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O Sakamoto

Publications and source records attributed to O Sakamoto.

52 records · Page 3Linked to original sources
PubMed1992

Novel derivatives of 5-fluorouridine and 5-fluorouracil having potent antitumor and lower immunosuppressive activities.

We studied the biological activities of several 5-fluorouridine (5-FUR) and 5-fluorouracil (5-FU) derivatives to find novel antitumor drugs with lower immunosuppressive effects. We examined 5-FUR and 5-FU derivatives acylated with (2-n-propyl-n-pentanoyl)glycine (KN-539). Among the examined compounds, we found satisfactory activities in a derivative of 5-FUR, 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), and a derivative of 5-FU, 1-(6-[N-(2-n-propyl-n-pentanoyl)glycyl] amino-n-hexylcarbamoyl)-5-fluorouracil (UK-25). UK-21 (0.05-0.2 mmole/kg, p.o., 10 days) and UK-25 (0.1-0.4 mmole/kg, p.o., 10 days) suppressed Meth A and E.L.4 tumor growths in the corresponding syngeneic hosts (BALB/c mice and C57BL/6 mice, respectively) without decreasing body weight and blood leukocyte count. UK-21 and UK-25 suppressed the proliferation of KB tumor cells in vitro (IC50: 3.0 x 10(-11) M and 4.4 x 10(-7) M, respectively) at concentrations almost equivalent to those of 5-FUR and 5-FU, respectively. These results suggest that UK-21 and UK-25 express their antitumor activity as 5-FUR and 5-FU, respectively. Neither UK-21 nor UK-25 suppressed thymus weight and humoral antibody production against sheep red blood cells (SRBC) in ddY mice, although 1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) and 5-FU suppressed them in their respective therapeutic dose ranges for tumors. Thus, UK-21 and UK-25 are expected to develop into anticancer drugs with lower immunotoxicological effects.

Animals↗
PubMed1992

Antitumor activity of two novel low immunosuppressive fluoropyrimidines UK-21 and UK-25.

We have previously reported that 2',3',5'-tris-O-[N-(2-n-propyl-n-pentanoyl)glycyl]-5-fluorouridine (UK-21), a derivative of 5-fluorouridine (5-FUR), and 1-(6-[N-(2-n-propyl-n-pentanoyl)-glycyl]amino-n-hexylcarbamoyl)-5- fluorouracil (UK-25), a derivative of 5-fluorouracil (5-FU), exert their antitumor activity in mice bearing Meth A or EL4 tumor, while their immunosuppressive effects are mild. In the present study, we examined the effects of these compounds on Sarcoma-180 (S-180), P388, L1210, and Lewis lung carcinoma (LLC) in mice by p.o. administration and i.p.-administration. UK-21 given p.o. showed an antitumor effect against S-180, but it showed virtually no antitumor effects against P388, L1210 and LLC. UK-21 given i.p., on the other hand, strongly inhibited the growth of Meth A tumor at a far lower dose than that for oral administration. The bioavailability of UK-21 given p.o. was suspected to be poor. UK-25 given p.o., in contrast, showed the antitumor effect on all of the tumors employed. The bioavailability of UK-25 given p.o. seemed to be comparable to those of other drugs. These results suggest that UK-21 has the potential for development as a parenterally applicable anticancer drug, and UK-25 has the potential as an oral one.

Administration, Oral↗
PubMed1992

[A case of bucillamine-induced interstitial pneumonia].

Bucillamine [N-(2-mercapto-2-methylpropionyl)-L-cysteine] is an anti-rheumatic drug which was developed in Japan. Interstitial pneumonia induced by bucillamine has been reported in two patients with rheumatoid arthritis. In this report, we describe another patient who developed bucillamine-induced interstitial pneumonia. In August 1990, a 53-year-old man was admitted because of fever, dry cough and dyspnea on exertion (DOE). Five months previously, he had noted polyarthritis, and treatment with bucillamine was started in May 1990. His polyarthritis improved about 2.5 months after starting bucillamine, but he developed fever, dry cough, and DOE in August 1990. Chest X-ray on admission showed diffuse acinar and interstitial shadows predominantly in the bilateral upper lung fields. Pulmonary function tests revealed decreased vital capacity and diffusing capacity. Arterial blood gas (ABG) analysis revealed moderate hypoxemia with PaO2 67 Torr. After stopping bucillamine, the fever, dry cough, and DOE improved gradually, and the abnormal shadows on chest X-ray and ABG analysis showed moderate improvements. Bronchoalveolar lavage studies showed that total cell counts and proportion of lymphocytes were increased, and CD4+/CD8+ ratio of T cell subsets was decreased to 0.56. Transbronchial lung biopsy specimen revealed lymphocytic alveolitis and mild interstitial thickening. Lymphocyte stimulation test to bucillamine was negative, but patch test with bucillamine was positive. From the patient's clinical course, laboratory data, and pathologic findings, we concluded that this is a case of bucillamine-induced interstitial pneumonia. After treatment with corticosteroid, his chest X-ray and pulmonary function test showed marked improvements.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Bleomycin-induced pulmonary fibrosis in genetically mast cell-deficient WBB6F1-W/Wv mice and mechanism of the suppressive effect of tranilast, an antiallergic drug inhibiting mediator release from mast cells, on fibrosis.

It has been well known that the number of mast cells increases during the development of fibrosis in various tissues including the lung. However, the role of mast cells in fibrosis still remains obscure. In the present paper, we evidenced that pulmonary fibrosis could be induced in genetically mast cell-deficient WBB6F1-W/Wv mice as well as WBB6F1-(+/+) mice having mast cells normally by the treatment with bleomycin (BLM, 5 mg/kg, i.v., 10 days), and there was not much difference in the histological changes of lungs between the two strains. An increase in the hydroxyproline content of the lung of WBB6F1-W/Wv mice was rather higher than that of WBB6F1-(+/+) mice. Previously, we reported that tranilast, an antiallergic drug inhibiting chemical mediator release from mast cells, suppressed the development of BLM-induced pulmonary fibrosis in ICR mice, suggesting the possibility that mast cells play certain roles in fibrosis. However, it was evidenced in the present report that tranilast suppressed BLM-induced fibrosis in WBB6F1-W/Wv mice. Tranilast neither suppressed the cytotoxic activity of BLM against KB cells and L-929 cells in vitro, nor inhibited the antitumor activity of BLM against Sarcoma-180 transplanted subcutaneously into ICR mice. Tranilast may act through suppressing BLM-induced activation of lymphoid cells including macrophage and neutrophil. These results indicate an inconsequential role of mast cells in the development of fibrosis. Increases in the number of mast cells and in histamine content of the lung, which were widely reported in the lungs of BLM-treated mice, may be the result of fibrosis.

Analysis of Variance↗
PubMed1990

A method for evaluating anti-allergic drugs by simultaneously induced passive cutaneous anaphylaxis and mediator cutaneous reactions.

Homologous passive cutaneous anaphylaxis (PCA) was induced by IgE antibody and, simultaneously, cutaneous reactions were induced by some allergic mediators such as histamine, serotonin and leukotriene (LT) C4 on rat back skin. Disodium cromoglycate and tranilast with inhibitory actions on mediator release inhibited PCA specifically, whereas antihistaminics, including ketotifen, azelastine, mequitazine and diphenhydramine, inhibited histamine- and serotonin-induced cutaneous reactions as well as PCA. Anti-slow-reacting substance of anaphylaxis drugs, KC-404 and FPL-55712, significantly inhibited PCA and histamine- and serotonin-induced reactions, but at the same doses they did not produce significant inhibition of the LTC4-induced reaction. All reactions tested were strongly inhibited dose dependently with the beta stimulants, salbutamol and isoproterenol, and a xanthine derivative, theophylline, which are known to increase the intracellular cyclic AMP level. We think that this method enables the determination of the properties of anti-allergic drugs.

Albuterol↗
PubMed1989

Solid phase enzyme-linked immunosorbent assay (ELISA) for anti-sheep erythrocyte antibody in mouse serum.

The solid phase enzyme-linked immunosorbent assay (ELISA) was developed to measure IgM and IgG anti-SRBC antibody titers in mouse serum. Sheep erythrocytes, which have a surface negative charge, were attached directly to the bottom of an aminoplate well (96-well flat bottom, Sumitomo Bakelite Co.) which is charged positively to provide a solid phase for the ELISA antigen. Serum samples titrated were obtained from mice 5 and 10 days after SRBC immunization. Alkaline phosphatase-labeled goat anti-mouse IgM and/or IgG preparations were used as second antibody. Alkaline phosphatase activity in a well was measured by the Kind and King method [Kind, P. R. N. & King, E. J. (1954). J. clin. Path., 7, 322-326]; the optical density (OD) value of quinone as a final product was measured at 492 nm. (1) A linear relationship was observed between the antiserum concentration and OD value over a wide enough dilution range to assay antibody titers of serum samples; (2) IgM and IgG fractions from antiserum showed almost the same antibody titer as did the reconstituted samples; (3) a good correlation was observed between the serum IgM titer and the number of IgM hemolytic plaque-forming cells (PFCs) in spleen 5 days after the immunization, and was also observed between serum IgG antibody titer and the number of IgG PFCs 5 and 10 days after. Therefore, the ELISA described here requires no fixative for preparation of cell-coated plates, and serum IgM and IgG anti-SRBC antibody titers can be measured without any fractionation technique.

Alkaline Phosphatase↗
PubMed1989

Immunological mechanisms of antitumor activity of some kinds of crude drugs on tumor necrosis factor production.

Previously, we described the antitumor activity of four crude drugs, A. capillaris, S. doederleinii, A. macrocephala and S. subprostrata. Tumor necrosis factor (TNF) can be produced in animals by injecting Bacillus Calmette-Guerin (BCG) or Corynebacterium parvum (CP) as priming agents and endotoxin (LPS) as an eliciting agent. However, because of their severe toxic action, it is inappropriate to use these agents to induce intrinsic TNF in cancer patients. In the present paper, we began with the investigation of a fluorometric method using ethidium bromide (EB) to assay TNF activity in serum in vitro, and then examined whether the four crude drugs displayed the priming and eliciting activities for TNF production. The TNF activity in a serum sample could be titrated using the fluorometric method in addition to a method using 3H-thymidine. The fluorometric method was superior to the radio-method as regards simplicity, safety and reproducibility. A. capillaris, S. doederleinii and S. subprostrata showed priming activity for TNF production in mice without the liver and spleen hyperplasia seen in the case of CP, S. subprostrata showed an eliciting activity in CP-primed mice. These results suggest that the crude drugs might be useful as inducers of intrinsic TNF in cancer patients.

Animals↗
PubMed1989

Mechanisms of antitumor activity of aqueous extracts from Chinese herbs: their immunopharmacological properties.

Previously we reported the antitumor activity of 4 kinds of Chinese herbs: A. capillaris, S. doederleinii, A. macrocephala and S. subprostrata. Evidence has been also presented that A. capillaris shows the activity mainly through a direct tumoricidal action and the others display the activity through the enhancement of tumor-immune response. The present results are as follows: A. capillaris did not affect Meth A tumor-neutralizing activity (Winn's assay) in spleen cells of BALB/c mice bearing the primary tumor. The other herbs enhanced the activity on days 10 and 15 and prevented the decay of the activity on day 20 after the Meth A tumor transplantation. However, none of them enhanced the local graft versus host reaction (GvHR) induced in CBF1 mice by spleen cells of BALB/c mice. A. capillaris hardly affected the humoral antibody formation against sheep red blood cells in mice. On the contrary, the other 3 herbs enhanced the formation. Blast transformation of murine lymphocytes with PHA-P or LPS was suppressed by 10(-5) to 10(-4) g/ml of A. capillaris. A. macrocephala enhanced the response by LPS. It should be noted that A. capillaris showed no immunosuppressive action in spite of having a direct tumoricidal action in vitro. Further investigations will be required on the latter 3 herbs to clarify the relationship between their humoral immunity-stimulating activity and their tumor immunity-enhancing activity.

Animals↗
PubMed1988

Immunological mechanisms of antitumor activity of some kinds of Chinese herbs: Meth A-induced delayed type hypersensitivity.

In the present paper, we confirmed that a delayed type hypersensitivity response can be elicited against Meth A tumor (Meth A-DTH) in BALB/c mice bearing the primary tumor. This response was augmented by lipopolysaccharide. We examined the effects of 4 kinds of Chinese herbs including A. capillaris, S. doederleinii, A. macrocephala and S. subprostrata on the Meth A-DTH, and the results were compared with that of the herbs on picryl chloride-induced delayed type hypersensitivity (PC-DTH). All of the herbs examined augmented the Meth A-DTH 10 days after the primary tumor transplantation, and S. doederleinii, A. macrocephala and S. subprostrata prevented the decay of the response on the 20th day, but A. capillaris did not. On the other hand, none of the herbs affected the PC-DTH. When both DTH responses were caused simultaneously in the same mouse, Meth A-DTH decayed 20 days after the transplantation but PC-DTH did not. In this case, the effects of these 4 herbs on Meth A-DTH and PC-DTH were essentially the same as those seen in the case of separate experiments. The previous and present results suggest that A. capillaris shows antitumor activity mainly through a direct cytotoxicity, although this herb might have certain components to enhance Meth A-DTH, and the other herbs display the activity through the enhancement of T cell-mediated tumor immunity, particularly tumor specific DTH.

Animals↗
PubMed1987

Effect of immunostimulants and antitumor agents on tumor necrosis factor (TNF) production.

OK-432, a lyophilized preparation of Streptococcus pyogenes, showed a priming activity for TNF production in mice, associated with an increase of spleen weight. PSK, a protein-bound polysaccharide preparation from Coriolus versicolor, did not show such activity. Both OK-432 and PSK potentiated the TNF production in mice primed with Corynebacterium parvum (CP) and challenged with Escherichia coli endotoxin (LPS). Cytotoxic antitumor agents of 5-fluorouracil (5-FU), cyclophosphamide (CY) and bleomycin (BLM) suppressed TNF production in mice primed with CP and challenged with LPS. TNF production suppressed by 5-FU, CY and BLM was partially restored by the combined treatment with OK-432 or PSK. These results suggest that the administration of cytotoxic antitumor agents suppresses the intrinsic TNF production in cancer patients, and the combined use of immunostimulants such as OK-432 and PSK is advantageous in restoring TNF production suppressed by cytotoxic antitumor agents.

Adjuvants, Immunologic↗
PubMed1985

Survey for soil-transmitted helminths in Asahan Regency, North Sumatra, Indonesia.

The survey on soil-transmitted helminthiasis was carried out in the three villages of Asahan Regency, North Sumatra, Indonesia, between October 1981 and December 1982. The prevalence rates of geohelminthiasis proved to be extremely high (average 97%) in the three villages and more than 70% harboured three or more helminths, especially Ascaris lumbricoides, Trichuris trichiura and hookworm. Necator americanus and Ancylostoma duodenale were detected in 61.1% and 52.2% of 835 fecal specimens, respectively. The effects of two anthelmintics, Combantrin and Trivexan, were essentially the same against A. lumbricoides and hookworm, although Trivexan was better than Combantrin against T. trichiura. The kinetic changes of parasitic infection in community after mass treatment were examined. Ten months after the first drug treatment, the incidence of Ascariasis or trichuriasis reverted nearly to pre-treatment level, while hookworm infection rate remained significantly low. Four months after the second mass treatment, the reinfection rate of A. lumbricoides was most prevalent followed by trichuriasis and hookworm infection. The reinfection rate (63.6%) of A. lumbricoides in children was about six times higher than that (10.4%) in adults at four month after the mass treatment. This study indicates that mass treatment with Trivexan at two month intervals for children and four month intervals for adults is necessary for the effective helminth control scheme in highly endemic areas of North Sumatra.

Adolescent↗
PubMedDate not supplied

Diagnosis and molecular analysis of an atypical case of holocarboxylase synthetase deficiency.

Holocarboxylase synthetase (HCS) deficiency is a disorder of biotin metabolism characterised by metabolic ketoacidosis and skin lesions due to reduced activities of multiple biotin-dependent carboxylases. The onset of this disease is usually between the neonatal and infantile period. Here we report the molecular analysis of an atypical case of HCS deficiency, where the patient developed his first episode of acidosis at age 8 years and had an exceptionally slow response to biotin therapy. A homozygous mutation was identified at the + 5 position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g-->a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the amount of normal HCS mRNA may account for the atypical, late-onset phenotype of this patient. Conclusion Molecular analysis is a useful tool for understanding the phenotypic variations in holocarboxylase synthetase deficiency.

Age of Onset↗