We have already reported antitumor activities of fungal and bacterial polysaccharides on mice. In the present experiment, the influence of the sex on antitumor effects on such material from Grifola umbellata, Coriolus versicolor Fries or Sargassum thumbergii and the immunity of mice against tumor were investigated. The growth velocities of Sarcoma 180, Ehrlich solid carcinoma, Pulmonary tumor 7423 and MF-sarcoma bearing mice both without treatment and those treated with polysaccharides were more rapid in males than in females. The regression rates in mice with the above tumors were higher in females than in males. However, a few DS Mie mice with Sarcoma 180 and A/Jax Mie mice with Ehrlich solid carcinoma regressed spontaneously. The growth velocity of Shionogi carcinoma 42 was not influenced by the sex. On other hand, both males and females which had experienced a regression of ascites tumor after the administration of polysaccharides rejected the re-implanted Ehrlich ascites carcinoma, Sarcoma 180, NF-sarcomma and Shionogi carcinoma 42. These results suggest that a strong ehancement of immune response occurs in the tumor implanted in the host animal by the administration of polysacchrides. The combination of X-ray irradiation Ehrlich ascites cells and polysacchrides strengthens the antitumor effect of NF-sarcoma and Shionogi carcinoma 42. Peritoneal exudate cells and lymphocytes were compared between the male and female mice after being treated with ATSO and P.GU-1. Such cells were present to a much greater extent in females.
To investigate the mechanism of tumor growth enhancement induced by operative stress in rats, laparo-thoracotomy was performed on day 2 after tumor cell inoculation associated with administrations of various kinds of immunopotentiators. OK-432 (Streptococcal preparation), PS-K (extract from mycelium of Coriolus Versicolor), Lentinan (extract from Lentinus Edodus) and C. parvum were administered intravenously or intraperitoneally in the fractionated form prior to or after inoculation. In general, administration of each immunopotentiator, except for Lentinan, resulted in a recovery from the reduction in survival days after laparo-thoracotomy. In particular, OK-432 administration prior to inoculation showed a significant improvement.
A polysaccharide preparation isolated from Coriolus versicolor (Fr.) Quél. of Basidiomycetes (PSK) predominantly consists of glucan and approximately 25% tightly bound protein. PSK was effective against various allogeneic and syngeneic animal tumors and has been given orally to cancer patients. Various suppressed or enhanced immune responses of tumor-bearing animals were restored to normal levels by the administration of PSK in the tumor models tested. The killer T cell activity was augmented in tumor-bearing mice by intraperitoneal or oral administration of PSK, and there was correlation between the PSK associated antitumor effect and the killer T cell activity. It was found that PSK competed with immunosuppressive substances isolated from tumor-bearing mice and that the intestinal immune system appeared to be modulated by oral administration of PSK. After oral administration of 14C- or 35S-labeled PSK to normal rats, it was found that small or large molecular substances appeared in the serum depending on the time elapsed after administration, an indication that large molecular size products were from the digestive tract.
To elucidate the effects of PSK, a protein-bound polysaccharide from Coriolus versicolor, on gene expression in tumor cells, we prepared cDNA clone libraries from PSK-treated and untreated cells of a rat ascites hepatoma line, AH66, which was previously shown to be susceptible to the antitumor action of this compound. Two PSK-induced and one suppressed cDNA clones were selected from these libraries by using a differential colony hybridization and RNA blot hybridization. PSK was thus shown to have a direct effect on the transcription and consequently on the translation of tumor cells.
PSK is a protein-bound polysaccharide prepared from cultured mycelium of the Basidiomycete Coriolus versicolor. Effects of PSK on the immunologic responsiveness in tumor-bearing animals were investigated using syngeneic or allogeneic tumors in mice (Lewis lung carcinoma, B16 melanoma, Meth A fibrosarcoma, adenocarcinoma 755, X5563 plasmacytoma, colon 26, MOPC 31C myeloma, sarcoma 180 and Ehrlich carcinoma), rats (BC47 bladder carcinoma, Walker 256 sarcoma and AH7974 hepatoma), hamsters (HA-1T tumor and RPMI 1846 melanoma), guinea pigs (line-10 hepatoma) and rabbit (VX2 and VX7 tumor). Oral or intraperitoneal administration of PSK restored the depressed delayed hypersensitivity against sheep erythrocytes to a normal level in these tumor-host systems. Also, oral administration of PSK lowered the activity of immunosuppressive substances in the serum of tumor-bearing animals. These results suggest that PSK exhibits antitumor effects by restoring the depressed immunologic responsiveness in tumor-bearing animals.
Department of Pharmacology, Gifu Pharmaceutical University, Japan.
Abstract
OK-432, a lyophilized preparation of Streptococcus pyogenes, showed a priming activity for TNF production in mice, associated with an increase of spleen weight. PSK, a protein-bound polysaccharide preparation from Coriolus versicolor, did not show such activity. Both OK-432 and PSK potentiated the TNF production in mice primed with Corynebacterium parvum (CP) and challenged with Escherichia coli endotoxin (LPS). Cytotoxic antitumor agents of 5-fluorouracil (5-FU), cyclophosphamide (CY) and bleomycin (BLM) suppressed TNF production in mice primed with CP and challenged with LPS. TNF production suppressed by 5-FU, CY and BLM was partially restored by the combined treatment with OK-432 or PSK. These results suggest that the administration of cytotoxic antitumor agents suppresses the intrinsic TNF production in cancer patients, and the combined use of immunostimulants such as OK-432 and PSK is advantageous in restoring TNF production suppressed by cytotoxic antitumor agents.
First Department of Biochemistry, School of Medicine, Showa University, Tokyo, Japan.
Abstract
PSK, a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor (Fr.) Quel, stimulated tumor necrosis factor-induced cytotoxicity against mouse L-929 fibroblast. PSK also stimulated interferon-gamma-induced differentiation of human myelogenous leukemic U-937 and THP-1 cells. The differentiated cells had higher proportions of cells that expressed NBT-reducing activity and alpha-naphthyl acetate esterase activity. Among four PSK subfractions, the highest molecular weight fraction (MW greater than 200 kD) had the most potent stimulating activity. This is the first report regarding direct PSK modulation of cytokine action.
Biomedical Research Laboratories, Kureha Chemical Industries Co., Ltd., Tokyo, Japan.
Abstract
We investigated the effect of PSK, a protein-bound polysaccharide obtained from the basidiomycetes Coriolus versicolor, on an immunosuppressive factor produced in tumor-bearing animals. Oral administration of PSK suppressed the growth of the tumor in C3H/He mice bearing X5563 plasmacytoma or MH134 hepatoma, but affected mice bearing MM102 mammary tumor little. PSK prevented the reduction in splenic lymphocyte blastogenesis caused by phytohemagglutinin that occurs in mice bearing X5563 tumors or MH134 hepatoma. The lymphocyte blastogenesis affected little by tumor or PSK in mice bearing MM102 tumors. The effect of sera on the blastogenesis of lymphocytes caused by phytohemagglutinin was different with different tumors in the C3H/He mice. Serum of mice bearing X5563 tumors inhibited blastogenesis, but serum of mice bearing MH134 hepatoma or MM102 tumors promoted it. The sera of mice bearing MH134 hepatoma contained both inhibitory and promotive factors; those of mice bearing X5563 tumors contained an inhibitory factor, and those of mice bearing MM102 tumors contained a promotive factor. The oral administration of PSK reduced the inhibition caused by the sera of mice bearing X5563 tumors. The promotive activity of sera from mice bearing MH134 hepatoma was augmented by PSK; that of sera in mice bearing MM102 tumors was not affected by PSK. Living Bacillus Calmette-Guérin did not have such effects in any of these mice. Serum immunosuppressive activity was also reduced by PSK in various tumor lines of rodents. These results suggest that PSK acts by reducing the activity of immunosuppressive factors produced in tumor-bearing hosts.
Department of Physiology, University of Hong Kong.
Abstract
A new small polypeptide was isolated from the crude extraction of polysaccharide peptide of Coriolus versicolor (Cov-1) by HPLC and CIEF. It has a smaller molecular weight (10K) compared with that of PSP (100K) and was named small peptide of Coriolus versicolor, SPCV. It was found that SPCV possesses potent cytotoxic effect on human tumor cell lines of HL-60, LS174-T, SMMU-7721, and SCG-7901. The IC50 of SPCV on HL-60 was 30 micrograms/ml. The inhibition rates of leukemia cells and SCG-7901 were significantly higher in SPCV treated group than that in PSP and PSK groups. SPCV also has immunopotentiating effect as it increased WBC and IgG levels. Pretreatment of SPCV for two weeks decreased the incidence of tumor mass in nude mice inoculated with tumor cells.