Polysaccharide Kureha Research Articles

Preoperative administration of polysaccharide Kureha and reduced plasma transforming growth factor-β in patients with advanced gastric cancer: A randomized clinical trial.

Systemic abrogation of TGF-β signaling results in tumor reduction through cytotoxic T lymphocytes activity in a mouse model. The administration of polysaccharide-Kureha (PSK) into tumor-bearing mice also showed tumor regression with reduced TGF-β. However, there have been no studies regarding the PSK administration to cancer patients and the association with plasma TGF-β. PSK (3 g/day) was administered as a neoadjuvant therapy for 2 weeks before surgery. In total, 31 advanced gastric cancer (AGC) patients were randomly assigned to group A (no neoadjuvant PSK; n=14) or B (neoadjuvant PSK therapy; n=17). Plasma TGF-β was measured pre- and postoperatively. The allocation factors were clinical stage (cStage) and gender. Plasma TGF-β ranged from 1.85-43.5 ng/ml (average, 9.50 ng/ml) in AGC, and 12 patients (38.7%) had a high value, >7.0 ng/ml. These patients were largely composed of poorly-differentiated adenocarcinoma with pathological stage III/IV. All the six elevated cases in group B showed a significant reduction of plasma TGF-β (from 21.6 to 4.5 ng/ml, on average), whereas this was not exhibited in group A. The cases within the normal limits of TGF-β remained unchanged irrespective of PSK treatment. Analysis of variance showed a statistically significant reduction in the difference of plasma TGF-β between groups A and B (P=0.019). PSK reduced the plasma TGF-β in AGC patients when the levels were initially high. The clinical advantage of PSK may, however, be restricted to specific histological types of AGC. Perioperative suppression of TGF-β by PSK may antagonize cancer immune evasion and improve patient prognosis in cases of AGC.

Maturation of morphology, phenotype and functions of murine bone marrow-derived dendritic cells(DCs) induced by polysaccharide Kureha(PSK)

The aim of this work was to evaluate the influence of protein-bound polysaccharide Kureha(PSK) on murine dendritic cells (DCs). These impacts of PSK on DCs from bone marrow derived DCs(BMDCs) were assessed with inverted phase contrast microscope, conventional scanning electron microscopy (SEM), transmission electron microscopy (TEM) for morphology, fluorescence activated cell sorting (FACS) analysis, cytochemistry assay for key surface molecules, FITC-dextran for phagocytosis, bio-assay and enzyme linked immunosorbent assay (ELISA) for cytokine production. We found that under the influence of PSK, immature DCs changed into mature DCs with decrease of antigens up-taking, simultaneously high expression of key surface molecules of the MHC classII,CD40, CD80, CD86 and CD83 as well as more production of IL-12p70 and tumor necrosis factor α (TNF-α). These data indicate that PSK could markedly promote maturation of DCs and this adjuvant-like activity may have potential therapeutic value in vaccine preparation.

Efficacy of Postoperative UFT (Tegafur/Uracil) Plus PSK Therapies in Elderly Patients with Resected Colorectal Cancer

To establish the sufficient therapy for elderly colorectal cancer patients, we retrospectively compared postoperative Tegafur/Uracil (UFT; Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) and UFT plus protein-bound polysaccharide kureha (PSK) therapies in elderly patients with resected colorectal cancer. A total of 63 patients were collected; 39 patients were administered only with UFT (control group) and 24 patients were treated with UFT+PSK (PSK group). There were no differences in patient background, surgical outcomes, and drug compliance between the two groups. The 3-year relapse-free survival rate was 47.8% in the control group and 76.2% in the PSK group (p = 0.041). The 3-year overall survival (OS) rate was 52.8% in the control group and 80.8% in the PSK group (p = 0.0498). By subset analysis, in the patients whose tumor location was the colon (p = 0.016) and whose preoperative lymphocyte percentage was below 18.7% (p = 0.017), RFS was significantly better in the PSK group. Adverse drug reactions were rarely observed. All the adverse reactions were grade 2 or below, with no severe reactions. The present retrospective study suggests a possible efficacy of postoperative adjuvant therapy with UFT plus PSK in elderly patients over 70 years of age with resected colorectal cancer.

Immunochemotherapy with PSK and Fluoropyrimidines Improves Long-Term Prognosis for Curatively Resected Colorectal Cancer

Long-term survival, which extends beyond 5 years, is a desired outcome for colorectal cancer patients. In the present study, we retrospectively compared the 10-year overall survival between the control group and the polysaccharide kureha (PSK) group and analyzed the factors influencing the prognosis. The control group was treated exclusively with oral fluoropyrimidines, whereas the PSK group was treated with fluoropyrimidines, given in conjunction with PSK for 24 months. The 10-year survival rates for the PSK group (81.9%) were significantly superior to those of the control group (50.6%). In Dukes' C cases, the 10-year overall survival rates for the PSK group were also significantly higher than those of the control group. In cases with lymphatic invasion graded ly2-ly3 or venous invasion graded v2-v3, the 10-year overall survival rates were 80.6% in the PSK group, which were significantly superior, compared to 25.9% in the control group. Analysis by Cox's proportional hazard model showed a significant difference between the control and PSK groups. These results indicate that postoperative adjuvant immunochemotherapy with PSK greatly improves prognosis at 10 years. On the basis of these results, we recommend postoperative adjuvant immunochemotherapy combined with PSK for patients with Dukes' C and in cases with ly2-ly3 or v2-v3 invasion.

Regulation of perioperative immunological changes following laparotomy: effects of biological response modifier (BRM) on surgical stress

Immune responses have been reported to decline following surgical stress, leading to an increased susceptibility to infection or to the growth of tumors. In this study, we report that pre-operative treatment with the biological response modifier (BRM) polysaccharide Kureha (PSK) can inhibit the decline of immunocompetence during the perioperative period. BALB/c mice were laparotomized, the intestinal tracts were exposed to room air for 1.5 h, and then the abdomens were closed. Six hours after the operation, the spleen and serum were collected. The concentrations of IL-6 in the serum and of IFNγ and IL-4 in the supernatant of splenocyte cultures were measured. In the surgical stress group that received surgical stress and the PSK treatment, the serum IL-6 concentration was significantly elevated in the group with surgical stress. PSK treatment controlled the stress-induced elevation. IFNγ concentrations were measured in the supernatant of Concanavalin A (Con A) stimulated splenocyte cultures. It was lower in the group with surgical stress than in the cultures derived from the non-treated group. The IFNγ concentration in the group with surgical stress plus PSK treatment was significantly higher than the level in the group with surgical stress alone. The IL-4 concentration was significantly lower in the surgical stress group than in the control group, however, the concentration tended to be higher in the surgical stress plus PSK treatment group than in the group with surgical stress alone. The IFNγ/IL-4 ratio in the group with surgical stress was lower than the ratio in the non-treated group. The ratio in the group with surgical stress plus PSK treatment was significantly higher than the ratio in the group with surgical stress alone. These results suggest that PSK restores the abnormality of the biological responses induced by surgical stress and corrects the reduced Th1/Th2 cytokine balance to a normal level.

担癌マウスに対するＩＬ‐２，ＰＳＫ併用投与による抗腫よう効果に関する研究

担癌マウスに対するＩＬ‐２，ＰＳＫ併用投与による抗腫よう効果に関する研究

Effect of PSK, a protein‐bound polysaccharide preparation, on liver tumors of Syrian hamsters induced by Thorotrast injection

The contrast medium Thorotrast, an agent well known to be carcinogenic, was injected into 400 congeneic Syrian hamsters. The resulting incidence of malignant hepatic tumors such as cholangiocarcinoma, hepatocellular carcinoma and hemangiosarcoma, was significantly higher in the male experimental group than in the control group, and the 50% survival period in the male group was shortened by about 100 days (P < 0.01). However administration of the antitumor drug PSK (Polysaccharide Kureha), a protein bound-polysaccharide extracted from basidiomycete fungi, prevented this carcinogenic effect. The incidence of malignant hepatic tumors in the experimental group was 22.5% compared with 2.8% in the control group (P < 0.01) and 10.5% in the PSK-treated group (P < 0.01). PSK also increased the 50% survival period by 61 days (P < 0.01).

Antitumor effect of a Coliolus preparation, PSK: induction of macrophage chemotactic factor (MCF) in spleens of tumor bearing mice.

The effect of administration of PSK (Polysaccharide Kureha), a Coliolus preparation, in Meth-A solid tumors was analyzed in BALB/c mice. Spleen cells prepared from normal, non-treated Meth-A bearing, PSK-treated normal and PSK-treated tumor bearing mice were examined for induction of macrophage chemotatic factor (MCF). Only spleen cells from the latter mice produced MCF after 48 hrs of cultivation in the presence of Meth-A cells or concanavalin A (Con A). MCF-producing cells were indicated to be Lyt-1 positive, L3T4 positive and Lyt-2 negative cells in the negative elimination assay. There were no differences in the production of other cytokines including interleukin-2, interferon and tumor necrosing factor, spleen cells obtained other different groups of mice. The antitumor effect of either crude or purified MCF (molecular weight 100,000) was examined by daily consecutive intratumoral injections into Meth-A tumor tissues, and a significant inhibitory effect was detected.

Activation by the Protein-Bound Polysaccharide PSK (Krestin) of Cytotoxic Lymphocytes that Act on Fresh Autologous Tumor Cells and T24 Human Urinary Bladder Transitional Carcinoma Cell Line in Patients with Urinary Bladder Cancer

PSK, a protein-bound polysaccharide Kureha, was tested for its ability to modulate the cytotoxicity of lymphocytes that act on autologous tumor cells and T24 human urinary bladder tumor cells in urinary bladder cancer patients in a 6-h 51Cr release assay. In vitro treatment of peripheral blood lymphocytes (PEL) with PSK for 18hours resulted in an augmentation or induction of cytotoxicity against relatively resistant T24 cells in previously reactive and nonreactive cases, respectively. The PSK-treated PBL were able to kill more effectively tumor cells that were freshly isolated from the same cancer patients than non-treated PBL. The effects of PSK were noted with PBL as well as tumor infiltrating lymphocytes (TIL) and with PSK at concentrations of 10 to 100μg./ml., while PSK at higher doses reduced their lytic activities. The addition of PSK to the assay at the same concentrations also enhanced the cytotoxicities. Autologous tumor killing (ATK) activities of both large granular lymphocytes (LGL) and T lymphocytes were enhanced by PSK. Treatment of PBL with PSK did not effect on the proportion of PBL binding to the tumor cells, while it augmented the cytotoxic activity. Cell-free supernatant of PSK-stimulated lymphocyte culture did not contain any detectable amounts of interferon-α (IFN-α), interferon-γ (IFN-γ) and interleukin-2 (IL-2). In addition, anti-IFN-α monoclonal antibody (MAb), anti-IFN-γ MAb and anti-IL-2 MAb did not inhibit PSK-induced agumentation of cytotoxicity against T24. Oral administration of PSK (three gm./day) to patients with urinary bladder cancer daily for seven days before operation resulted in an augmentation of the cytotoxicity against T24 cells in five out of 10 patients and no change of the cytotoxicity In the other five patients. ATK activity was also enhanced by oral administration of PSK in three out of five patients. These results indicate that the antitumor activity of PSK may be in part mediated through activation of tumor killing system independent of IFN-α, IFN-γ and IL-2.

Observation of cellular immunity in head and neck cancer patients during adjuvant immunochemotherapy by Polysaccharide Kureha (PSK)

Observation of cellular immunity in head and neck cancer patients during adjuvant immunochemotherapy by Polysaccharide Kureha (PSK)

Effects of the Antitumor Agents from Various Natural Sources on Drug-Metabolizing System, Phagocytic Activity and Complement System in Sarcoma 180-Bearing Mice

Correlation between antitumor activity and effects on some biological properties, such as phagocytic activity of the reticuloendothelial system, the third component of complement (C3) activation, hepatic drug-metabolizing activities and pentobarbital-induced narcosis, of antitumor agents from various natural sources such as B B (Broncasma Berna), GU-P (Grifora umbellata polysaccharide), OK-432, PS-K (Polysaccharide Kureha), and RA-P (Rumex acetosa polysaccharide) were studied with female ICR mice implanted with Sarcoma 180 solid tumor. All of these agents depressed aniline hydroxylase and aminopyrine demethylase activities, prolonged the duration of pentobarbital-induced narcosis, and significantly enhanced the phagocytic activity and C3 activity. Especially, RA-P which has the strongest antitumor activity was the most effective in changing these activities. The biological activities of GU-P at a dose of 10 mg/kg reached the same level as that found with PS-K at a dose of 100 mg/kg. A possible mechanism of inhibition of Sarcoma 180 solid tumor growth by the treatment with the antitumor agents could be interpreted as due to the C3 activation, the stimulation of phagocytic activity and .depression of the hepatic microsomal drug-metabolizing system in tumor-bearing mice.

Screening of host-mediated antitumor polysaccharides by crossed immunoelectrophoresis using fresh human serum.

On crossed immunoelectrophoresis, human serum C3 (the third component of complement) converted by antitumor polysaccharides (ATSO [antitumor polysaccharide oral], AB-P [Agaricaus blazei polysaccharide], GU-P [Grifora umbellata polysaccharide], PS-K [polysaccharide Kureha] and zymosan) moved faster than native C3, appearing as the 3rd peak. The ratio of height of the 3rd peak to the alpha 2-macroglobulin (alpha 2-M) peak was linearly proportional to the dose of ATSO. At the dose of 500 micrograms/ml antitumor polysaccharides, the ratios were higher than 0.76, and the ratios for the serum treated with polysaccharide of no antitumor activity (dextran and gum arabic) were less than about 0.52. This ratio readily determined in vivo can be used as a measure for the antitumor activity of polysaccharides.

SCREENING OF H O ST-MEDIATED ANTITUMOR POLYSACCHARIDES BY CROSSED IMMUNOELECTROPHORESIS USING FRESH HUMAN SERUM

On crossed immunoelectrophoresis, human serum C3 (the third component of complement) converted by antitumor polysaccharides (ATSO [antitumor polysaccharide oral], AB-P [Agaricausblazei polysaccharide], GU-P [Griforaumbellata polysaccharide], PS-K [polysaccharide Kureha] and zymosan) moved faster than native C3, appearing as the 3rd peak. The ratio of height of the 3rd peak to the α2-macroglobulin (γ2-M) peak was linearly proportional to the dose of ATSO. At the dose of 500 μg/ml antitumor polysaccharides, the ratios were higher than 0.76, and the ratios for the serum treated with polysaccharide of no antitumor activity (dextran and gum arabic) were less than about 0.52. This ratio readily determined in vivo can be used as a measure for the antitumor activity of polysaccharides.

Acceleration by BCG and PS-K of the rejection of male skin grafts by female mice

BCG, protein-bound polysaccharide Kureha (PS-K) and levamisole which have been used in tumor immunotherapy were studied for the effect on the rejection of male skin grafts by female mice. The graft rejection was significantly accelerated by one s.c. injection of BCG (5×105 microorganisms/mouse) into recipients on the day of transplantation. PS-K injected 250 mg/kg s.c. or i.p. once every other day from the day of transplantation significantly stimulated the graft rejection. Oral administration of 1000 mg/kg PS-K by the same schedule was also effective. Levamisole 20 mg/kg injected s.c. once on the day of transplantation was without any effect.From these results it is concluded that PS-K has an immunostimulant action similar to that of BCG. This property may be important to the antineoplastic activity of PS-K.

Experimental study of immunochemotherapy of brain tumors--experimental brain tumor model and immunochemotherapy by a combination of PS-K and ACNU (author's transl)

Syngeneic brain tumor cell lines were made from inbred Wistar King Aptekman/HKM (WKA/HKM) rats using ethylnitrosourea in our laboratory. Ethylnitrosourea was injected intravenously at a dose of 50 mg/kg into pregnant rats. Two kinds of tumor cell lines were established from offsprings after cell culture. One was mixed glioma which was named KEG-1, and the other was neurinoma which was named KEN-1. A immunochemotherapeutic study was attempted using KEG-1 cell lines. ACNU was injected intraperitoneally as chemotherapy. PS-K (protein-bound polysaccharide Kureha isolated from Basidiomycetes) was administered intraperitoneally as immunochemotherapy. Animals were divided into the following four groups. Group 1 : Five×104 viable cells of KEG-1 were inoculated to the right caudate nucleus on day 0. All rats receiving tumor cells died, with a mean survival time of 19.8 days. Group 2: ACNU was injected intraperitoneally at a dose of 20 mg/kg on day 3. Mean survival time was 32.6 days, showing a 64 percent increase. Group 3: PS-K was injected intraperitoneally at a dose of 300 mg/kg, according to the time schedule. PS-K alone did not affect the mean survival time. Group 4: Five different timings of the combination of chemotherapy and immunotherapy (group (a) to (e)) were investigated in this group. Group (a) animals received PS-K on days 0, 1 and 2 before ACNU. Mean survival time was 32.6 days showing no increase compared to ACNU alone. Group (b) animals received PS-K on days 0, 1, 2, 3, 4 and 5 before and after ACNU. Mean survival time was 39.3 days, showing a 97.8% increase compared to controls. Group (c) animals received PS-K on days 0, 1, 2, 6, 7 and 8 before and after ACNU. Mean survival time was 37.2 days, showing an 87.8% increase. Group (d) animals received PS-K on days 3, 4 and 5 after ACNU. Mean survival time was 37.3 days, showing an 88.4% increase. Group (e) animals received PS-K on days 6, 7 and 8 after ACNU. Mean survival time was 38.0 day, showing a 91.9% increase. A marked effect was obtained when PS-K was injected before and after ACNU or after ACNU. When PS-K was injected before ACNU the mean survival time did not show any increase compared with that for ACNU alone. It appears that PS-K enhanced the rat's immunity which was suppressed by ACNU. The immunity of the rats was not enhanced when PS-K was administered before ACNU since the biological activity of PS-K might be short lasting. It is suggested that therapeutic effects are not always augmented if immunotherapy is combined with chemotherapy at random, but it depends on the timing of the combination.

Effects of BCG, levamisole and PS-K on the rejection of male skin grafts by female mice

Rejection of male skin grafts by BALB/c female mice was accelerated by one s.c. injection of BCG (5 X 10(5) microorganisms/mouse) into recipients on the day of transplantation. Levamisole 20 mg/kg injected similarly was without any effect. Protein-bound polysaccharide Kureha (PS-K) injected 250 mg/kg s.c. or i.p. once every other day from the day of transplantation stimulated graft rejection. The s.c. route was more effective than the i.p. route. These results show that, in sex-linked graft rejection in mice, PS-K has an immunostimulant action similar to that of BCG. This property may be important to the antineoplastic activity of PS-K.

173 - Effects of BCG, levamisole and PS-K on the rejection of male skin grafts by female mice

Rejection of male skin grafts by BALB/c female mice was accelerated by one s.c. injection of BCG (5×105 micro-organisms/mouse) into recipients on the day of transplantation. Levamisole 20 mg/kg injected similarly was without any effect. Protein-bound polysaccharide Kureha (PS-K) injected 250 mg/kg s.c. or i.p. once every other day from the day of transplantation stimulated graft rejection. The s.c. route was more effective than the i.p. route.