Takeshi Ogura

Adjuvant immunotherapy of lung cancer with BCG cell wall skeleton (BCG-CWS).

Four hundred fifty‐five patients with lung cancer were treated with oil‐attached cell‐wall skeleton of bacillus Calmette‐Guérin (BCG‐CWS) as adjuvant immunotherapy following initial conventional therapy. The overall survival period of the patients was prolonged significantly as compared with that of 380 patients in a historical control group receiving initial conventional therapy alone (p < 0.0001). The prolongation of the survival period of the patients was also statistically significant when classified according to clinical stages and histological cell types. The therapeutic effect was remarkable in patients combined with malignant pleurisy. Intrapleural injection of BCG‐CWS resulted in not only prevention of accumulation of pleural effusion and abrogation of tumor cells but also in prolongation of survival period (p = 0.016). No serious side effects due to BCG‐CWS were experienced. From the previous experimental studies and clinical experiences with human tumors, it can be concluded that adjuvant immunotherapy with BCG‐CWS is a useful therapeutic modality for lung cancer, especially in cases combined with malignant pleurisy.

Primary lung cancer producing alpha‐fetoprotein: A case report

A case of primary lung cancer that produced both alpha‐fetoprotein (AFP) and carcinoembryonic antigen (CEA) is presented. Alphafetoprotein in the supernatant of tissue extract from the primary lesion amounted to more than 40 μg/ml, and its exact origin from tumor tissues was confirmed by the immunofluorescent study. We suppose that since the lung is one of the foregut derivatives it is not unlikely for lung cancer cells to produce AFP as well as CEA. Cancer 47:926–929, 1981.

In vitro tumor cell killing by peritoneal macrophages from mitomycin C-treated rats.

SummaryThe local cellular response induced by intraperitoneal injection of mitomycin C was examined in terms of cell-mediated cytotoxicity for tumor cells. An in vitro cytolysis assay involving 125I-iododeoxyuridine-labeled tumor target cells revealed that treatment of normal ACI/N rats (200 g) with a single intraperitoneal injection of mitomycin C (50, 100, or 200 μg) induced tumoricidal macrophages in the peritoneal cavity. The tumoricidal activity was dependent on the dose of mitomycin C injected and it was detectable as early as 1 day after the intraperitoneal injection of mitomycin C. In addition to the increased tumoricidal activity, the functional activities of the peritoneal macrophages were found to be increased with respect both to uptake of 2-deoxy-d-glucose and to phagocytosis of latex beads. Additional experiments excluded the possibility that the tumor cell cytolysis was the result of direct cytotoxicity by mitomycin C that might have been incorporated in the peritoneal macrophages or of nutrient depletion in the medium during the cytolysis assay. Furthermore, endotoxin contamination of the mitomycin C, which might have produced the activated macrophages, was not detected. The mechanism by which mitomycin C injected intraperitoneally induced the tumoricidal macrophages locally remains uncertain; however, it is possible also in clinical situations.

Induction of activated macrophages by intraperitoneal injection of mitomylin C in mice

SummaryThe host cellular response to IP injection of mitomycin C was studied in C3H/HeN mice. As assessed by in vitro cytolysis assay using 125I-iododeoxyuridine-labelled tumour target cells, mitomycin C-induced peritoneal macrophages showed the maximum tumouricidal activity 4 days after the IP injection. The tumouricidal activity was dependent on the dose of mitomycin C injected and it was detectable against syngeneic, allogeneic and xenogeneic tumour target cells. In addition, these tumouricidal macrophages were found to be augmented in functions of both incorporation of 2-deoxy-D-glucose and phagocytosis of sheep red blood cells. Among the other anti-cancer drugs, which were used at a dose of three-fifths of LD50, only adriamycin (7.5 mg/kg) was capable of inducing activated macrophages as much as mitomycin C (3 mg/kg). Cyclophosphamide (225 mg/kg), methotrexate (60 mg/kg) and vincristin (1.5 mg/kg) were able to augment incorporation of 2-deoxy-D-glucose and phagocytosis of sheep red blood cells, but not tumouricidal actvity. Differential cytolysis assay was performed for two cell lines of P 388 tumour target cells, the mitomycin C-sensitive original cell line and the mitomycin C-resistant subline, demonstrating no significant difference in macro-phage-mediated tumour cell lysis between these cell lines. Based on these results, it was concluded that mitomycin C, when injected IP induced activated macrophages in the peritoneal cavity. A better understanding of the effect of anti-cancer drugs on macrophage tumouricidal activity may be useful in designing more effective local chemotherapy for malignant peritoneal effusions.

Mechanism(s) of in vitro macrophage activation with Nocardia rubra cell wall skeleton. The effects on macrophage activating factor production by lymphocytes

SummaryBALB/c mouse peritoneal macrophages prepared from WPC which had been treated with N. CWS demonstrated potent cytostatic activity against syngeneic Meth A fibrosarcoma cells. The maximum cytostatic activity developed in the macrophages when WPC were incubated with 25 μg/ml N. CWS for 3 days. NAPC from BALB/c mice given an i. p. injection with 100 μg N. CWS 7 days previously (N. CWS-NAPC) or supernatants from N. CWS-NAPC also activated peritoneal macrophages in vitro. However, when peritoneal macrophages were incubated with N. CWS in the absence of NAPC, or when T cells were depleted from WPC by treatment with anti-Thy 1.2 antibody and complement, N. CWS failed to enhance the cytostatic activity of the macrophages. Furthermore, thioglycollate-elicited peritoneal macrophages from C3H/HeN mice increased their cytolytic properties by incubation with supernatant fluids from N. CWS-treated spleen cells. These findings suggest that in vitro macrophage activation with N. CWS depends on MAF secreted from T lymphocytes.

Pulmonary alveolar proteinosis: Analysis of pulmonary washings

Bronchopulmonary washings from a patient with pulmonary alveolar proteinosis who underwent therapeutic pulmonary lavage were examined. There were large amounts of protein and lipids of which main classes were phospholipid, cholesterol and free fatty acid. The major component of phospholipids recovered from the washings was lecithin rich in palmitic acid. We also found a high IgG level in the washings. Both the findings of free cholesterol in high concentration in the washings and the electrophoretic pattern of protein in the washings suggested that the alveoli-filling material of our patient was not wholely derived from passive transudation of plasma constituents.

Analysis of the high‐field domain dynamics in a planar Gunn diode by using a stroboscopic SEM

An analysis has been made for the high‐field domain dynamics in a planar Gunn diode, based on stroboscopic observations by a scanning electron microscope. The 1‐GHz pulsed electron beam was synchronized with the microwave‐triggered oscillating diode. The movement of the domain could be clearly observed. The domain dynamics is discussed in detail, taking the time fluctuation in microwave triggering into account. The experimental results are also supported by a theoretical analysis.

Effect of Nocardia rubra cell-wall skeleton treatment on tumor formation in two-stage chemical carcinogenesis of mouse skin

SummaryIn two-stage chemical carcinogenesis of mouse skin, Nocardia rubra cell-wall skeleton (N-CWS), a potent immunopotentiator, was injected SC at various times. The dorsal skin of C57BL/6 male mice (about 10 cm2) was painted with 20 μg 7,12-dimethylbenz(a)anthracene (DMBA) in 0.1 ml acetone when the animals were 11 weeks old (initiation). Seven weeks later, they were painted with 2.5 μg 12-0-tetradecanoyl-phorbol-13-acetate (TPA) in 0.1 ml acetone twice weekly for 30 weeks (promotion). The timing of N-CWS treatment was important. N-CWS treatment before initiation reduced the incidence of skin tumor and the mean number of skin tumors per mouse most effectively. It is speculated that the antitumor activity of N-CWS may be composed of at least two mechanisms, being achieved through the enhancement of immunological surveillance and through changes in the metabolism of chemical carcinogens.

Analysis of therapeutic effect in experimental chemoimmunotherapy for rat ascites tumor.

SummaryThe lyophilized, squalene-treated Nocardia rubra cell wall skeleton (N-CWS) was confirmed to produce tumoricidal peritoneal macrophages resulting in inhibition of tumor growth when injected locally into the syngeneic ascites fibrosarcoma, AMC 60 in ACI/N rats. Furthermore, N-CWS was found to augment therapeutic effect when administered repeatedly after a single local injection of mitomycin-C (MMC). To analyze the effects, various in vitro cytolysis assays were performed using N-CWS-activated peritoneal macrophages. When tumor target cells were exposed in vitro to MMC, the resulting cytolysis in the presence of N-CWS-activated macrophages was similar to cytolysis of intact target cells. On the other hand, when N-CWS-activated macrophages were exposed to MMC, the tumoricidal activity was lost significantly, depending on exposure to MMC. When tumor target cells and N-CWS-activated macrophages were simultaneously exposed to MMC, tumor-cell cytolysis was strikingly depressed. In the final experiment, combined injection of MMC and N-CWS into the ascites tumor resulted in remarkable increases not only in peritoneal exudate cell number, but also in in vitro tumoricidal activity of peritoneal macrophages as compared to those induced by either agent alone. In addition, the production of tumoricidal macrophages by IP injection of MMC alone was also noticeable, as described previously. These results possibly indicate the involvement of macrophage activation in induction of therapeutic effect in chemoimmunotherapy.

Study of two‐dimensional Gunn domain dynamics using a stroboscopic SEM

Two‐dimensional domain dynamics has been clarified in a cathode‐slanted planar Gunn diode under the pulse‐biased operation using a stroboscopic scanning electron microscope. Experimental results are in reasonable agreement with theoretical results.