Suppression of murine natural killer cell activity by adherent cells from aging mice.

Natural killer (NK) cell activity declines with age in mice. The purpose of this study was to investigate the effect of peritoneal and splenic adherent cells from young and old mice on NK activity to determine whether adherent cell suppressor function might contribute to this decline. Peritoneal adherent cells from old mice suppressed NK activity of young splenic non-adherent indicator cells more than peritoneal cells from young mice. Splenic adherent cells from old but not from young mice also suppressed this activity. That (1) the suppressive activity of the adherent cell populations was not affected by treatment with anti-Thy-1 plus complement, and that (2) the adherent cell population contained 77-92% cells positive for alpha-naphthyl acetate esterase activity, suggests that the active adherent suppressor cell may be a macrophage. Therefore, the age-related decline in NK activity in mice can be explained, in part, by an increase in adherent cell suppressor function.

Analysis of natural killer activity and antibody-dependent cellular cytotoxicity in healthy volunteers and in patients with primary lung cancer and metastatic pulmonary tumors.

To clarify the contribution of ADCC and NK activities to host immune response against cancer, the characteristics of cells mediating these activities were examined in the peripheral blood lymphocytes of normal volunteers, and the changes of these activities were also evaluated in patients with lung cancer and metastatic pulmonary tumors before and after chemotherapy. OAT cells derived from small cell carcinoma of the lung and K-562 cells derived from erythroleukemia were used as target cells of ADCC and/or NK assay. ADCC and NK activities were not changed according to age, sex, and blood type. Mild and marked personal difference were observed in ADCC and NK activity, respectively. These activities were also influenced by environment. ADCC and NK activities of normal adult volunteers were diversely correlated at the coefficient of gamma-0.426. NK activities were high against K-562 and CCRF-CEM cells, and low against BALL and OAT cells. NK activity against K-562 cells was strongly inhibited by K-562 or CCRF-CEM cells with high NK sensitivity, on the other hand, it was slightly inhibited by OAT and BALL cells with low NK sensitivity. NK activity against OAT cells was strongly inhibited by OAT, K-562 and CCRF-CEM cells, but not inhibited by BALL cells. The effector cells mediating NK activity were identified as non-adherent, E-receptor-positive, Fc-receptor-positive small lymphocytes. NK activity was not decreased before chemotherapy in patients with stage III primary lung cancer and metastatic pulmonary tumors. It was decreased only in patients of bad performance status, and it was significantly decreased in all patients after chemotherapy. ADCC also exhibited the tendency to decrease after chemotherapy in tumor-bearing patients. The recovery of NK-activity after chemotherapy well correlated with the effect of chemotherapy.

[Effect of immunosuppressants on the subrenal capsule (SRC) assay as a chemosensitivity test].

Six-day SRC assay as a chemosensitivity test has an advantage of high predictive rate for clinical response. However, it is pointed out that very few viable tumor cells are observed at the end of the assay, so that it may make the assay results unreliable. In this paper, we tested the effect of immunosuppressants on SRC assay using Walker carcinosarcoma originated from Wistar rat xenografted under the renal capsule of BDF1 mice. The changes of tumor size, pathological features and proliferative ability of xenografted tumor under the renal capsule of mice treated with cyclophosphamide, mizolibine or cyclosporin A are examined. Only cyclosporin A treatment could maintain the viable tumor cells and proliferative ability of the tumor grafted under the renal capsule 21 days after transplantation. In order to compare the original 6-day SRC assay developed by Bogden et al, we applied immunosuppressants to the 6-day assay. It is suggested that cyclosporin A and mizolibine amplify the sensitivity of tumor in 6-day SRC assay.

[A six-day subrenal capsule assay for predictive testing of primary human tumors].

We carried out a total of 36 in vivo chemosensitivity tests in 33 cases of human malignant tumor using the subrenal capsule assay, developed by A.E. Bogden et al. Of the 36 assays, 31 were evaluable. The chemosensitivity of each tumor varied individually. UFT, 5-fluorouracil, mitomycin-C and adriamycin were administered to gastrointestinal cancer patients regularly, but our SRC-assay showed a high sensitivity rate for UFT and 5-fluorouracil but a low sensitivity rate for mitomycin-C and adriamycin. Nine patients had clinically evaluable lesions and a correlation between the assay results and clinical response existed in 6 cases. The true positive rate was 50% (3/6), the true negative rate 100% (3/3), and the overall predictive accuracy 66% (6/9). This study suggested that 6-day SRC assay is useful for selecting effective anti-tumor agents for the treatment of cancer patients.

Effect of BCG on cytostatic activity of peritoneal macrophages from normal and tumor-bearing rats.

In tumor-bearing rats inoculated intramuscularly with 5 x 10(4) SLC cells, the cytostatic activity of peritoneal macrophages was elevated in the early stage (7 days after transplantation) and decreased in the advanced stage (21 days after transplantation). When BCG was intraperitoneally administered into normal and tumor-bearing rats, peritoneal macrophages showed higher cytostatic activity than the untreated macrophages. This elevated cytostatic activity of the marcophages obtained from BCG-treated tumor-bearing rats was maintained even at an advanced stage.

Effect of 1(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) on Sato lung carcinoma (SLC). Preliminary result of immunochemotherapy for SLC by combination of ACNU and Propionibacterium acnes.

ACNU was highly effective for Sato lung carcinoma transplanted intravenously or intramuscularly by using a large single dose, and the cytotoxic action of ACNU for SLC showed clear dependence upon tumor size. Nonspecific activation of host-defence mechanism by Propionibacterium acnes contributed to the suppression for the regrowth of solid SLC treated by ACNU.

Combined effect of BCG and coenzyme Q10 on ATP-ase activity and coenzyme Q content in spleen lymphocytes of tumor-bearing rats.

Effect of BCG, coenzyme Q10, or their combination on ATPase activity in spleen lymphocytes of tumor-bearing rats was investigated in relation to changes in the content of individual coenzyme Q homologs in these cells. Contents of both coenzyme Q9 and Q10 in spleen lymphocytes significantly decreased in the late stage of Donryu rats bearing Sato lung carcinoma. Oligomycin-sensitive ATPase activity in spleen lymphocytes was also significantly depressed in this stage. The depressed, oligomycin-sensitive ATPase activity was significantly recovered by a 3-time intramuscular administration of coenzyme Q10 emulsified with ethanol and saline, and the decreased contents of coenzymes Q9 and Q10 were slightly restored by this treatment. This enzyme activity was also significantly recovered by an intravenous administration of BCG, and was elevated more by the combined treatment with BCG and the emulsified coenzyme Q10. These results suggest that the combined treatment with BCG and emulsified coenzyme Q10 can contribute to the improvement of the depressed bioenergetics in lymphocytes of tumor-bearing animals, and that this combined effect of BCG and emulsified coenzyme Q10 might be based on the combination of their individual activating effect on lymphocytes.

Effects of BCG and cyclophosphamide on the spontaneous and antibody-dependent cell-mediated cytotoxicity of peritoneal and spleen lymphocytes of ACI/N rats.

The effects of BCG and cyclophosphamide on the antibody-dependent cell-mediated cytotoxicity (ADCC) and natural killer (NK) activity of spleen and peritoneal lymphocytes were serially examined after treatment. The changes of ADCC and NK activity were different in peritoneal and spleen lymphocytes according to the route and timing of administration. The decrease of NK activity induced by cyclophosphamide is not marked, and the degree of decrease depends on the timing of cyclophosphamide administration. The ADCC and NK activity of peritoneal lymphocytes after intravenous BCG administration were elevated 7 days after treatment, but the NK activity of spleen lymphocytes was decreased. On the other hand, the NK activities of peritoneal and spleen lymphocytes were elevated in rats given intraperitoneal BCG. Spleen lymphocytes and peritoneal lymphocytes from rats given intravenous BCG suppressed tumor growth in the Winn test during the early tumor-bearing stage. The spleen lymphocytes with low NK activity in rats given intravenous BCG strongly suppressed the NK activity of normal spleen lymphocytes.

In vivo and in vitro effects of Nocardia rubra cell wall skeleton on natural killer activity in mice.

The in vivo and in vitro effects of Nocardia rubra cell wall skeleton (N-CWS) on natural killer (NK) activity of spleen and peritoneal lymphocytes of C57BL/6 mice were studied. The NK activity of spleen and peritoneal lymphocytes against YAC-1 lymphoma cells and cultured B-16 melanoma cells peaked at 3 days after intraperitoneal or intravenous administration of N-CWS, and returned to the normal value 7 days later. The NK activity of spleen lymphocytes was augmented by in vitro incubation with N-CWS. The appropriate concentration of N-CWS for the in vitro stimulation of NK activity in spleen lymphocytes was 2-5 micrograms/ml.

Effect of chemotherapy on natural-killer activity and antibody-dependent cell-mediated cytotoxicity in carcinoma of the lung.

The effect of chemotherapy on natural killer (NK) activity and antibody-dependent cell-mediated cytotoxicity (ADCC) in 15 advanced carcinomas of the lung was examined with regard to the drug, dose, route and timing of administration. The relationship between the effect of chemotherapy on the prognosis for the patients, and the changes in NK activity and ADCC, was also analysed. The NK activity and ADCC in patients with poor prognosis were significantly subnormal, even before treatment. The NK activity and ADCC began to decrease 2 weeks after the initiation of treatment and reached the lowest level during the 3rd or 4th week in all patients. Thereafter, they returned to the pretreatment level in 8 patients with stabilized disease. In contrast, they were not restored in 7 patients with progressive disease and poor prognosis. In 4 patients it was found that the effect of chemotherapy with pepleomycin and carbazilquinone on NK activity and ADCC differed according to the drug used. From this pilot study it is suggested that NK activity and ADCC are valuable prognostic factors in patients with advanced carcinoma of the lung, and that detailed analysis of the effect of each anticancer agent on NK activity and ADCC is desirable for the establishment of better treatment regimens for advanced carcinoma of the lung.