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H Ishitsuka

Publications and source records attributed to H Ishitsuka.

At least 55 records · Page 3Linked to original sources
PubMed1988

Hemolytic activity of a cyclic peptide Ro09-0198 isolated from Streptoverticillium.

Ro09-0198, a cyclic peptide isolated from culture filtrates of Streptoverticillium griseoverticillatum, induced lysis of erythrocytes. Preincubation of the peptide with phosphatidylethanolamine reduced the hemolytic activity, whereas other phospholipids present in erythrocytes in nature had no effect. A study of the structural requirements on phosphatidylethanolamine necessary for interaction with the peptide indicates that Ro09-0198 recognizes strictly a particular chemical structure of phosphatidylethanolamine: dialkylphosphoethanolamine as well as 1-acylglycerophosphoethanolamine showed the same inhibitory effect on hemolysis induced by Ro09-0198 as diacylphosphatidylethanolamine, whereas phosphoethanolamine gave no inhibitory effect. Neither phosphatidyl-N-monomethylethanolamine nor alkylphosphopropanolamine had an inhibitory effect. Consequently, the hydrophobic chain is necessary for the interaction and the phosphoethanolamine moiety is exactly recognized by the peptide. Ro-09-0198-induced hemolysis was temperature-dependent and the sensitivity of hemolysis differed greatly among animal species.

Actinomycetales↗
PubMed1988

Interaction of a cyclic peptide, Ro09-0198, with phosphatidylethanolamine in liposomal membranes.

Ro09-0198 is a cyclic peptide isolated from Streptoverticillium griseoverticillatum. This peptide caused permeability increase and aggregation of liposomes containing phosphatidylethanolamine. Liposomes containing phosphatidylserine, phosphatidylinositol or cardiolipin instead of phosphatidylethanolamine were, however, not appreciably reactive with the peptide. Among the structural analogs of phosphatidylethanolamine, dialkylphosphatidylethanolamine and 1-acylglycerophosphoethanolamine incorporated into liposomes could interact with Ro09-0198 to cause a permeability increase, whereas liposomes consisting of alkylphosphoethanolamine or phosphatidyl-N-monomethylethanolamine were insensitive to the peptide. These findings indicate that a glycerol backbone and a primary amino group of phosphatidylethanolamine are necessary for interaction with Ro09-0198 to cause membrane damage. Ro09-0198 induced a selective permeability change on liposomes. Glucose and umbelliferyl phosphate were effluxed significantly, but sucrose was only slightly permeable and inulin could not be released. Consequently, the permeability increase induced by Ro09-0198 is rather specific to molecules smaller than sucrose. Line broadening of electron spin resonance signals of spin-labeled phosphatidylethanolamine was observed upon treatment of liposomes with Ro09-0198. It was suggested from these results that Ro09-0198 can alter the physical organization of phosphatidylethanolamine in membranes, thus providing a basis for changes in membrane permeability.

Actinomycetales↗
PubMed1988

[Antitumor activity and toxicity to the immune system and intestine, of the fluorinated pyrimidines FUra, 5'-DFUR, tegafur and UFT].

Antitumor activity and the toxicities of 5-fluorouracil (FUra) and its depot form derivatives with different mechanisms such as 5'-DFUR, tegafur and UFT, were compared in mice, and the therapeutic indices were measured. 5'-DFUR was less toxic to immune organs and the functions than those by other fluorinated pyrimidines. The therapeutic indices of 5'-DFUR obtained by using parameters of particular side effects, reduction of the number of GM-CFU in the bone marrow, shrinkage of the thymus, functional disorders in the immune systems, were several times higher than those of tegafur and UFT. On the other hand, there were no marked differences in the intestinal toxicities among the compounds. 5'-DFUR was only about two times less toxic on the intestinal tract than tegafur and UFT when the incidence-of diarrhea and damage to the duodenum were compared. These studies suggest that the difference in the mechanisms converting to FUra is a result of the toxicities causing different extent.

Animals↗
PubMed1988

[Comparative studies on the antitumor activity of the fluorinated pyrimidines 5'-DFUR, tegafur, UFT and FUra on various murine tumors].

Antitumor activities of fluorinated pyrimidines by oral administration were compared with various murine tumor models. 5'-Deoxy-5-fluorouridine (5'-DFUR) showed a better antitumor activity in terms of the growth inhibition and increase of the survival time than those of 5-fluorouracil(FUra), tegafur and UFT, particularly with respect to the chemotherapeutic indices. The activity of these fluorinated pyrimidines were further investigated in more detail with mice bearing colon 26 adenocarcinoma to suggest some means to optimize their treatment regimens in clinical trials. 5'-DFUR showed the activity irrespective of the size of tumor mass at the time of start of therapy. Additionally only 5'-DFUR was safely administered to the mice daily for long period up to more than 100 days, suppressing the tumor growth and increasing the survival to great extent.

Animals↗
PubMed1987

Potentiation of the chemotherapeutic action of 5'-deoxy-5-fluorouridine in combination with guanosine and related compounds.

The effect of inosine, guanosine, and guanosine 5'-monophosphate (GMP) on the antitumor activity of 5'-deoxy-5-fluorouridine (5'-DFUR) was investigated using P388 leukemia and P815 mastocytoma. The antitumor activity of 5'-DFUR was markedly enhanced by coadministration of inosine or guanosine. The increase in lifespan (ILS) of mice treated with 5'-DFUR was augmented by the combination with guanosine or inosine in a dose-dependent fashion, and the maximum ILS was about 160% with the combination, while that in the case of 5'-DFUR alone was only 48% in the P388 leukemia system. The therapeutic ratio (dose at ILSmax/dose at ILS30) of the combination with guanosine or inosine was 333 and 136, respectively, whereas that of 5'-DFUR alone was 3.6. GMP also markedly potentiated the antitumor activity of 5'-DFUR in both P388 leukemia and P815 mastocytoma systems, just as it potentiated the activity of 5-fluorouracil in the latter system. The uric acid level in the serum was elevated after IP injection of guanosine or inosine but the value was much lower in the case of guanosine than in inosine.

Animals↗
PubMed1987

Intranasal chalcone, Ro 09-0410, as prophylaxis against rhinovirus infection in human volunteers.

The antirhinovirus agent chalcone Ro 09-0410 was tested in double-blind place-controlled volunteer trials for its protective efficacy against experimental rhinovirus infection. Fifty volunteers received either drug (26 volunteers) or placebo (24 volunteers) both before and after challenge with 20-40 tissue culture infecting dose (TCID50) of human rhinovirus 2 (RV2). There was no evidence that medication significantly reduced the incidence of infection or illness, indeed there was some increase in the nasal secretion produced.

Administration, Intranasal↗
PubMed1987

[Conversion of 5'-deoxy-5-fluorouridine to 5-FU by pyrimidine nucleoside phosphorylases in normal and tumor tissues from rodents bearing tumors and cancer patients].

Enzyme levels of pyrimidine nucleoside phosphorylase, which is an essential enzyme for the phosphorolysis of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil (5-FU), in normal and tumor tissues were investigated. In all mouse strains tested, the enzyme level was found to be higher in the small intestine and stomach than other tissues, while in rats a higher level of the enzyme in the lung was also observed additionally. The enzyme levels of tumor tissues varied in tumor cell lines transplanted. P388 leukemia, Ehrlich ascites carcinoma, sarcoma 180, colon 26 carcinoma, and Lewis lung carcinoma cells contained high levels of the enzyme and the mice bearing these tumors responded well to the therapy with 5'-DFUR than its active metabolite 5-FU, while 5'-DFUR did not show clear advantage over 5-FU against L1210 or LSTRA leukemia, in which the enzyme levels were low. These results indicate that there is some correlation between the enzyme level and antitumor efficacy of 5'-DFUR. In human specimens, the enzyme levels were 2-6 times higher in tumors than those of the corresponding normal tissues and those adjacent to the tumors. These results predict that 5'-DFUR seemed to be converted efficiently to 5-FU also in human tumors.

Animals↗
PubMed1987

[Antitumor effects of 5'-deoxy-5-fluorouridine (5'-DFUR) against various murine tumors in combination with recombinant interferon alpha or cytostatics].

Antitumor effects of oral fluorinated pyrimidines including 5'-DFUR and their combination with recombinant interferon (rIFN) alpha A/D (Bgl) or cytostatics were investigated using various tumor models in mice. 5'-DFUR was more effective against Colon 26 than tegafur and 5-FU as a single agent, and their therapeutic indices were 14.7, 2.3 and 1.2, respectively. In combination with various cytostatics, 5'-DFUR as well as 5-FU and tegafur showed better efficacy against mouse Colon 26, Meth A fibrosarcoma and A755 adenocarcinoma than any other single agents. Combination therapy with 5'-DFUR and rIFN-alpha A/D also showed better efficacy against all seven murine tumors tested than their single therapy. In these combination therapies, increased toxicities measured by a body weight change and the incidence of toxic death were also observed to some extent. Among combinations with fluorinated pyrimidines, those with 5'-DFUR showed the toxicities at a lesser degree than those with 5-FU or tegafur. These results indicate that 5'-DFUR would be useful for the multiple combination chemotherapy like 5-FU and tegafur.

Animals↗
PubMed1986

Molecular basis of drug resistance to new antirhinovirus agents.

The modes of action of antirhinovirus agents and mechanisms of resistance to the agents are compared. Chalcone Ro 09-0410, 4',6-dichloroflavan (DCF) and RMI-15,731, which were active against rhinoviruses, inactivated the virus directly. Inactivation was associated with the binding of the agents to the virus particles, since the infectivity, reduced by exposure to the compounds, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]chalcone to rhinovirus type 2 was inhibited by any of the three unlabelled agents. Furthermore, virus sublines selected for resistance to both dichloroflavan and RMI-15,731 showed cross-resistance to chalcone and vice versa. These findings indicate that the three agents exert their activities through the same mode of action (namely binding to or interaction with a specific site on the viral capsid protein) and that the binding or interaction sites for these three agents are either the same or very close to each other. Since the sublines resistant to chalcone and to RMI-15,731 have little or no capability to bind to chalcone, the resistance to these agents is conferred by changes in the viral capsid protein. On the other hand, flavone Ro 09-0179 and enviroxime, which were active widely against picornaviruses, had no ability to inactivate the virus directly, and their antiviral activity was not associated with the capsid protein.

Benzimidazoles↗
PubMed1986

Antitumor, antiviral and natural killer-inducing activities of human recombinant interferon-alpha in the guinea pig.

It was found that human recombinant interferon-alpha (Hu rIFN-alpha) was biologically active in the guinea pig. Namely, intratumor injection of either Hu rIFN-alpha A or A/D regressed tumors and prevented metastasis of guinea-pig line 10 tumor. These rIFNs augmented splenic natural killer activity of the guinea pig and reduced the cytopathic effect of virus on guinea-pig cells. Hu IFN-gamma showed no such activity.

Animals↗
PubMed1985

Comparative studies on the modes of action of the antirhinovirus agents Ro 09-0410, Ro 09-0179, RMI-15,731, 4',6-dichloroflavan, and enviroxime.

Modes of action of five antirhinovirus agents were compared. Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 were active preferentially against human rhinovirus. Serotypes of the virus varied in their susceptibility to these three agents, whereas Ro 09-0179 and enviroxime showed activity against all the serotypes of the virus tested to date. Ro 09-0410, RMI-15,731, and 4',6-dichloroflavan inactivated the virus directly, although 4',6-dichloroflavan did so only slightly. Inactivation by 4',6-dichloroflavan and RMI-15,731 was associated with the binding of the agents to the virus, since the infectivity, reduced by exposure to the agents, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]Ro 09-0410 to human rhinovirus type 2 was inhibited by unlabeled Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 but not by Ro 09-0179 or enviroxime. Furthermore, subtypes resistant to both 4',6-dichloroflavan and RMI-15,731 showed cross-resistance to Ro 09-0410 and vice versa. On the other hand, sublines resistant to these three agents were not cross-resistant to Ro 09-0179 or enviroxime. These results indicate (i) that Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 exert their activities through the same mode of action, namely, binding to or interaction with some specific site on the viral capsid protein, and (ii) that the binding or interaction sites for these three agents are either the same or very close to each other.

Antiviral Agents↗
PubMed1984

Antivirus agent, Ro 09-0410, binds to rhinovirus specifically and stabilizes the virus conformation.

The antiviral mechanisms of Ro 09-0410 (4'-ethoxy-2'-hydroxy-4,6'-dimethoxychalcone), which inactivates rhinovirus exclusively, have been investigated. It was suggested that Ro 09-0410 bound to human rhinovirus type 2 (HRV-2) and made it inactive, since the reduced infectivity was completely restored to original levels by extraction of the agent with chloroform [H. Ishitsuka, Y. Ninomiya, C. Ohsawa, M. Fujiu, and Y. Suhara (1982) Antimicrob. Agents Chemother. 22, 617-621]. This was confirmed using radioactively labeled Ro 09-0410 and HRV-2. HRV-2 was inactive while bound to the agent, whereas a subline of HRV-2 resistant to the agent had no binding site for the agent. Ro 09-0410 appeared to bind to some specific site(s) on the virion of susceptible virus strains. Treatment of rhinovirus at pH 5 or 56 degrees caused a change of the virion size and greatly reduced its infectivity. Ro 09-0410 could no longer bind to HRV-2 after such treatment. On the other hand, when the virion bound with Ro 09-0410 was treated at pH 5 or 56 degrees, the Ro 09-0410 remained bound and the conformational alteration of the virion did not take place. Furthermore, Ro 09-0410 protected HRV-2 from the reduction of infectivity caused by mild acid or heat treatment, as revealed by infectivity measurements after extraction of the agent with chloroform. These results suggest that Ro 09-0410 binds to the HRV-2 virion and prevents viral replication in the cell.

Antiviral Agents↗
PubMed1983

Protective activity of thymosin alpha 1 against tumor progression in immunosuppressed mice.

The effect of thymosin alpha 1 was examined in mice immunosuppressed by cytostatics or X-ray irradiation. Inoculation of B16 melanoma or L1210 leukemic cells into these immunosuppressed mice caused a high incidence of pulmonary metastasis or rapid death, respectively. Thymosin alpha 1 given concomitantly with cytostatics or after X-ray prevented such deleterious effects of these agents. One of possible mechanisms causing the rapid death and increasing the metastasis is the damage to NK cells. Thymosin alpha 1 prevented the reduction of NK cell activity caused by these agents. The preventive activity could be transferred to immunosuppressed recipients by spleen cells and those deprived of T cells, but not by those deprived of NK cells. Another possible mechanism is the aberration of the barrier system for spread of tumor cells in blood circulation, which may allow the tumor cells to migrate to various sites in the host. In 5-FU-treated mice, distribution of 125I-L1210 cells upon inoculation was higher in blood and lung, but lower in liver and spleen as compared with that in normal mice. On the other hand, when thymosin alpha 1 was given with 5-FU, the pattern of the tissue distribution was almost the same as that in normal mice. Thus, thymosin alpha 1 protected mice which received immunosuppressive agents from undesirable effects of the agents on surveillance systems against tumor. Thymosin alpha 1 may be useful as an adjuvant in cancer therapies.

Animals↗
PubMed1983

Thymosin alpha 1 restores NK-cell activity and prevents tumor progression in mice immunosuppressed by cytostatics or X-rays.

The effect of thymosin against tumor progression was examined in mice immunosuppressed by cytostatics or X-ray irradiation. When pretreated with cytostatic agents, such as 5-fluorouracil (5-FU) or BCNU, or by X-ray, and then inoculated with P388 or L1210 leukemias, mice died rapidly within a few days. In these systems, thymosin alpha 1 given concomitantly with the cytostatic agents or after X-irradiation prevented rapid death and extended survival, although the mice eventually died with leukemia like normal mice inoculated with cells of the same tumor. Rapid death in the 5-FU-treated mice was also prevented by adoptive transfer of spleen cells from the donor mice if these had been treated with 5-FU plus thymosin alpha 1, but not if they had received 5-FU alone. However, the restorative activity of the donor spleen cells was abrogated by treatment with anti-asialo GM1, but not by treatment with anti-Thy 1 or anti-mouse Ig serum, suggesting that the effector cells in the spleen are NK cells. In fact, thymosin alpha 1, when given concomitantly with 5-FU or after X-irradiation, maintained the NK activity of spleen, which was damaged by treatment with 5-FU or X-irradiation alone. The present study indicates that thymosin alpha 1 exerts a preventive activity against progression of leukemias at least in part through an effect on NK cells or their progenitor cells.

Animals↗
PubMed1983

Protective activity of thymosin against opportunistic infections in animal models.

Animal models for opportunistic infections were developed by using mice immunosuppressed by 5-FU. These mice were susceptible to various microorganisms, while normal mice had greater tolerance to such microbial infections. In these models, thymosin alpha 1 was found to protect mice against lethal infections with Candida albicans, Listeria monocytogenes, Pseudomonas aeruginosa, and Serratia marcescens when it was administered during 5-FU treatment prior to the infections. Thymosin alpha 1 was effective in some infections at 0.4-400 micrograms/kg/day IP, about 1/100 of the dose required for thymosin fraction 5. Activity was also demonstrated against L-monocytogenes and Ps. aeruginosa by counting the viable bacteria in the liver after infection. The protective activity against Candida, elimination of which macrophages were essential, was abrogated by anti-thymocyte serum and/or carrageenan, indicating that thymosin alpha 1 serves to maintain the functions of macrophages by reducing the damage to T cells by 5-FU. On the other hand, the activity against Pseudomonas infection was not affected by anti-thymocyte serum or carrageenan. It is probable that thymosin alpha 1 also exerts its effect on neutrophils without participation of T cells and macrophages.

Animals↗
PubMed1982

Antipicornavirus flavone Ro 09-0179.

Ro 09-0179 (4',5-dihydroxy-3,3',7-trimethoxyflavone), isolated from a Chinese medicinal herb, was found to have potent antiviral activity. It selectively inhibited the replication of human picornaviruses, such as rhinoviruses and coxsackieviruses in tissue culture, but not other DNA and RNA viruses. Ro 09-0298 (4',5-diacetyloxy-3,3',7-trimethoxyflavone), an orally active derivative of Ro 09-0179, prevented coxsackievirus (B1) infection in mice. The critical time for the inhibition of rhinovirus replication by Ro 09-0179 was 2 to 4 h after virus adsorption, i.e., in the early stages of virus replication. It markedly inhibited coxsackievirus and rhinovirus RNA synthesis in infected HeLa cells, but not in a cell-free system using the RNA polymerase complex isolated from the infected cells. In the infected cells, the RNA polymerase complex was not formed in the presence of Ro 09-0179. Therefore, it is suggested that Ro 09-0179 interferes with some process of viral replication which occurs between viral uncoating and the initiation of viral RNA synthesis.

Animals↗