previously demonstrated that the red blood cells (RBCs) in the blood circulation of SCID mice could be almost completely substituted with bovine RBCs by means of repeated transfusions. In the present study, transfusion experiments were carried out with RBCs from various animal species to investigate the ability of SCID mice to accept xenogeneic RBCs. Bovine (Bo), equine (Eq), human (Hu) and murine (Mu) RBCs were labeled with a fluorescent dye to trace their trafficking in the blood stream. Following the intravenous injection these RBCs were cleared from the circulation at various rates; the 1/100 reduction time in the labeled cell counts was 2 to 7 days, 4 to 7 hr and 1 to 2 hr with Bo-, Hu- and Eq-RBCs, respectively. In contrast, labeled Mu-RBCs from not only syngeneic but also allogeneic mouse strain were able to stay over 50 days. The difference in clearance rates was attributable to the difference in uptake of the RBCs by the splenic macrophages. The clearance rates of labeled RBCs were significantly decreased by co-transfusion with unlabeled RBCs of the same species, indicating that xenogeneic RBCs were recognized by the reticulo-endothelial system of SCID mice in a species-specific fashion. Furthermore, at least in the case of Hu-RBC, the complement component 3 may play a role in the Hu-RBC clearance in SCID mice since C3 deposition was observed on Hu-RBCs but not on Bo- and Eq-RBCs.
Animals↗
[Effect of UF-021 on optic nerve head circulation in rabbits].
We studied the effect of UF-021, a prostaglandin-related compound under application as an anti-glaucoma agent, on the circulation of the optic nerve head (ONH) in normal and endothelin-1 treated albino rabbit eyes. Measurement of the capillary blood flow in the ONH with a hydrogen gas clearance flowmeter as well as intraocular pressure (IOP) measurement was done for five hours. Instillation of UF-021 reduced IOP (maximum: 3.7 mmHg) but had no significant effect on the ONH blood flow in normal eyes. Intravitreal injection of UF-021 reduced IOP to less extent (maximum: 1.8 mmHg) and significantly increased the ONH blood flow (maximum increment: 14% of initial value) from 1 hour to 3.5 hours after injection in normal eyes. In model eyes of circulatory disorder, UF-021 did not affect IOP but inhibited the decrease in the ONH blood flow at 2.5 and 3.5 hours after administration. These results indicate that the effect of UF-021 on ONH circulation is favorable because its blood flow is maintained.
Animals↗
[Evaluation of bunazosin hydrochloride with a model of ocular circulation disturbance induced by endothelin-1].
We studied the effect of bunazosin hydrochloride, a selective alpha-1 blocker under development as an antiglaucomatous drug, on the circulation of the optic nerve head (ONH) in normal and endothelin-1 treated albino rabbit eyes. The effect was investigated by measurement of the capillary blood flow in the ONH, using a hydrogen gas clearance flowmeter (for 5 hours). The relative caliber of the retinal artery (the caliber of the retinal artery at the edge of the ONH/that of the ONH) was also measured, using fundus photography. Administration of bunazosin hydrochloride had no significant effect on the capillary blood flow in the ONH in normal eyes, but it inhibited the decrease of blood flow for at least 5 hours in the endothelin-1 treated eyes. The relative caliber of the retinal artery decreased in the endothelin-1 treated eyes (maximum at 5 hours), but previous administration of bunazosin hydrochloride inhibited the decrease. Thus, Bunazosin hydrochloride inhibits the disturbance of ONH circulation induced by endothelin-1 and promises to be useful also with regard to the ocular circulation.
Adrenergic alpha-Antagonists↗
[Recent management of glaucoma with a view toward future research].
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Forecasting↗
Prevention of cancer metastasis in mice with fibronectin-related substances.
Since the adhesive interaction between tumor cells and host cells, or extracellular matrix (ECM), presumably plays a crucial role in metastatic formation during a series of complex events, we used synthetic or recombinant polypeptide analogues, poly(RGD) or CH-271-based on Arg-Gly-Asp(RGD) sequence or functional domains in fibronectin. Use of these analogues regulated the mechanisms involved in cell adhesion during the metastatic process. Poly(RGD) effectively inhibited the experimental lung and liver metastasis when coinjected i.v. with different types of tumors. In a spontaneous lung metastasis model using B-16-BL6 melanoma, multiple administrations of this polypeptide, before or after surgical excision of the primary tumor, resulted in significant inhibition of tumor metastasis without affecting the growth of the primary tumor. Further, it substantially prolonged the survival time of mice. The mechanism responsible for the inhibition of tumor metastasis by the polypeptides is partly associated with the ability to interfere with cell functions such as adhesiveness, motility, and invasiveness in the cellular adhesive process of metastasis. The combination of CH-271 fusion polypeptide and anticancer drugs, i.e., anti-adhesion therapy and chemotherapy, caused a dramatic inhibition of lung and liver metastasis of tumors when compared with either treatment alone, or in the control. Since the polypeptides derived from cell adhesion molecules showed no short-term toxicity to the host, they may provide a promising approach for the control of cancer metastasis.
Animals↗
Role of aminopeptidase N (CD13) in tumor-cell invasion and extracellular matrix degradation.
We have investigated the effect of monoclonal antibodies (MAbs) specific for aminopeptidase N/CD13 on the invasion of human metastatic tumor cells into reconstituted basement membrane (Matrigel). The invasion of human metastatic tumor cells (SN12M renal-cell carcinoma, HT1080 fibrosarcoma and A375M melanoma) into Matrigel-coated filters was inhibited by an anti-CD13 MAb, WM15, in a concentration-dependent manner. However, this MAb did not have any effect on tumor-cell adhesion and migration to the extracellular matrices, which may be involved in tumor-cell invasion. MAb WM15 inhibited the degradation of type-IV collagen by tumor cells in a concentration-dependent manner. We also found that WM15 inhibited hydrolysing activities towards substrates of aminopeptidases in 3 different tumor cells. Since our previous study indicated that bestatin, an aminopeptidase inhibitor, was able to inhibit tumor-cell invasion, as well as aminopeptidase activities of murine and human metastatic tumor cells, cell-surface amino-peptidase N/CD13 may be partly involved in the activation mechanism for type-IV collagenolysis to achieve tumor-cell invasion, and anti-CD13 MAb WM15 may inhibit tumor-cell invasion through a mechanism involving its inhibitory action on the aminopeptidase N in tumor cells.
Aminopeptidases↗
Protective immunity of Hantaan virus nucleocapsid and envelope protein studied using baculovirus-expressed proteins.
Recombinant Hantaan virus nucleocapsid protein (rNP) and recombinant envelope (rEnv) proteins were prepared using a baculovirus expression system to examine the role of Hantaan virus structural proteins in protective immunity. Passive transfer of spleen cells from mice immunized with rNP conferred partial protection or prolongation of time to death from fatal Hantaan virus infection in suckling mice which were challenged with Hantaan virus at 40 LD50 (survival rate: 43%) or 4 LD50 (survival rate: 43%). The T cell-enriched fraction protected one mouse from lethal infection but the B cell-enriched fraction had no such effect on fatal HTN infection. The protective effects of the antibody against HTN challenge were examined by passive immunization. The monoclonal antibody ECO 2 directed to NP also conferred partial survival and significant difference in time to death. Although rEnv antigen failed to induce neutralizing antibody, both immune spleen cells and immune serum to rEnv conferred partial protection upon suckling mice. These results indicate that both nucleocapsid and envelope proteins of Hantaan virus were responsible for induction of cell mediated protective immunity. Vero E 6 cells infected with Hantaan virus expressed envelope protein on the surface, as determined by flow cytometry. However, there was only negligible expression of nucleocapsid protein.
Animals↗
Anti-viral activity of sulfated chitin derivatives against Friend murine leukaemia and herpes simplex type-1 viruses.
Sulfated chitin derivatives, selected for their low toxicity and high inhibitory activity of melanoma metastasis, were examined for anti-viral activity against Friend murine leukaemia, herpes simplex type-1 (HSV) and Sendai viruses. Carboxymethyl chitin with a 7.66% degree of sulfation (SCM-chitin III) showed a significant inhibition of Friend murine leukaemia helper virus (F-MuLV) and HSV, but not of Sendai virus growth in vitro. Sulfated N-deacetylated chitin had a significant but weak activity against F-MuLV and HSV infections. Carboxymethyl chitin showed no effect on these infections in vitro. SCM-chitin III also exhibited anti-viral activity in vivo by suppressing the splenomegaly which was caused by prior infection of mice with FV, a complex of F-MuLV and spleen focus-forming virus.
Animals↗
Comparison of virulence between Seoul virus strain SR-11 and Hantaan virus strain 76-118 of hantaviruses in newborn mice.
Virulence of hantavirus strain of SR-11 Seoul virus and Hantaan 76-118 (HTN) of Hantaan virus were compared. Infections of both strains were lethal in newborn mice. However, inoculum required to cause lethal infection was about 4,000 times higher for strain HTN (1.65 x 10(3) PFU/mouse/LD50) than for strain SR-11 (0.36 PFU). Thus, both strains were considered pathogenic to newborn mice but they possessed different levels of virulence. The assay system used for these strains in newborn mice proved to be useful in the study of hantavirus virulence. Growth curves of the two strains in CV-7 cell cultures were compared. Strain SR-11 was shown to have higher activity of virus replication and virus release into the culture fluids than strain HTN. The possibility of a relationship between replication activity and high levels of virulence in mice was suggested.
Animals↗
Antimetastatic activity of polymeric RGDT peptides conjugated with poly(ethylene glycol).
Polymeric peptides containing defined repetitive or cyclic structures of RGDT sequence, (RGDT)n (n = 1 to 11) and cyclo(RGDT)n (n = 2 to 4), at a dose of 500 micrograms exhibited an inhibitory effect on experimental lung metastasis upon co-injection with tumor cells and the magnitude of the effect increased in parallel with the increase of degree of repetition of the RGDT sequence. The conjugation of (RGDT)n (n = 1, 5, 11) with poly(ethylene glycol), PEG as a polymeric carrier led to enhanced inhibition of lung metastasis in proportion to the degree of RGDT sequence repetition and in a dose-dependent manner. Multiple i.v. administrations of PEG-(RGDT)11, at 2-day and 3-day intervals before the excision of primary tumors, effectively inhibited spontaneous lung metastasis by s.c. inoculation of tumors, whereas (RGDT)11 exhibited inhibition of lung metastasis only when given at 2-day intervals. This indicates that the conjugation of PEG with (RGDT)n allowed the prolongation of administration interval, implying a sustained inhibitory effect on tumor metastasis. In support of this supposition, a decrease in the arrest of radiolabeled tumor cells in the lungs was observed when PEG-(RGDT)11 was co-injected i.v. with tumor cells, or injected i.v. one day before tumor inoculation. In contrast, (RGDT)11 significantly inhibited the tumor cell arrest in the lungs only upon co-injection with tumor cells. We also noted that (RGDT)n, cyclo(RGDT)n and PEG-(RGDT)11 inhibited tumor cell invasion into Matrigel in a concentration-dependent manner and in proportion to the degree of RGDT sequence repetition, indicating that the peptide-mediated antimetastatic effect is partly associated with the anti-invasive potential. Thus, the conjugation of anti-cell adhesive and anti-metastatic RGDT peptide with PEG might provide a therapeutically promising basis for the prevention of cancer metastasis ("anti adhesion therapy").
Amino Acid Sequence↗
Antimetastatic effect by anti-adhesion therapy with cell-adhesive peptide of fibronectin in combination with anticancer drugs.
We have investigated the therapeutic effect of CH-271 fusion polypeptide containing both cell-binding domain (C-274) and heparin-binding domain (H-271) of fibronectin in combination with anticancer drugs such as doxorubicin (DOX) or mitomycin C (MMC) on tumor metastasis of different types of tumors. CH-271 fusion polypeptide alone significantly inhibited both liver and lung metastasis when it was co-injected with L5178Y-ML25 T-lymphoma, RAW117-H10 B-lymphoma or B16-BL6 melanoma cells, and spontaneous lung metastasis of B16-BL6 melanoma cells when administered i.v. seven times before or after surgical excision of the primary tumors. Combined treatments with CH-271 and either DOX or MMC significantly inhibited liver and lung metastasis of lymphoma or melanoma cells respectively, as compared with either treatment alone or the untreated control. Administrations of CH-271 and DOX in combination substantially prolonged the survival time of mice injected i.v. with L5178Y-ML25 cells. CH-271 or DOX was effective for inhibiting the invasion of L5178Y-ML25 cells into Matrigel in a concentration-dependent manner. Our previous study has shown that CH-271-mediated inhibition of tumor invasion may be due in part to the anti-cell adhesive property without affecting the cell growth, whereas the anti-invasive effect of DOX was established to have resulted from the growth inhibition of tumor cells. Moreover, the combination of CH-271 with DOX provided a more effective inhibition of tumor invasion into Matrigel than did either alone. Thus, we have demonstrated that the combination of anti-cell adhesive CH-271 and anticancer drugs such as DOX or MMC, i.e. anti-adhesion therapy and chemotherapy, is a new approach that offers enhanced (additive) inhibitory effects on tumor metastasis and invasion.
Amino Acid Sequence↗
Polymorphism in genes for the enzyme arginine deiminase among Mycoplasma species.
The extent of restriction fragment length polymorphism in genes for the arginine deiminase enzyme among 28 species of mycoplasmas was assessed by Southern blot analysis of DNA digested with EcoRI or TaqI nuclease probed with a 725-bp internal fragment of the arginine deiminase gene from Mycoplasma arginini. The results indicated unexpected heterogeneity among species of a single genus.
Blotting, Southern↗