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Biomedical subjects

K Orita

Publications and source records attributed to K Orita.

At least 289 records · Page 16Linked to original sources
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

Eradication of syngeneic tumor (Meth A fibrosarcoma) from mice by adoptive immunotherapy of immunized spleen cells induced by Corynebacterium parvum-pyridine extract residue.

Eradication of immunologically-syngeneic tumors was achieved by adoptive chemotherapy using effector cells induced by Corynebacterium parvum-Pyridine Extract Residue (CP-PER). A mixture of 2 X 10(6) Meth A cells and 0.1 mg CP-PER was subcutaneously inoculated into the back of donor BALB/c mice, with the result that their spleen cells showed an antitumor effect 10 to 13 days after the inoculation. These cells were used as immune cells. Recipient mice were inoculated with 1 X 10(6) Meth A cells, and 2 days later were administered cyclophosphamide. On the following day, 1 X 10(8) immune cells were adoptively transferred into the recipient mice. As a result, the tumor began to regress 7 to 12 days after the adoptive transfer. An immuno-histochemical study of the donors' spleens and the recipients' regressing tumors revealed that the ratio of L3T4+ T cells to Lyt-2+ T cells in the donors' spleens was increased and that the infiltrating cells in the recipients' tumors were mainly composed of L3T4+ T cells. This confirmed that the transfer of L3T4+ T cells led to the infiltration of L3T4+ T cells into the recipients' tumors, causing their eradication.

Animals↗
PubMed1988

Antitumor effect of combined intraperitoneal administration of human recombinant interferon-beta and interferon-gamma against intraabdominal carcinomatosis in nude mice.

The development of useful therapy for intraabdominal carcinomatosis originating from gastrointestinal cancer is an important theme in cancer therapy. We developed recently an experimental model of intraabdominal carcinomatosis in nude mice by intraperitoneal transplantation of human colon cancer cells (RPMI 4788). Using this model, we investigated the antitumor effects of recombinant human interferon (rIFN)-beta and rIFN-gamma administered singly or in combination. Treatment was initiated 2 days after CD-1 nude mice were inoculated intraperitoneally with 5 X 10(6) RPMI 4788 cells. Intraperitoneal administration for 10 consecutive days of either rIFN-beta (2.5 X 10(5) IU/mouse/day) or rIFN-gamma (2.5 X 10(5) JRU/mouse/day) resulted in a significant prolongation of survival compared with the saline control group [survival in the control: 41.8 +/- 5.6 days (mean +/- SD)]. Combined administration of rIFN-beta and rIFN-gamma for 10 days yielded a marked synergistic effect on the prolongation of survival (114.0 +/- 8.2 days). However, combined administration of rIFN-beta and rIFN-gamma in a single dose equal to the total dose given fractionally over 10 days did not yield a synergistic effect. These results suggest that daily administration of rIFN-beta and rIFN-gamma combined may provide a highly potent antitumor effect against human peritoneal carcinomatosis.

Animals↗
PubMed1988

Prolongation of cardiac allograft survival in rats by treatment with anti-interleukin 2 antiserum.

Interleukin-2 (IL2) is the obligatory signal for both T cell mitogenesis and in vitro generation of alloreactive cytotoxic T lymphocytes (CTL). An investigation was made to determine whether an antibody directed against IL2 would suppress the rejection reaction of rat cardiac allografts. Rabbit anti-interleukin 2 (anti-IL2) antiserum was obtained by immunizing at 2 week intervals over a period of 8 weeks with 10(6) U of recombinant human IL2 along with complete Freund's adjuvant. The bioassay for inhibition of IL2 activity by anti-IL2 antiserum was carried out in conjunction with the IL2-dependent cytotoxic T cell (CTLL cell) assay. Cardiac allografts of F344 rats were heterotopically transplanted into ACI rats. Seven daily doses of 1 ml of anti-IL2 antiserum were administered intravenously following transplantation. IL2-driven [3H]thymidine incorporation in CTLL cells was significantly inhibited by rabbit anti-IL2 antiserum. Graft survival in the anti-IL2 serum-treated group was significantly prolonged in a dose-dependent fashion compared to control groups. In conclusion, these results indicate that rabbit anti-IL2 antiserum may prove to be of significant value as an immunosuppressive agent in clinical organ transplantation.

Animals↗
PubMed1988

Effects of insulin and glucagon on energy and carbohydrate metabolism of rat hepatocytes in primary culture.

We studied the effects of insulin and glucagon on energy and carbohydrate metabolism of rat hepatocytes in primary culture. The aim of this study is to elucidate the mechanism of the synergistic action of insulin and glucagon and to evaluate the combined effects of these hormones on liver injury. Insulin increased the level of adenosine triphosphate in hepatocytes in the presence of glucagon. Insulin increased the activities of glucokinase (EC 2.7.1.1), phosphofructokinase (EC 2.7.1.11), pyruvate kinase (EC 2.7.1.40) type L and glucose 6-phosphate dehydrogenase (EC 1.1.1.49). Glucagon had no antagonistic effect on these increases. Glucagon increased the activity of glucose 6-phosphate (EC 3.1.3.9) (G6Pase) in the presence or absence of insulin, while insulin had no effects on the levels of G6Pase and fructose 1,6-bisphosphatase (EC 3.1.3.11) in the presence or absence of glucagon. Metabolite analysis of cultured hepatocytes indicated that insulin and glucagon have antagonistic effects on the glycolytic activity of hepatocytes. These combined effects of insulin and glucagon may partially explain the preventive effects of these hormones on liver injury.

Animals↗
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

Effects of a single donor-specific blood transfusion on the survival of rat cardiac allografts.

It is now well recognized that pre-transplant donor-specific blood transfusion (DST) has a beneficial effect on the survival of allografts. To determine the optimal interval between DST and transplantation, and to analyze the mechanisms of this effect, the survival of cardiac allografts to rats which received a single DST was examined. The cardiac allograft survival was found to be prolonged when the DST was performed 1 to 6 weeks before grafting. In addition, recipient rat sera collected 1 to 6 weeks after a single DST showed significant inhibition of a mixed lymphocyte reaction (MLR). This MLR inhibition correlated with prolongation of survival of histoincompatible rat cardiac allografts. It thus appears that a single DST given from 1 to 6 weeks before transplantation has a beneficial effect on allograft survival and that MLR inhibition may be essential for inducing the effect of transfusion on organ transplantation.

Animals↗
PubMed1988

[Combination chemotherapy including cisplatin in lung cancer by bronchial artery infusion].

Chemotherapy with bronchial artery infusion (BAI) was given to 34 patients with primary lung cancer. Treatment regimens usually employed cis-diammine-dichloroplatinum (CDDP) plus peplomycin for squamous cell carcinoma, and CDDP plus vindesine for adenocarcinoma. The provisional therapeutic effects were evaluated roentgenographically with reference to histological type, T factor and degree of vascularization. Out of 10 cases of squamous cell carcinoma, 7 cases (70%) showed tumor regression greater than 50%, in contrast to 4 of 17 cases (23.5%) of adenocarcinoma. The effects in cases of squamous cell carcinoma were correlated with tumor vascularity. Twenty-two surgically treated cases were examined for the histological effects of BAI. Five of 6 cases (83.3%) of squamous cell carcinoma showed IIb effects by Shimosato's criteria. These results showed that the therapeutic effect of BAI was excellent in cases of squamous cell carcinoma in comparison with cases of adenocarcinoma. Serious side effects including esophago-bronchial fistula, massive hemoptysis and esophageal ulcer were observed in 4 cases.

Adenocarcinoma↗
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

[Large scale production of natural lymphokines with antitumor activity (OH-1) using transplantable human cell lines and its clinical use].

OH-1, consisting of purified natural human TNF-alpha and natural human IFN-alpha induced from BALL-1 cells stimulated with HVJ, has been obtained in large scale using Hayashibara's hamster method and has synergistically enhanced antitumor activity against wider spectrum of tumor cells, in vitro and in vivo. One of the action mechanism of OH-1 is clarified to be a result of arrest in the S phase of the cell cycle. In phase I study of OH-1 by intravenous administration to 23 patients with different advanced and/or metastatic malignant tumors, OH-1 shows the similar side effects to that of IFN-alpha without serious ones. The maximum tolerant dose is assumed as over 2,000 x 10(4) U/body. The early phase II clinical study of OH-1 is now on going, in which OH-1 shows anti-tumor effect with intravenous administration of over 200 x 10(4) U/body/day. As a preliminary result, OH-1 in dose of over 200 x 10(4) U/body/day to 62 patients with disseminated or advanced solid tumor shows an efficacy rate of 21.0%; CR in one patient of breast cancer and PR in three patients each of breast cancer, hepatocellular carcinoma and renal-cell carcinoma and PR in three other advanced cancer.

Animals↗
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↗
PubMed1988

Radical block resection of hepatoduodenal ligament for carcinoma of the bile duct with double catheter bypass for portal circulation.

A new concept of radical block resection of the hepatoduodenal ligament for carcinoma of the bile duct and new double bypass technique of portal circulation for the procedure were introduced. Clinical experiences of six patients were reported. By combined use of radical block resection of the hepatoduodenal ligament and double bypass technique, the radical resectability of carcinoma of the bile duct became a reality, and improvement of postoperative survival rate is expected.

Biliary Tract Neoplasms↗
PubMed1988

A subrenal capsule assay for testing the effect of anticancer drugs against human tumors.

Fresh surgical explants of solid tumors obtained from 50 patients were tested against six chemotherapeutic agents in the in vivo subrenal capsule assay. Control growth adequate to meet evaluable assay criteria was obtained in 36 of 50 tumors (72.0%). With activity criteria set at current drug screening levels as a change in modifidd PAPAN score in less than or equal to -2.0 for the SRC assay, 36.1% of the human tumors evaluable and 11.6% of drugs tested were sensitive, respectively. Our research reveals that gastric cancers respond to drugs about 2.5-fold higher than colorectal cancers. Comparisons were made of the drug sensitivity in terms of histologic differentiation, and it was strongly suggested that the sensitivity of the poorly differentiated type was higher than that of well or moderately differentiated type.

Adenocarcinoma↗