[Action mechanism of cell wall skeleton of BCG and Nocardia rubra as immunomodulator].
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Biomedical subjects
Publications and source records attributed to F Hirao.
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Cefroxadine dry syrup was studied clinically and the following results were obtained. The drug was administered to 19 cases of bacterial infections: acute tonsillitis (6), acute bronchitis (6), scarlet fever (2), acute pyelonephritis (4) and acute cystitis (1). The daily dose was about 30 approximately 50 mg/kg except for 1 patient. The drug was given orally, 3 times a day and the duration of administration was from 4 to 11 days. The overall efficacy rate was 100%, i.e., excellent in 17 cases, good in 2 cases. One patient experienced a mild S-GOT elevation and another patient in mild vomiting. From the results obtained in this study, cefroxadine dry syrup seems to be useful in the treatment of infectious diseases of children.
Differential induction of squamous cell carcinomas, adenomas, and adenocarcinomas was observed in the lungs of male C57BL/6 and C3H/He mice after repeated intratracheal instillation of benzo(a)pyrene (BP) and charcoal powder suspended in 0.9% NaCl solution. when a high dose of BP (1.0 mg BP and 0.5 mg charcoal powder) was instilled intratracheally once a week for 8 weeks or when a low dose of BP (0.5 mg BP and 0.5 mg charcoal powder) was instilled once a week for 16 weeks, squamous cell carcinomas were induced in high incidence (77 to 87%) in the early period of observation, whereas pulmonary adenomas and adenocarcinomas were induced in low incidence (0. to 48%) in the late period of observation in both strains of mice. On the other hand, when a low dose of BP was instilled intratracheally once a week for 8 weeks, pulmonary adenomas and adenocarcinomas were induced in high incidence (76 to 91%), but squamous cell carcinomas were induced in low incidence (9 to 26%). These results show that a larger quantity of BP instilled intratracheally was needed for induction of squamous cell carcinomas than for induction of adenomas and adenocarcinomas in the lung of mice. Thus, when the carcinogen is administered to a single organ of a single mouse strain by the same route, different amounts of carcinogen have different effects on the incidences of various histological types of tumors.
Cefoperazone (CPZ) was studied clinically and the following results were obtained. The drug was administered to 21 cases of bacterial infections; respiratory tract infection (17), lymphadenitis (1), urinary tract infection (1), enterocolitis (1) and purulent meningitis (1). The daily dose was 50 approximately 125 mg/kg. The drug was given by one-shot intravenous injection, 3 approximately 4 times a day and the duration of administration was from 3 approximately 18 days. The overall efficacy rate was 81.0%, i.e., excellent in 11 cases, good in 6 cases, moderate in 2 cases and poor in 2 cases. CPZ was potent in the treatment of ampicillin-resistant Haemophilus influenzae meningitis. One patient developed exanthema. No other serious side effects were observed.
Carcinogenic activity of benzo[a]pyrene alone was tested for the induction of lung cancer in rabbits. Rabbits received intrabronchial instillation of 5 or 40 mg of benzo[a]pyrene suspended in sterile saline every 10 to 14 days. Cancer incidences were approximately 42% of the rabbits that survived for more than 300 days. These cancers included squamous cell carcinoma, adenocarcinoma, undifferentiated cell carcinoma, fibrosarcoma, and mixed type. In the same experiment amyloidosis was seen in 16 rabbits.
Repeated intravenous administrations of oil-attached Nocardia rubra cell-wall skeleton (N. rubra-CWS) prevented the induction of lung cancer by intrabronchial instillations of 3-methylcholanthrene in rabbits. Amyloidosis was seen after giving 3-methylcholanthrene, and the incidence was higher in the N. rubra-CWS administered rabbits than in the controls.
The effect of oil-attached cell-wall skeletons of BCG (BCG-CWS) and Nocardia rubra (N. rubra-CWS) on macrophage functions was examined regarding phagocytosis of zymosan particles, uptake of 2-deoxy-D-glucose (2-dG), and cytostatic activity against syngeneic tumor cells. A single intraperitoneal injection of either BCG-CWS or N. rubra-CWS in mice resulted in accumulation of a large number of macrophages in the peritoneal cavity. They demonstrated, in vitro, a significant cytostatic effect on target cells as well as increase in phagocytic activity and uptake of 2-dG. These results suggest that one of underlying mechanisms for the antitumor activity of BCG-CWS and N. rubra-CWS is possibly the activated macrophage-mediated system.
Administration of oil-attached Nocardia rubra cell-wall skeleton (N. rubra-CWS) was evaluated for the effect of the induction of lung cancers in ACI/N rats. Lung cancers were induced by 15 weekly intratracheal instillations of 3 mg benzo[a]-pyrene with 3 mg ferric oxide. After the 10th instillation of the carcinogen, rats received seven subcutaneous injections of 100 microgram of N. rubra-CWS at 2-week intervals. In the observation period of 56 weeks, the cumulative incidence of lung cancer was 71.4% in the control group and 48.0% in the N. rubra-CWS treated group. The latent period of tumor induction was prolonged in the group treated with N. rubra-CWS.
The antitumor activities of the cell wall skeleton (CWS) of Nocardia rubra were demonstrated for syngeneic fibrosarcoma (AMC-60) in ACI/N rats in regard to macrophage activation. In the 24-hr cytolytic test, activated macrophages which were fractionated from peritoneal exudate cells induced by i.p. injection of Nocardia CWS showed significant cytolytic activity for [125I]iododeoxyuridine-labeled tumor cells. Activated macrophages also strongly inhibited [3H]thymidine incorporation into the tumor cells during the 24-hr cytostatic test. When tumor cells were inoculated s.c. with activated macrophages in the Winn-type transfer assay, subsequent tumor growth was significantly inhibited. Repeated i.p. injection of the CWS seemed to enhance these antitumor activities of macrophages. The therapeutic effect of Nocardia CWS was assessed with the ascites tumor and with the solid tumor inoculated i.m. into the hind leg. In the former treatment, repeated i.p. injections completely prevented the accumulation of ascites fluid and resulted in prolongation of the survival period. The peritoneal macrophages harvested from these survivors had a strong cytolytic activity for tumor cells in the cytolytic test. In the latter treatment, repeated intratumoral injections inhibited the growth of primary tumor and prevented metastasis. Furthermore, peritoneal resident macrophages from these tumor-bearing rats treated intratumorally with the CWS were found to be cytolytic for tumor cells in the cytolytic test.
Intravenous injection of oil-attached BCG cell-wall skeleton showed potent preventive activity for induction of lung cancer by the intrabronchial instillation of chemical carcinogens (3-methylcholanthrene, 4-nitroquinoline 1-oxide) in rabbits. On the other hand, the thymectomized rabbits developed lung cancer by instillation of chemical carcinogens at an 80% incidence, compared to 47.2% in the controls. There were no differences in the appearance of amyloidosis between thymectomized and BCG cell-wall skeleton-treated rabbits and the controls.
Oil-attached BCG cell-wall skeleton (BCG-CWS) was demonstrated to have an activity inducing lymphocyte trapping in the draining node in rats. It acts also as a potent adjuvant for the lymphocyte trapping when injected into the growing syngeneic transplantable tumor. Treatment with repeated intratumor injections into the primary tumor resulted in suppression of tumor growth in both primary and metastatic sites. Even when the primary tumor escaped regression, inhibitory effect on metastatic spread was attained by the therapy. The contribution of BCG-CWS to suppression of metastasis especially in the draining node was discussed from the point of lymphocyte trapping in the draining node.
Peritoneal exudate cells (PEC) induced by oil-attached cell-wall skeleton of Mycobacterium bovis BCG (BCG-CWS) in ACI/N rats were tested for their effect on both in vivo and in vitro growth of syngeneic fibrosarcoma cells (AMC-60). Treatment of rats with intraperitoneal injections of BCG-CWS induced regression of syngeneic ascites tumor and increased the number of survivals. Whole PEC and adherent PEC from rats injected intraperitoneally with BCG-CWS inhibited the uptake of tritiated thymidine into the fibrosarcoma cells in an in vitro cytostasis test. This in vitro cytostatic effect was more marked as the ratio of effector to target cells increased. In addition, when tumor cells were inoculated subcutaneously with BCG-CWS activated PEC, tumor takes decreased markedly. Oil-stimulated PEC and normal peritoneal resident cells were inactive in inhibition of tumor growth in vivo and in vitro.
The effect of radiotherapy on peripheral blood lymphocytes (PBL) of lung cancer and the effect of BCG cell-wall skeleton (BCG-CWS) on recovery of impaired PBL were examined. A remarkable depression of the absolute number of E- or EAC-rosette cells and of the response of PBL to mitogens were observed immediately after radiotherapy, and these continued for several months. With BCG-CWS immunotherapy, the response of PBL to phytohemagglutinin recovered rapidly, compared with non-vaccinated patients. The response of PBL to pokeweed mitogen seemed to give similar results. These results suggested that BCG-CWS injection to the patient receiving radiotherapy was effective for recovery of T-cell response.
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The basic protein prepared from AH-130 ascites hepatoma cells was tested for its effect on the cell-mediated immune response of Donryu strain rats. The basic protein suppressed the response of peripheral and lymph node lymphocytes to phytohemagglutinin and lymphocyte trapping in the antigen-draining lymph node. These results indicated that the basic protein from tumor tissue possibly had an immunosuppressive activity and affected inadequately the cell-mediated immune response as usually observed in tumor-bearing hosts.
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Squamous cell carcinomas were readily induced in the lung of C57BL/6 mice by repeated intratracheal instillations of benzo[a]pyrene with charcoal powder suspended in saline solution. Intratracheal instillations were performed once a week for 8 weeks, and the observation period of the experiment was 40 weeks. Some of the tumors were highly keratinized and others were moderately keratinized squamous cell carcinomas. At a later period of observation, poorly differentiated squamous cell carcinomas were found. Invasion into blood vessels was occasionally seen but metastasis to regional lymph nodes or distant metastasis was not found. One tumor from the mouse killed on the 280th day was successfully transplanted subcutaneously into C56BL/6 mice. This mouse, killed on the 84th day after the first tranplantation, had a pulmonary metastasis.
Adjuvant and antitumor activities of CWS prepared from cells of mycobacteria, nocardia, and corynebacteria were examined. Oil-attached CWS of M. bovis BCG (BCG-CWS) stimulated the generation of cell-mediated cytotoxic effector cells in mice. Tumor growth was suppressed in mice inoculated intradermally with a mixture of oil-attached CWS and living tumor cells. Systemic and specific tumor immunity was demonstrated in mice in which tumor growth was suppressed. Tumor growth was also suppressed by oil-attached CWS of BCG or N. rubra in autochthonous autografts of spontaneous mammary adenocarcinoma and methylcholanthrene-induced fibrosarcoma in mice. The intravenous injection of oil-attached BCG-CWS prevents the appearance of lung cancer in rabbits by the instillation of chemical carcinogens. It was also shown that treatment with oil-attached BCG-CWS was able to elevate the immunologically depressed state of tumor-bearing mice to a normal level, as determined by a cell-mediated cytotoxicity assay that empolyed chromium release as the standard. Preliminary results suggest that oil-attached BCG-CWS is useful as an immunotherapeutic agent for both lung cancer and for malignant melanoma, leukemia, Hodgkin's disease, and other neoplastic diseases and that this agent operates without any significant complications.