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Biomedical subjects

S Fuchimoto

Publications and source records attributed to S Fuchimoto.

At least 55 records · Page 3Linked to original sources
PubMed1989

The effect and distribution of a protein-bound polysaccharide preparation, PSK (Krestin), intratumorally injected prior to surgery into gastric cancer patients.

In order to improve the postoperative prognosis of gastric cancer patients we have performed preoperative endoscopic intratumoral administration of various biological response modifiers. In the present study we have investigated the kinetics and the immune response augmenting effect of intratumorally injected PSK, a protein-bound polysaccharide preparation, by immunohistochemical methods using anti-PSK antibody and various other antibodies. PSK-containing cells were located in the tumor tissues and follicular marginal zones of regional lymph nodes. Intratumorally administered PSK appeared to be phagocytized by the histiocytes and to cause them to become antigen-presenting cells. These cells may play a major role in augmenting immune responses in gastric cancer patients.

Adult↗
PubMed1989

Antitumor effect of natural human tumor necrosis factor-beta against Lewis lung carcinoma in mice and its synergistic potentiation by interferon.

We investigated the antitumor effect of purified natural human tumor necrosis factor-beta (nHuTNF-beta) produced by human acute lymphoblastic leukemia BALL-1 cells stimulated with HVJ on pulmonary metastatic tumors of Lewis lung carcinoma (3LL) transplanted into BDF1 mice. nHuTNF-beta showed antiproliferative effects on metastatic tumors in a dose-dependent manner when administered daily for 10 days by the intravenous route. Histological examination of the tumors treated with nHuTNF-beta revealed that the tumor size and number of metastases were much reduced. Lytic cellular changes, including cytoplasmic vacuolation, loosening of the intercellular junction and both cytoplasmic and nuclear swelling, were found, but tumor necrosis was not. These findings indicate a therapeutic effect of Grade IIa according to the histological criteria of Shimosato and Ohboshi. In addition, synergistic augmentation of the antiproliferative effects of nHuTNF-beta by natural murine interferon-alpha/beta (nMu-IFN-alpha/beta) or recombinant murine interferon-gamma (rMuIFN-gamma) was recognized by median effect plot analysis. The results suggested that nHuTNF-beta may well deserve clinical trial as a new immunotherapeutical agent for human cancer.

Animals↗
PubMed1989

Synergistic antitumor effects of natural human tumor necrosis factor-alpha and natural human interferon-alpha or -gamma on human cancer cell lines.

This study was conducted to assess the enhanced antitumor effects of natural human tumor necrosis factor alpha (nHuTNF-alpha) and natural human interferon alpha or gamma (nHuIFN-alpha or -gamma), in combination, on ten human cancer cell lines. The cell lines tested were colon cancer (RPMI4788), lung cancer (PC10), gastric cancer (MKN-1 and MKN-28), nasopharyngeal cancer (KB), leukemia (K562), lymphoma (Daudi), Liver cancer (H-7) and breast cancer (ZR-75-30 and ZR-75-1). A mixture of nHuTNF-alpha and nHuIFN-alpha (1:1, by unit) showed cytotoxic effects on nHuTNF-alpha resistant cell lines such as RPMI4788, KB and Daudi or nHuIFN-alpha resistant cell lines such as KB, and ZR-75-1, as well as on nHuTNF-alpha or nHuIFN-alpha sensitive cells. A synergistic antitumor effect occurred in four cell lines (RPMI4788, PC10, Daudi and ZR-75-1) treated with a combination of nHuTNF-alpha and nHuIFN-alpha. Also, a combined treatment with nHuTNF-alpha and nHuIFN-gamma (1:1/100, by unit) showed cytotoxic effects on nHuTNF-alpha or nHuIFN-gamma resistant cell lines such as MKN-1, MKN-28, Daudi, H-7 and ZR-75-1. A synergistic antitumor effect occurred in eight cell lines (RPMI4788, PC10, MKN-1, MKN-28, KB, Daudi, H-7 and ZR-75-1). Thus, the combined treatment with nHuTNF-alpha and nHuIFN-alpha or -gamma expanded the spectrum of sensitive cells. These results indicate that the combined use of nHuTNF and nHuIFN may provide a certain approach to cancer treatment.

Antineoplastic Agents↗
PubMed1989

Histopathologic evaluation of response to treatment of human tumors implanted under the renal capsule of normal immunocompetent mice.

The histopathologic changes following chemotherapy treatment of fresh human tumors implanted under the renal capsule of normal immunocompetent mice were evaluated. On the basis of the histopathologic profile of the xenografts, four parameters were recognized: (1) cancer area (C), (2) necrosis area (N) (each measured by image analysis), (3) pathologic effect of cancer cells (P) (assessed histopathologically), and (4) number of mitoses (M) (counted microscopically), and were scored in a semiquantitative fashion from 0 to 2 or 4. The drug sensitivity (S) was scored using the following formula: S = C + P + M - N; this score varied from -4 to 10. Histopathologic changes represent a sensitive indicator of the response of implanted human tumors under the renal capsule to anticancer drugs. Availability and correct interpretation of the post-treatment histopathologic picture is of importance in selecting the proper combination treatment which would maximize tumor response.

Adenocarcinoma↗
PubMed1989

[The effect of endoscopical intratumoral injection of OK-432 in gastric carcinoma].

Many BRMs (biological response modifiers) have been used for post-operative immunochemotherapy. And their usefulness were also reported. Nevertheless it is still unknown that which route, how much doses and which timing are the most effective to administer these drugs. We used BRMs intratumorally and preoperatively. To reconfirm the efficacy of intratumoral injection therapy randomized study was performed in gastric carcinoma. Three hundred and ninety-five cases were entered, 199 cases in group A which were treated preoperatively with OK-432 intratumorally and 196 cases in group B which were control, respectively. In the cases which had marked infiltration of lymphoid cells in tumor sites, the two year survival rate of group A was significantly better than that of group B (p less than 0.05). On the study of recurrent forms, the distal lymph node metastasis was markedly decreased in group A. The ratio of metastasis to the distal lymph nodes in group A was 5-10% lesser than that in group B on the each depth of tumor invasion. The ratio of lymph nodes metastasis was almost similar in the each group, but the number of metastatic lymph nodes was significantly reduced in high grade tumor infiltrated cases in group A (p less than 0.005). These results suggest that preoperative endoscopically intratumoral administration of OK-432 suppresses the lymph node metastasis and improves the postoperative survival rate.

Biological Products↗
PubMed1989

[The metastatic tumor and immunotherapy].

Metastasis is one of the great characteristics of malignant tumors. On the basis of our data, we reported here the immunotherapy for hematogenous metastasis. A randomized controlled study of preoperative transendoscopic intratumoral injection of BRM into gastro-intestinal cancer, which was performed in our Department, revealed a decreasing tendency of distant metastases in lymph node for the injection group, suggesting the disappearance of micro-metastasis due to the injection, namely, systemic immuno-enhancement due to the local effect, leading to diminution of hematogenous metastasis. Next, a mixture of natural human TNF-alpha (nHuTNF-alpha) and natural human IFn-alpha(nHuIFN-alpha), the so-called OH-1, was described. The results of a clinical study dealing with the antitumor effect on advanced and recurrent malignant tumors made it clear that all of the effective results (72 cases) such as CR and PR were obtained by an administration schedule with a maintenance dose of more than 200 X 10(4)U; rate of efficacy was 19.4% (4 cases of CR, 10 of PR and 4 of MR). By disease, breast cancer, renal cancer and liver cancer evidenced the most remarkable effects. Examination of the antitumor effect by metastatic organ revealed the effectiveness on hematogenous metastasic tumor of lung, bone and liver, though dependent upon underlying diseases. Finally, being based on our in vitro and in vivo results, we discussed the role of these immunotherapies for metastatic tumors.

Humans↗
PubMed1989

Suppression of lymphokine activated killer (LAK) cells by immunosuppressive substance.

We investigated the effect of immunosuppressive substance (ISS) on the immune responses mediated by interleukin 2 (IL 2). The induction of LAK cells was intensely inhibited by a high concentration of ISS (1000 micrograms/ml), but a low concentration of ISS (250-500 micrograms/ml) had no affect on the generation of LAK cells. ISS had no ability either to neutralize the activity of IL 2, or to compete with IL 2. Endogenous production of IL 2 in PHA response was not reduced by ISS, but the expression of the IL 2 receptor in the PHA response was significantly suppressed by ISS. These results suggest that ISS exerts its inhibitory effect on immune response-mediated IL 2 through modification of the IL 2 receptor.

Cell Division↗
PubMed1989

Comparison of the subrenal capsule assay and succinate dehydrogenase inhibition test.

Fresh surgical explants of solid tumors obtained from 50 patients were tested against the same chemotherapeutic agents in both the in vivo subrenal capsule (SRC) assay and the in vitro succinate dehydrogenase inhibition (SDI) test. Control growth adequate to meet evaluable assay criteria was obtained in 36 of 50 tumors tested in the SRC assay (72.0%). In the SDI test, 46 of 50 tumors were evaluable (92.0%). Correlations between the two test systems were dependent upon the activity criteria established for each system. With activity criteria set at current drug screening levels as a change of less than or equal to -2.0 in modified PAPAN score (S) for the SRC and an inhibition of greater than or equal to 50.0% in succinate dehydrogenase activity (SD) for the SDI, 12.5% of the drugs tested were active in the SRC and 22.3% were active in the SDI. Correlations of tumor response between the two test systems were 31.7% for sensitive (13/41) and 95.1% for resistant (98/103).

Antineoplastic Agents↗
PubMed1988

Interferon-gamma activates the voltage-gated calcium channel in RPMI 4788 cells.

Interferon (IFN) increases cytoplasmic free calcium ([Ca2+]i) in RPMI 4788 cells, a human colon cancer cell line. Addition of IFN to the cells loaded with Fura-2, a fluorescent Ca2+ indicator, causes an immediate increase in [Ca2+]i, which is the earliest event after IFN stimulation. A cyanine dye, dis-C3- (5) was used to determine the effects of IFN on the membrane potential in cancer cells. The depolarization was seen with IFN-gamma, but not with IFN-beta. These results taken together, suggest that the IFN-gamma and -beta induced [Ca2+]i mobilization are clearly different in their dependence on Ca2+ entry through voltage-gated Ca2+ channels.

Calcium↗
PubMed1988

Hyperthermic enhancement of the antitumor effect of natural human tumor necrosis factor-alpha and -beta: an in vitro and in vivo study.

A synergistic antitumor effect of natural human tumor necrosis factor-beta (TNF-beta) in combination with hyperthermia was found, in comparison with that of TNF-alpha, using an in vitro antiproliferative assay on a human colon cancer cell line (RPMI4788) and an in vivo tumor growth inhibition assay on Meth A sarcoma cells. In vitro combined treatment with TNF-beta (10,000 U/ml) and hyperthermia (at 43 degrees for 60 min) synergistically inhibited the proliferation of the cells. Combined effects of TNF-alpha or natural human interferon-alpha or -gamma (IFN-alpha, -gamma) and hyperthermia were also examined, and furthermore, the combinations of TNFs and IFNs were examined in combination with hyperthermia at 42 degrees; their antiproliferative effects were further augmented by hyperthermia. In vivo growth of Meth A sarcoma cells (5 x 10(5)), transplanted subcutaneously into BALB/c mice, was inhibited significantly (P less than 0.05) with the combination of TNF-alpha or -beta (2 x 10(5) U/mouse) and hyperthermia (at 43 degrees for 60 min) as compared to either a single intravenous injection of TNF-alpha or -beta alone or the hyperthermia alone. The influence of TNF-beta and hyperthermia on the cell cycle was examined. Flow cytometric analysis showed that RPMI4788 cells treated with TNF-alpha or -beta accumulated in the S phase of the cell cycle, and that hyperthermia (at 42 degrees for 60 min) alone had no influence on the cell cycle and did not augment the S phase accumulation of the cells treated with TNF-alpha or -beta.

Animals↗
PubMed1988

Synergistic effect of natural human tumor necrosis factors alpha and beta in the clonogenic assay.

We tested the antiproliferative effect induced by the natural human tumor necrosis factors alpha and beta (nHuTNF-alpha, -beta) or a combination of these in the clonogenic assay. The antiproliferative effects were evaluated by examining the inhibition of clonogenic growth of RPMI-4788 cells, which had been established from a human colon cancer. TNF-alpha and -beta were natural human types produced by a B cell leukemia line (BALL-1 cells) and were both over 99% pure. The antiproliferative effect in combination of nHuTNF-alpha and -beta was analysed by using the median effect plot and the combination index. The results indicate a synergism between two factors.

Cell Division↗
PubMed1988

Comparison of the subrenal capsule assay and succinate dehydrogenase inhibition test as drug sensitivity tests for cancer.

The same chemotherapeutic agents were tested against fresh surgical explants of solid tumors obtained from 50 patients using the in vivo subrenal capsule (SRC) assay and the in vitro succinate dehydrogenase inhibition (SDI) test in comparison. Control growth adequate to meet evaluable assay criteria was obtained in 36 of the 50 tumors tested in the SRC assay (72.0%). In the SDI test, 46 of 50 tumors were evaluable (92.0%). Correlations between the two test systems were dependent upon the activity criteria established for each system. With activity criteria set at a change of less than or equal to -2.0 in the drug sensitivity score for the SRC assay and greater than or equal to 50.0% inhibition of succinate dehydrogenase activity for the SDI test, 12.5% of the drugs tested were active in the SRC assay and 22.3% were active in the SDI test. Correlations of tumor response between the two test systems were 31.7% for sensitivity (13/41) and 95.1% for resistance (98/103). In spite of the fundamental difference between the SRC assay and SDI test, meaningful correlations between the test results and clinical tumor responses in both test systems were obtained. This fact suggests that the two methods are complementary to each other.

Animals↗
PubMed1988

[Favorable response of advanced hepatocellular carcinoma to proper hepatic arterial administration of cytokines and the significance of the administration].

The objectives in administering anti-cancer therapeutics to the feeding artery of the tumor are to allow the agent to come in direct contact with the tumor cells, to lower the concentration of the agent in body circulation, to lessen the severity of side effects, and to augment efficacy of the agent. A remarkable partial regression was observed in two patients with advanced hepatocellular carcinoma, both at the stage in which surgical excision was diagnosed impossible; one was given successive and daily bolus administration of OH-1, a anti-tumor agent consisting of natural human tumor necrosis factor-alpha (nHuTNF-alpha) and natural human interferon (nHulFN-alpha), and the other a successive and daily combined bolus administration of OH-1 and 5-FU. On investigating the role of the anti-cancer activity of OH-1 by analyzing the NK activity of rat liver large granular lymphocytes, we found that the NK activity was suppressed dose-dependently by nHuTNF-alpha, but not significantly. Thus, an increase in TNF dose in hepatic artery therapy seems undesirable from the standpoint of NK activity. The authors are presently carrying out investigations to elucidate the effector mechanism of the anticancer activity of OH-1.

Animals↗
PubMed1988

[Monitoring of the effect of anticancer drugs on the membrane potential and cytoplasmic free calcium ion mobilization in cancer cells as a drug sensitivity test].

When the plasma membrane capacity to maintain an ionic gradient is correlated with the cell viability, the anticancer drug-induced-cation (K+, Ca2+) mobilization, an early event associated with cell death, might be used as a rapid in vitro drug sensitivity test. A cyanine dye, dis-C3-5, was used to determine the membrane potential (Em), which was calculated as the following formula; Em = -RT/F In ([K+] in/[K+] out) in cancer cell lines. The change in cytoplasmic free calcium ion ([Ca2+]i) mobilization induced by the drugs was measured by fluorescent dye Fura2-AM. The results suggest that the sensitive drug, which showed greater than or equal to 50% inhibition of succinate dehydrogenase activity in SDI test, induced greater than or equal to 30% fall of membrane potential after 2 hour exposure to the drugs and also induced [Ca2+]i mobilization. On the other hand, the resistant drug showed no change of Em and [Ca2+]i.

Antineoplastic Agents↗
PubMed1988

Therapeutic potential of natural human tumor necrosis factor-alpha in combination with natural human interferon-alpha or -gamma on human cancer cells.

We assessed the antiproliferative effects of natural human tumor necrosis factor alpha (nHuTNF-alpha) and natural interferon alpha and gamma (nHuIFN-alpha and -gamma), either alone or in combination, on human lung, colon, breast cancer, leukemia and lymphoma cell lines (PC10, RPMI4788, ZR-75-1, K562 and Daudi). PC10 and ZR-75-1 were minimal sensitive (30-50% inhibition) to nHuTNF-alpha. PC10 and RPMI4788 were sensitive to both nHuIFN-alpha and -gamma. K562 and Daudi were resistant to nHuTNF-alpha and also to nHuIFN-alpha and -gamma at the concentration tested. The combination treatment with nHuTNF-alpha and nHuIFN-alpha or -gamma showed the marked antitumor effects in four cell lines (PC10, RPMI4788, ZR-75-1 and Daudi). Though further investigations using fresh tumors or in vivo experiments need to be conducted, our results may have therapeutic implications.

Antineoplastic Agents↗
PubMed1988

[Drug sensitivity and cellular potassium release of cancer cells].

The tumor lysis syndrome, consisting of severe hyperkalaemia, hyperphosphatemia and hypocalcemia, occurs after the effective induction chemotherapy of rapidly growing responsive tumors. The metabolic abnormalities are thought to be secondary to the release of intracellular products. For the purpose to examine quantitative relation between cellular potassium release and drug sensitivity, we compare the inhibition of valinomycin (K-ionophore)-induced-hyperpolarization (MPR Test) with that of succinate dehydrogenase activity (SDI test). Our present research revealed a high correlation of MPR test and SDI test, and suggested the significant association of drug sensitivity with potassium release from cancer cells. Therefore, it seems appropriate to monitor potassium levels when therapy of a responsive tumor is initiated.

Animals↗