Biomedical subjects

A Tohgo

Publications and source records attributed to A Tohgo.

49 records · Page 3Linked to original sources

PubMed1989

Effect of combined intrapleural administration of Lactobacillus casei (LC9018) and adriamycin on experimental malignant pleurisy in mice.

The combined effect of Lactobacillus casei YIT9018 (LC9018) and adriamycin (ADR) on malignant pleurisy was investigated using an experimental model in BALB/c mice in which Meth A fibrosarcoma cells were intrapleurally implanted. The control mice died from dyspnea due to pleural effusion, before significant growth of tumor nodules could be achieved in the thoracic cavity. Intrapleural (ipl) administration of LC9018 (20-200 micrograms/head) on days 1 and 5 reduced the effusion volume and induced pleural adhesions in a dose-related manner. A statistically significant and reproducible prolongation of survival was observed at a dose of LC9018 200 micrograms/head: increase of lifespan (ILS) values of 15-39% were obtained. An ipl administration of ADR (2-4 mg/kg) on day 1 was also effective in prolonging survival without severe toxicity (ILS values of 100-122%). The combined use of ADR and LC9018 induced a high incidence of pleural adhesions, a delay in effusion accumulation, and an additive prolongation of lifespan (ILS values of 133-178%), compared with ADR monotherapy. In the combination therapy group, a marked and continuous ipl exudation of neutrophils, macrophages, and lymphocytes was observed with a significant decrease in pleural tumor cells. These findings suggest that ipl administration of LC9018 enhances the effect of ADR, probably through both host-mediated tumoricidal activity and sclerosing effects on the pleura.

Animals↗

PubMed1987

Inhibitory effects of heparin plus cortisone acetate on endothelial cell growth both in cultures and in tumor masses.

A combination of heparin and cortisone acetate significantly inhibited both embryonic angiogenesis and the tumor growth of Lewis lung carcinoma (3LL) transplanted into C57BL/6 mice, although each of these agents used alone affected neither angiogenesis nor tumor growth. On the other hand, this combination neither decreased the number of metastatic foci in the lung nor prolonged the survival time of mice with 3LL. All tumor-bearing mice died of hemothorax due to pulmonary metastases. Cortisone acetate by itself increased metastasis, and addition of heparin did not affect accelerated metastasis. Because an antiangiogenic activity appears independent of metastasis acceleration by cortisone acetate, the use of steroids other than cortisone acetate having no metastasis-promotion effect should be required for an antiangiogenic tumor therapy in the presence of heparin. Heparin plus cortisone acetate prevented the DNA synthesis of cultured vascular endothelial cells but not that of cultured 3LL cells. Additionally, oral administration of this combination decreased the [3H]thymidine labeling of endothelial cells of tumor blood vessels prior to the suppression of tumor growth. The specific inhibition of the growth of endothelial cells by heparin plus cortisone acetate was revealed in both the in vitro and the in vivo tests.

Animals↗

PubMed1986

Inhibitory effects of anti-angiogenic agents on neovascularization and growth of the chorioallantoic membrane (CAM). The possibility of a new CAM assay for angiogenesis inhibition.

Protamine sulfate and combinations of heparin-cortisone acetate known as having anti-angiogenic activities impaired the growth of chorioallantois at the dose inducing no decrease in growth rate of the embryos. This inhibitory effect of the agents is presumed to be mediated by the specific inhibition of the growth of endothelial cells forming chorioallantoic blood vessels based on the following results: significant correlations were found between the length of CAM vessels measured by an automatic image analyzer and the estimated volumes of chorioallantois (correlation coefficient r = 0.94) and these agents specifically inhibited the (3H)-thymidine incorporation into cultured endothelial cells at the dose having no effects on that into cultured chick embryonic cells. On the other hand, all DNA-synthesis inhibitors, mitomycin C, 5-fluorouracil, and paraformaldehyde suppressed the growth of both CAM and embryo and resulted in early embryonic death, which might be due to the nonspecific impairment of DNA synthesis by these agents. These results indicate the possibility that the present CAM assay could screen agents having anti-angiogenic activity.

Allantois↗

PubMed1986

Platelet-aggregating activities of metastasizing tumor cells. V. In situ roles of platelets in hematogenous metastases.

Intravenous inoculations of B16 cells having high procoagulant, thrombingenerating, and platelet-aggregating (PA) activities resulted in severe platelet reduction and fibrin-rich thromboembolism in the lungs, whereas those of 3LL cells, whose activities were moderate, caused only moderate changes. MH134 cells with low procoagulant, no thrombin-generating and moderate PA activities induced moderate platelet reduction and the formation of thrombi containing less fibrin. In contrast to the respective high and moderate colonizing abilities of B16 and 3LL cells, MH134 cells failed to form lung colonies in half of the recipients. Thrombocytopenia markedly impaired lung colonization by B16 and 3LL cells. However, thrombin injection enhanced lung colonization by MH134 cells.

Animals↗

PubMed1986

Platelet-aggregating activities of metastasizing tumor cells. IV. Effects of cell surface modification on thrombin generation, platelet aggregation and subsequent lung colonization.

Platelet-aggregating and thrombin-generating activities of B16 and 3LL cells were inhibited by trypsin, phospholipase A2 and by heating, but not by neuraminidase. It was confirmed that the platelet aggregation effect of these cells is due to thrombin generation. The lung-colonizing ability of treated cells injected intravenously was directly proportional to the ability to generate thrombin and to aggregate platelets. These results suggest that B16 and 3LL cells aggregate platelets through thrombin generation probably via their heat-labile surface lipoprotein, and that emboli composed of platelets, fibrin, and tumor cells may aid further the metastatic process.

Animals↗

PubMed1985

Platelet-aggregating activities of metastasizing tumor cells. III. Platelet aggregation as resulting from thrombin generation by tumor cells.

Thrombin generated in the process of platelet aggregation induced by three metastasizing murine tumors was measured using a chromogenic substrate specific for thrombin. Addition of B16 cells or 3LL cells to the platelet-rich plasma induced the generation of a significant amount of thrombin during the lag period preceding aggregation, while that of MH134 cells did not. Thrombin generation was observed in both the presence and the absence of platelets, indicating that platelets are not necessarily required for thrombin generation by these tumor cells. This suggests that the adherence of platelets to tumor cells is not an essential step for the initiation of thrombin-mediated aggregation induced by B16 and 3LL cells. Furthermore, the results of a one-stage clotting assay using plasma deficient in coagulation factors indicated that B16 and 3LL cells generated thrombin through direct activation of factor X.

Animals↗

PubMed1984

Platelet-aggregating activities of metastasizing tumor cells. II. Variety of the aggregation mechanisms.

The mechanisms by which B16, 3LL and MH134 tumor cells induce platelet aggregation were studied. The B16 and 3LL tumors, which have high or moderate procoagulant activities, aggregated platelets only in the presence of Ca2+ and plasma factors. MH134, which had much lower procoagulant activity, aggregated platelets even in the absence of these factors. The induction of aggregation by B16 and 3LL could be prevented by thrombin inhibitors but not by the ADP scavenger, suggesting that thrombin, generated by procoagulant activities of tumor cells themselves, might play a major role in initiating aggregation. MH134-induced aggregation was not affected by any of the inhibitors, indicating that the mechanisms by which MH134 initiate platelet aggregation are independent of both thrombin and ADP.

Adenosine Diphosphate↗

PubMed1983

Effects of human fibroblast interferon on human gliomas transplanted into nude mice.

Daily intratumor injection of human fibroblast interferon (HuIFN-beta) resulted in significant growth inhibition of human gliomas transplanted into nude mice. Light and electron microscope examinations were conducted to estimate the efficacy of HuIFN-beta. A 29-day daily treatment with HuIFN-beta induced complete regression of oligodendroglioma KG-1--a slowly growing tumor line positive for S-100 protein and negative for glial fibrillary acidic protein (GFAP)--in 9 out of 10 mice receiving 6 X 10(5) IU and 6 out of 9 given 1 X 10(5) IU. In mice with glioblastoma multiforme TMIMS-583, which showed more rapid growth and was positive for GFAP, dose-dependent growth inhibition was observed during 23 days of HuIFN-beta administration. Pathological changes of TMIMS-583 induced by HuIFN-beta were characterized by a decrease of the metaphase tumor cells, by enhanced degeneration of tumor cells with stromal reaction and round cell infiltrates, and by prominence of multinuclear giant cells containing glial filaments. Tumor weights were well correlated with the number of tumor cells in the metaphase (r = 0.89).

Adult↗

PubMed1983

Cytostatic action of human fibroblast interferon in direct growth inhibition: effect on human malignant melanoma.

The mode of action of the direct antiproliferative effect of human fibroblast interferon (HuIFN-beta) on tumor cells was analyzed in vitro with a human malignant melanoma cell line, HMV-1. HuIFN-beta inhibited the growth of HMV-1 cells in a time-dependent fashion (50%-inhibition concentration: less than 50 IU/ml). Its action was cytostatic. DNA synthesis was inhibited before the antitumor effect appeared, and apparent dose-dependent inhibitions of RNA and protein synthesis were induced. An increase of cell protein content was seen with the occurrence of growth inhibition. Increase of cell volume and prolongation of doubling time were seen from the second day after the addition, which corresponded well with the effects of HuIFN-beta on the cell cycle (the accumulation of cells in the S phase). These results indicate that the direct antitumor effect of HuIFN-beta on HMV-1 cells may result from cell cycle retardation mediated through obstruction of DNA synthesis.

Cell Cycle↗

PubMedDate not supplied

Quantification of experimental pulmonary metastases by image analyzer.

Image analysis techniques for quantifying experimental pulmonary metastases were developed using Lewis lung carcinoma (3LL) and B16 melanoma. Binary images of the metastatic colonies were differentiated by staining the lung parenchyma. Thus, it became possible for the image analyzer to determine automatically the size and number of the metastatic foci. Image analysis was used successfully to evaluate the inhibitory effect of adriamycin on spontaneous metastases of 3LL. Although the inhibitory effect was not detected by the usual counting method, a significant reduction of the area of metastatic foci was detected by image analysis.

Animals↗

PubMedDate not supplied

Effects of DN-9693, a new metastasis inhibitor, on murine hematogenous metastasis.

1,5-Dihydro-7-(1-piperidinyl)-imidazo[2,1-b]quinazolin-2(3H)-one dihydrochloride hydrate (DN-9693), a new c-AMP: phosphodiesterase inhibitor was examined for its inhibitory effects on platelet aggregation induced by metastasizing tumor cells and on blood-borne metastases of these tumors. 1-3 microM of DN-9693 completely inhibited platelet aggregation induced by B16 melanoma subline BL6 and Lewis lung carcinoma (3LL) cells. Platelets prepared from mice intravenously or orally administered with DN-9693 failed to aggregate after the addition of BL6 cells. Intravenous injection of DN-9693 was effective in protecting the mice inoculated with 1 X 10(6) BL6 cells against acute pulmonary embolic death. Either intravenous or oral administration of DN-9693 (1-10 mg/kg) sufficiently suppressed thrombus formation and subsequent pulmonary metastasis caused by intravenously inoculated BL6 or 3LL cells. Spontaneous pulmonary metastasis of 3LL was also inhibited by DN-9693. Continuous administration of DN-9693 during and after surgical excision of the primary tumors was the most effective treatment against the development of pulmonary metastases of 3LL.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

DT-5461a, an antitumor synthetic lipid a analog, causes selective blood flow reduction in tumor tissue.

We previously reported that a synthetic low-toxicity lipid A analog, DT-5461a, exhibited a significant antitumor effect was characteristically accompanied by extensive tumor necrosis, suggesting that DT-5461a causes a local circulatory disturbance in tumor tissues. In this study, we investigated the effect of DT-5461a on regional blood flow in various organs including tumor tissue with a radiolabeled tracer-distribution technique using 14C-iodoantipyrine. Intravenous administration of DT-5461a induced blood flow reduction in Meth A tumor subcutaneously implanted into BALB/c mice, but not in liver, spleen or lung of these mice. This tumor tissue-specific reduction in blood flow was significantly inhibited by pretreatment with antisera against tumor necrosis factor (TNF) alpha, interferon (IFN) alpha/beta, and IFN gamma. These results indicate that endogenously induced cytokines, namely TNF alpha and IFNs, are involved in the intratumor blood flow reduction caused by DT-5461a.

Animals↗

PubMedDate not supplied

Systemic administration of a synthetic lipid A derivative, DT-5461a, reduces tumor blood flow through endogenous TNF production in hepatic cancer model of VX2 carcinoma in rabbits.

Intravenous administration of DT-5461a, synthetic low-toxicity lipid A derivative, significantly inhibited the growth of VX2 tumor transplanted in the liver of rabbits. DT-5461a induced high levels of TNF activity in tumor tissue from 30 to 60 min after the administration, while no TNF activity was detected in the adjacent nontumorous liver tissue. Simultaneous measurement of microcirculatory blood flow in both tumorous and nontumorous regions in the liver by laser doppler velocimetory revealed that intravenous administration of DT-5461a caused a significant blood flow reduction in tumor region, but not in nontumorous counterparts. Tumor blood flow was significantly reduced by 40 to 60% at 30 to 90 min after the DT-5461a administration as compared with preadministration value. In contrast, local administration of human recombinant TNF alpha through the hepatic artery induced blood flow reduction not only in tumor region but also in nontumorous liver tissue. These results suggest that systemic administration of DT-5461a induced selective tumor microcirculatory blood flow reduction via local endogenous TNF production.

Animals↗