Effects of FK 506 on in vivo immunity in comparison to cyclosporine.
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Animals↗
Biomedical subjects
Y Nio
Publications and source records attributed to Y Nio.
[A double blind study to evaluate the optimal dose and its frequency for oral administration of OK-432 (picibanil) by immunological parameters (the 2nd report)].
The present study was designed to determine the optimal dose and frequency of oral administration of a biological response modifier, OK-432 (Picibanil), which has been used for cancer immunotherapy by injection. Ninety one stomach cancer patients were randomly assigned into 7 groups and were administered a placebo or OK-432 at a dose of 5, 20 or 40KE, once or 3 times a week before operation (5KE X 1/W, 20KE X 1/W, 40KE X 1/W, or X 3/W). Misregistration excluded 3 patients and the data of 88 patients were analysed. There was no significant difference in the background status of the patients in each group. In the 1st report, we already showed that 5KE X 3/W might be the optimal regimen to augment the natural killer (NK) activity of regional lymph node lymphocyte (RNL). In the 2nd report, we searched for the optimal regimen to augment the antitumor immunity of T lymphocytes. The proliferative response of RNL to SuPR (protein derived from OK-432) was augmented in all the groups administered OK-432. The responsiveness of PBL to autologous tumor extract enhanced by IL-2 was augmented by 5KE X 1/W, and that of RNL was augmented by 5KE X 3/W. The killer/suppressor (Leu2+15-/Leu2+15+) ratio in RNL increased in all the groups administered OK-432 especially in 20KE X 3/W group. Oral administration of OK-432 augmented both non-specific and the specific antitumor immunity of PBL as well as RNL, and 5KE X 3/W may be the optimal regimen to augment the antitumor immunity, especially of RNL.
Administration, Oral↗
[A double blind study of the evaluation of the optimal dose and its frequency in oral administration of OK-432 (Picibanil) by immunological parameters (the 1st report)].
A biological response modifier, OK-432 (Picibanil) administered by injection has been used for cancer immunotherapy. The present study was designed to determine the optimal dose and frequency of oral administration of OK-432. Ninety-one stomach cancer patients were randomly assigned into 7 groups and were administered a placebo or OK-432 at a dose of 5, 20 or 40 KE, once or 3 times a week before their operation (5 KE X 1/W, 20 KE X 1/W, 40 KE X 1/W, or X3/W). ++Missregistration excluded 3 patients and the data of 88 patients were analysed. There was no significant difference in the background status of the patients in each group. The NK activity of PBL was augmented by the administration of 40 KE X 1/W or 20 KE X 3/W and that of RNL was augmented by the administration of 5 KE X 3/W or 40 KE X 1/W, in conjunction with an increase in the number of % positive cells of leu 11a+ or leu 19+ analysed by flow cytometry. The killing activity of PBL, RNL, or MNL against allogeneic lined gastric cancer cells (KATO III) was not augmented by the oral administration of OK-432 for one week. The skin reactivity to Su-PS or PPD, serum levels of tumor markers, or serum levels of immunoglobulins did not help in determining the optimal dose or its frequency. These results suggest that 5 KE X 3/W may be the optimal regimen to augment the antitumor immunity of RNL.
Administration, Oral↗
[Chemotherapy with fluoropyrimidines for MOPC-104E plasmacytoma transplanted in mice with CCl4 induced chronic liver dysfunction].
The masked compounds of 5-fluorouracil (5-FU) have been widely used for chemotherapy in digestive organ cancer. Among them it has been considered that FT (Tegafur) is metabolized into the active form by the drug-metabolizing enzyme P-450 in the microsomes of hepatocytes, and that their activation and anti-tumor activity may decrease under the condition of chronic liver dysfunction. However, this hypothesis has never been experimentally proved. In the present study the therapeutic effect and metabolism of 5-FU and its masked compounds: FT, UFT (uracil + FT), HCFU (Carmofur), 5'-DFUR (Doxifluridine) were assessed by using MOPC-104E plasmacytoma transplanted subcutaneously in BALB/c mice with CCl4-induced chronic liver dysfunction. Agents were administered daily directly into the stomach with stainless steel canule over days 7 to 13 after tumor transplantation, and the tumor weights, drug concentrations in the liver or the tumor, and serum levels of GOT, GPT and LDH were measured on day 14. In mice with chronic liver dysfunction the tumor-inhibitory effect of 5-FU, FT, UFT and HCFU did not necessarily decrease and serum levels of GOT, GPT and LDH of mice administered with 5-FU, FT, HCFU and 5'-DFUR were higher than in normal animals treated with them. By contrast UFT had no influence on them. The most remarkable difference was observed in uracil concentrations, which were significantly lower in the tumor and the liver of mice with chronic liver dysfunction than in those of normal mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Chemosensitivity correlation between the primary tumors and simultaneous metastatic lymph nodes of patients evaluated by DNA synthesis inhibition assay.
The chemosensitivities of primary tumors (PT) and simultaneous metastatic lymph nodes (MN) to mitomycin C (MMC), 5-fluorouracil (5-FU), Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), carboquone (CQ), or cisplatin (CDDP) were assessed in a group of 29 patients (11 gastric, 8 colorectal, 4 breast, and 6 other cancers) by a DNA synthesis (3H-thymidine incorporation) inhibition assay. PT and MN from the same patient showed heterogeneity in chemosensitivity. MN were more sensitive to the agents than PT. PT were sensitive to 5-FU, whereas MN were sensitive to CDDP. An analysis of the sensitivity correlations showed that the sensitivities of PT to MMC, 5-FU, CQ, and CDDP correlated with each other, but ADR sensitivity correlated with only CQ sensitivity. The sensitivities of MN correlated with each other, except for those to ADR and CDDP. In contrast, MMC, ADR, or CQ sensitivity showed a correlation between PT and MN. These results suggest that patients should be treated according to the sensitivity of the target lesion. However, if the sensitivity assay is not available, the sensitivity correlation may be useful when choosing the agent. It also may be important that ADR sensitivity does not correlate with the sensitivities of other agents.
Breast Neoplasms↗
Orally administered streptococcal preparation, OK-432 augments the antitumor immunity of patients with gastric or colorectal cancer.
A streptococcal preparation, OK-432, was orally administered at a dose of 5 KE to patients with gastric or colorectal cancer for 7-14 days before their operations, and its immunomodulatory effects on peripheral blood lymphocytes (PBL), regional node lymphocytes (RNL) and tumor infiltrating lymphocytes (TIL) were assessed. The group treated with OK-432 included 8 gastric and 6 colorectal cancer patients, and the control group included 8 gastric and 8 colorectal cancer patients. The NK cell activity of PBL was significantly augmented by the oral administration of OK-432, and the proportions of Leu 7+ and Leu 11+ cells in PBL also increased. The responses of PBL and TIL to autologous tumor extracts in the presence of interleukin-2 were enhanced after the oral administration of OK-432. The proportion of OKT8+ cells in PBL increased after treatment with oral OK-432, whereas the proportion in RNL significantly decreased. These results indicate that oral OK-432 affects NK and T cells and may augment the antitumor immunity of patients with gastrointestinal cancer.
Administration, Oral↗
Cycloheximide-induced modulation of TNF-mediated cytotoxicity in sensitive and resistant ovarian tumor cells.
The mechanism of sensitivity and resistance of various ovarian carcinoma lines to recombinant tumor necrosis factor (rTNF)-mediated cytotoxicity has been investigated using a 24-h 51Cr-release assay. The cell line PA-1 is sensitive to TNF in a dose-dependent manner, whereas the cell line SKOV-3 is resistant to TNF even at high concentrations. The simultaneous addition of TNF and cycloheximide (CHX) in the assay converted the resistant SKOV-3 line into a sensitive line, but no detectable change was observed with PA-1. rTNF inhibited DNA, RNA, and protein synthesis of the sensitive PA-1 line, whereas it had no effect on SKOV-3. This finding was not due to differences in the expression of TNF receptors, as both cell lines expressed equivalent numbers of receptors. The addition of CHX to TNF resulted in suppression of DNA, RNA, and protein synthesis in both the sensitive and the resistant cell lines. Pretreatment of the cell line with TNF for 3 h and subsequent washing resulted in significant cytotoxicity of the sensitive PA-1 line and some cytotoxicity against SKOV-3. However, if the cells were pretreated with CHX for 3 h followed by rTNF for 24 h, a significant decrease in cytotoxicity was observed in both cell lines. Under these conditions, there was no significant inhibition of DNA, RNA, or protein synthesis. Pretreatment of cells for 24 h with TNF and 24 h with CHX resulted in augmentation of the cytotoxicity of PA-1 and SKOV-3, whereas pretreatment for 24 h with CHX followed by 24 h with TNF resulted in no cytotoxicity. Cells pretreated with CHX for 24 h showed poor binding of [125]I-TNF and poor internalization, whereas cells pretreated for 24 h with TNF showed marked enhancement of internalization. The sensitivity of freshly derived ovarian carcinoma lines to TNF and CHX demonstrated that TNF-resistant cells became more sensitive if treated with CHX. These results demonstrate the potential use of metabolic inhibitors in increasing the sensitivity of fresh ovarian tumor cells to TNF.
Cell Survival↗
Increased number of suppressor T-cells and impaired IL-2 mediated T-cell function in peripheral blood of gastric cancer patients.
The present study was designed to investigate the mechanisms responsible for suppressed T-cell immunity in gastric cancer patients. The peripheral blood T-cell functions in gastric cancer patients were evaluated by measuring responses to PHA and IL-2, and T-cell subpopulations were assessed by flow cytometry. Both the PHA and IL-2 responses decreased in patients with gastric cancer, although the proportions of CD3+ and CD25+ cells were the same for gastric cancer patients and healthy volunteers. The PHA response, but not that of IL-2, was lower in patients with liver metastasis or peritoneal dissemination than in patients without these conditions. Single regression analysis showed that with lymph node involvement in the disease the IL-2 response was more strongly suppressed than PHA response. The serum level of IAP did not correlate with the response to either PHA or IL-2. The proportion of CD4+ cells was not affected by any factor related to gastric cancer, although CD4+/CD8+ and CD8+11b-/CD8+11b+ ratios did decrease in patients with distant lymph node involvement. These changes may be due to a comparative increase in suppressor cells. These results suggest that gastric cancer patients exhibit impaired IL-2 mediated T-cell function and that the number of suppressor cells may increase with progressive lymph node involvement. These two serial effects may be indeed responsible for the impaired blood T-cell function in patients with gastric cancer.
Adult↗
Sensitivity of ovarian tumor cells to effector cells generated by various biological response modifiers.
The sensitivity of freshly derived human ovarian tumors (FOT) to various allogeneic cytotoxic effector cells stimulated by recombinant interleukin 2 (rIL-2), recombinant interferon alpha 2 (rIFN-alpha 2), OK-432, and concanavalin A was examined using the 51Cr release assay. Peripheral blood lymphocytes (PBL) of normal female donors were used as source of effector cells. Incubation of PBL with these biological response modifiers for 24 h generated effector cells with high natural killer activity, and only 20% (1/5) of the FOT examined were susceptible to lysis. By contrast, 83% (5/6) of the FOT were sensitive to lymphokine-activated killer (LAK) cells generated by rIL-2. OK-432 and concanavalin A activation of PBL also generated cytotoxic cells, though the cytotoxic activity against FOT was much less than that obtained by LAK cells. The addition of OK-432 to LAK culture medium containing rIL-2 generated effector cells with higher cytotoxicity against FOT than cultures with IL-2 alone. However, the addition of rIFN-alpha 2 in LAK culture medium resulted in the generation of effector cells with lower cytotoxicity. The addition of rIL-2, rIFN-alpha 2, or OK-432 to LAK cells during the in vitro cytotoxicity assay had no significant effect. When FOT target cells were pretreated with OK-432 they became more sensitive to LAK than nontreated tumor cells. However, pretreatment with rIL-2 or rIFN-alpha 2 did not influence cytolysis. These results suggest that the generation of LAK cells in vitro using rIL-2 plus OK-432 may be a more effective way to prepare these cells for adoptive immunotherapy in the treatment of ovarian cancer.
Concanavalin A↗
[Oral administration of OK-432 (picibanil). (8th report) clinical application: its immunomodulatory effects on the patients with gastrointestinal cancers].
A streptococcal preparation, OK-432 at a dose of 5 KE was orally administered to the patients with gastric or colorectal cancer for 7 approximately 14 days before operation, and its immunomodulatory effects on peripheral blood lymphocytes (PBL), regional lymph node lymphocytes (RLNL) and tumor infiltrating lymphocytes (TIL) were assessed. OK-432 treated group included 5 gastric and 6 colorectal cancers, and control group included 6 gastric and 8 colorectal cancers. After oral administration of OK-432 the proportion of Leu 7+ and Leu 11+ cells in PBL increased, and NK cell activity of PBL also was augmented. The proportion of OKT8+ cells increased in PBL and those of OKT3+ cells and OKT8+ cells decreased in RLNL after oral administration of OK-432. The responsiveness of TIL to autologous tumor extracts in the presence of interleukin-2 was enhanced in oral OK-432 group. These results indicate that oral OK-432 affects on NK and T cells and augments the antitumor immunity of the patients with gastrointestinal cancer.
Administration, Oral↗
Cytotoxic and cytostatic effects of the streptococcal preparation OK-432 and its subcellular fractions on human ovarian tumor cells.
Previous studies have indicated that OK-432 is a potent biologic response modifier (BRM) and that it augments immune responses to tumor cells. We studied the direct effect of OK-432 on tumor cells. Established and freshly derived human ovarian carcinoma lines were examined for their susceptibility to OK-432 or its subcellular fractions in direct cytotoxicity, cytostatic activity, and inhibition of metabolic activity. OK-432 was cytotoxic to 13 of 15 freshly derived ovarian carcinoma lines in a 24-hour chromium-51 (51Cr) release assay. The optimal effect was noticed at OK-432 concentrations between 0.1 and 1.0 Klinishe Einhert (KE) per milliliter. The cytostatic effect on two established lines and one fresh line correlated with the cytotoxic activity. In all three lines, however, the metabolic activities (DNA, RNA, and protein synthesis) were inhibited by OK-432, suggesting that cell lysis by OK-432 may not be directly correlated with the inhibition of metabolic activities. Several subcellular fractions were derived from OK-432 and only the cytoplasmic and protoplast membrane fractions showed cytotoxic activity against the OK-432-sensitive tumor cell lines, although the cytotoxicity obtained was greatly less than the whole microorganism OK-432. The direct binding of 14C-OK-432 to tumor cells was examined. Binding took place rapidly after 1 hour of incubation and reached a maximum activity at 37 degrees C. Binding in all three lines ranged between 1.7 and 2.7 pg/cell. These results demonstrate the direct cytotoxic effect of OK-432 and some subcellular fractions on human ovarian carcinoma lines. These results also show that the BRM OK-432 may exert its effect by both potentiating the antitumor response and directly inhibiting tumor cell growth.
Biological Products↗
[Anti-tumor effect of fluoropyrimidines on human tumor cell lines transplanted in nude mice with CCl4-induced liver dysfunction].
Tegafur (FT) is a masked compound of 5-fluorouracil (5-FU) and supposed to be activated in the liver. The present study was designed to estimate anti-tumor effect of FT on human tumors transplanted in nude mice with liver dysfunction induced by CCl4. Histologically, cirrhotic changes of liver were observed after injection with 1ml/kg 10% CCl4 twice a week for 8 weeks. Mice were transplanted with human gastric (GC-SF) or colonic cancer (CC-ZK) lines, and daily administered intragastrically with 5-FU (15mg/kg), FT (100mg/kg) or UFT (FT 20mg/kg + Uracil 44.8mg/kg) for 4 weeks. The growth of GC-SF was enhanced by liver dysfunction, but that of CC-ZK was not affected. The mean growth inhibition rates (MGIR) of CC-ZK by 5-FU, FT or UFT were 18.3, 33.1 and 54.2%, respectively, in mice without liver dysfunction, and 14.0, 50.0 and 59.5%, respectively, in mice with liver dysfunction. The MGIRs of GC-SF were 39.0, 63.8 and 48.0%, respectively, in mice without liver dysfunction, and 12.6, 53.6 and 50.0%, respectively, in mice with liver dysfunction. In both lines effect of 5-FU was reduced in liver dysfunction, but those of FT and UFT was not. These results suggest that FT and UFT can be used for cancer patients with liver dysfunction.
Animals↗
Lymphocytes anticancer chemosensitivity testing in vitro--an approach to predict immunosuppressive effect of anticancer agents.
In an attempt to predict immunosuppression by chemotherapy, an in vitro lymphocytes chemosensitivity assay was developed. The effect of mitomycin C (MMC), carboquone (CQ), adriamycin (ADR) and 5-fluorouracil (5-FU) on spleen cells of BALB/c mice were assessed by phytohemagglutinin (PHA) response inhibition assay. ADR and 5-FU highly suppressed PHA response, whereas MMC or CQ had only a slight influence. The administration of ADR or 5-FU to mice resulted in a significant decrease of peripheral blood lymphocytes and cortical thymocytes in number, and pretreatment with ADR or 5-FU prior to tumor inoculation shortened the survival time of the mice. All these four agents highly suppressed in vitro DNA synthesis of MOPC-104E plasmacytoma, but ADR or 5-FU did not induce complete regression of the tumor. MMC or CQ induced complete regression of MOPC-104E, but they did not induce complete regression of the tumor transplanted in athymic nude mice. These results suggest that T cells participate in tumor regression and immunosuppression reduces antitumor activity of the host and that PHA response inhibition assay may be useful to predict immunosuppressive effect of anticancer agents.
Animals↗
Induction by cyclophosphamide administration of two distinct anti-tumor effector cells at tumor site and spleen of mice transplanted with MOPC-104E plasmacytoma.
BALB/c mice were inoculated intraperitoneally (i.p.) with MOPC-104E syngeneic plasmacytoma cells and seven days later the mice were treated with i.p. cyclophosphamide (CY). All mice exhibited a complete regression of MOPC-104E, and in addition acquired the resistance to second challenge of MOPC-104E, but not to syngeneic Meth-A fibrosarcoma. Following CY treatment, a large number of viable MOPC-104E cells were seen in the peritoneal cavity of the mice on day 7, and then they decreased and disappeared on day 14. By contrast, athymic BALB/c nude mice with MOPC-104E did not respond to CY and died. Only a transient decrease in the number of tumor cells was observed in the peritoneal cavity of nude mice. Following CY treatment, whole peritoneal cells (tumor cells and peritoneal exudate cells) was not transplanted to conventional mice, while transplantation was possible following treatment of whole peritoneal cells with anti-Thy1, anti-Lyt 1 or anti-Lyt 2 plus complement (C). The in vivo anti-tumor activity of spleen cells of mice in regression was nullified by treatment with anti-Thy 1 and anti-Lyt 1 plus C, but not anti-Lyt 2 plus C. These results indicate that CY administration results in only a transient decrease of tumor cell number and that an induction of Lyt 1 +, Lyt 2 + T cells in the peritoneal cavity and Lyt 1 + T cells in spleen may be responsible for a complete disappearance of tumor cells.
Animals↗
[Immunity of gut-associated lymphoid tissue and the role of the oral immunotherapy in multi-disciplinary treatment of the digestive organ cancer].
In order to augment antitumor immunity of gut-associated lymphoid tissue in digestive organ cancer, oral administration of various biological response modifiers were studied using mice transplanted with cecal tumor. Among them OK-432 was the most effective and clinical application of oral OK-432 was studied. Autoradiogram and immunofluorescence studies showed the absorption of orally administered OK-432 from the gut. In phase I study oral OK-432 was much less toxic than other administration routes. Phase II study showed that oral OK-432 at various doses augmented antitumor immunity of the lymphocytes of peripheral blood and regional lymph node. In a multi-institutional study on postoperative adjuvant immunotherapy, 1011 gastric cancer patients were accumulated and randomized to compare the effects of oral and intradermal OK-432. In patients who underwent curative operation, 1-, 2- and 3-year survival rates (%) were 95, 88 and 82 for oral OK-432 group (n = 255), 88, 83 and 80 for the placebo group (n = 260), and 89, 79 and 73 for intradermal OK-432 group (n = 261). There was significant differences among cumulative survivals of three groups, and this life-prolonging effect of oral OK-432 was remarkable for stage II or III patients. These results demonstrate that oral immunotherapy with OK-432 is useful as an immunotherapy of digestive organ cancers.
Administration, Oral↗
[Immunomodulating effects of oral administration of PSK. II. Its effects on mice with cecal tumors].
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Adjuvants, Immunologic↗
Sensitivity of fresh and cultured ovarian tumor cells to tumor necrosis factor, interferon-alpha 2, and OK-432.
The in vitro sensitivity to rTNF, rIFN-alpha 2, and OK-432 of 11 freshly derived human ovarian tumors and 2 established tumor cell lines was examined in a cytotoxic assay using the 51 Cr release test. Nine fresh lines were sensitive to rTNF, 8 to OK-432, and only 2 were sensitive to rIFN-alpha 2. Cytotoxicity by rIFN-alpha 2 was of lesser magnitude than the cytotoxicity mediated by rTNF or OK-432. The time of exposure and the concentration of BRM required for maximal cytotoxicity varied from line to line. Two fresh tumor cell lines and 1 established cell line (PA-1) were sensitive to all 3 BRMs, while 2 other FOCs and 1 cell line (SKOV-3) were resistant to all BRMs. The remaining FOC showed an intermediate degree of sensitivity. These results demonstrate the existence of heterogeneity of ovarian carcinoma tumor cell lines to lysis by BRMs. Among the FOCs, the 2 endometrioid carcinomas tested were highly sensitive to rTNF, whereas the serous carcinomas were more sensitive to OK-432. Low grade tumors were more sensitive to BRM than high grade tumors, and tumor extension did not correlate with sensitivity to the BRM. When tumor targets were exposed to more than 1 BRM added either simultaneously or sequentially, the net cytotoxic effect achieved was usually inferior to the sum cytotoxicity obtained by each BRM alone. Furthermore, rTNF and OK-432 were cytostatic to most ovarian tumor cell lines examined. The results of this study demonstrate that certain BRMs exert a direct effect on fresh ovarian tumor cells independently of host factors. These findings suggest that in vitro screening of a patient's tumor cells for sensitivity to a particular BRM prior to therapy could be beneficial for the proper identification of patients most likely to benefit from the treatment.
Antineoplastic Combined Chemotherapy Protocols↗
Immunologic control of ovarian cancer.
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Clinical Trials as Topic↗