Category Archives: Immunotherapy

Antimetastatic Effects of P5K (Krestin), a Protein-bound Polysaccharide Obtained from Basidiomycetes: An Overview

Hiroshi Kobayashi, Kenichi Matsunaga,1 and Yoshiharu Oguchi

P5K, a protein-bound polysaccharide obtained from cultured mycelia of Coriolus versicolor in basidiomycetes, is a biological response modifier, diverse operations of which include an antitumor action. We have previously reviewed recent research which had demonstrated that in animals, P5K has a preventive effect on chemical carcinogen-induced, radiation induced, and spontaneously developed carcinogenesis (Kobayashi et aL, Cancer Epidemiol., Biomarkers & Prey., 2: 271-276, 1993). We now focus on the effects of PSK once the progression of carcinogenesis has begun, and review what is now known of the preventive action of PSK on cancer metastasis.

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ANALYSIS OF IMMUNOMODULATING CYTOKINE mRNAs IN THE MOUSE INDUCED BY MUSHROOM POLYSACCHARIDES

The immunomodulating action of two mushroom antitumor polysaccharides, polysaccharide-protein complex (PSPC) and lentinan, was elucidated through analysing the expression profile of cytokines during a time course (0 h to 48 h) after their administration. Among the 5 cytokine genes, the induction of a marked increase in the mRNA levels of IL-la, IL-lp, TNF-a, IFN-)I and M-CSF by PSPC and lentinan was observed in the peritoneal exudate cells and splenocytes. However, the time point of their increased production was different after PSPC and lentinan administration.

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An effect of adjuvant immunochemotherapy using krestin and 5-FU on gastric cancer patients with radical surgery (first report)–a randomized controlled trial by the cooperative study group. Study Group of Immuno-chemotherapy with PSK for Gastric Cancer

To evaluate the efficacy of PSK for adjuvant immuno-chemotherapy in patients who had undergone radical gastrectomy, a randomized controlled trial has been in progress in collaboration with 46 institutions in the Chubu district of Japan. A total of 262 patients were registered for this trial during the two years from July 1985 to June 1987 with a centralized registration system, and were allocated into the 5-FU+PSK group (Group P) and 5-FU alone group (Group C) by the minimization method following the random permuted blocks method. Between the two groups, the parameters of sex, age, serosal invasion (S), lymph-node metastasis (N), and the combination of S . N factor levels were distributed without significant differences. An induction treatment with MMC 6 mg/m2 was given to all patients following curative mastectomy and on the 7th post-operative day. Two weeks after surgery, Group P received alternately PSK 3 g/day for 4 week and 5-FU 150 mg/day for 4 weeks as one course, and 10 courses were given. Group C received 5-FU alone for 4 weeks using alternate rest interval for 4 weeks. Since both experimental and clinical studies suggested that alternate treatments using PSK and anticancer agents were effective, treatment in this trial alternated PSK and 5-FU. A final follow-up study will be completed in June 1992, when all patients shall have survived more than 5 years after surgery. The administration of 5-FU was completed by January. 1989, but PSK has been administered to group P. The period from 18 to 42 months after surgery was reached in all eligible patients (253) at the end of December 1988. The disease-free survival curves and overall survival curves of group P were significantly (p = 0.018 and p = 0.045,) better than those of group C.

Alternating immunotherapy of advanced gastric carcinoma: A randomized comparison of carbazilquinone and PSK to carbazilquinone in patients with curative gastric resection

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carabzilquinone (CQ) and PSK (Krestin) or carbazilquinone alone.  Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses.  In each course of 6 weeks, CQ was administered on day 0, 8, and 15.  In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2g/m^2/day from the day of the third CQ administration for consecutive 4 weeks.  Estimated survival rate and cumulative survival curve were compared untilizing the data up to 7 years after the operation.  There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients survived significantly longer when treated with the combination of CQ and PSK.  Neither in more advanced cases nor in cancers of early stages, the addition of PSK provided an additive effect.  The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.?

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Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators.

Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M.

Clinical Division, Department of Herbal Medicine, Tai Sophia Institute, 7750 Montpelier Road, Laurel, MD 20723, USA. spelman123@earthlink.net.
Abstract

Modulation of cytokine secretion may offer novel approaches in the treatment of a variety of diseases. One strategy in the modulation of cytokine expression may be through the use of herbal medicines. A class of herbal medicines, known as immunomodulators, alters the activity of immune function through the dynamic regulation of informational molecules such as cytokines. This may offer an explanation of the effects of herbs on the immune system and other tissues. For this informal review, the authors surveyed the primary literature on medicinal plants and their effects on cytokine expression, taking special care to analyze research that utilized the multi-component extracts equivalent to or similar to what are used in traditional medicine, clinical phytotherapy, or in the marketplace.

METHODOLOGY: MEDLINE, EBSCO, and BIOSIS were used to identify research on botanical medicines, in whole or standardized form, that act on cytokine activity through different models, i.e., in vivo (human and animal), ex vivo, or in vitro.

RESULTS: Many medicinal plant extracts had effects on at least one cytokine. The most frequently studied cytokines were IL-1, IL-6, TNF, and IFN. Acalypha wilkesiana, Acanthopanax gracilistylus, Allium sativum, Ananus comosus, Cissampelos sympodialis, Coriolus versicolor, Curcuma longa, Echinacea purpurea, Grifola frondosa, Harpagophytum procumbens, Panax ginseng, Polygala tenuifolia, Poria cocos, Silybum marianum, Smilax glabra, Tinospora cordifolia, Uncaria tomentosa, and Withania somnifera demonstrate modulation of multiple cytokines.

CONCLUSION: The in vitro and in vivo research demonstrates that the reviewed botanical medicines modulate the secretion of multiple cytokines. The reported therapeutic success of these plants by traditional cultures and modern clinicians may be partially due to their effects on cytokines. Phytotherapy offers a potential therapeutic modality for the treatment of many differing conditions involving cytokines. Given the activity demonstrated by many of the reviewed herbal medicines and the increasing awareness of the broad-spectrum effects of cytokines on autoimmune conditions and chronic degenerative processes, further study of phytotherapy for cytokine-related diseases and syndromes is warranted.

PMID: 16813462 [PubMed – indexed for MEDLINE]Free Article

http://www.ncbi.nlm.nih.gov/pubmed/16813462

Induction of cell cycle changes and modulation of apoptogenic/anti-apoptotic and extracellular signaling regulatory protein expression by water extracts of I’m-Yunity (PSP).

Hsieh TC, Wu P, Park S, Wu JM.

Department of Biochemistry & Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. Tze-Chen_Hsieh@nymc.edu

Abstract

BACKGROUND: I’m-Yunity (PSP) is a mushroom extract derived from deep-layer cultivated mycelia of the patented Cov-1 strain of Coriolus versicolor (CV), which contains as its main bioactive ingredient a family of polysaccharo-peptide with heterogeneous charge properties and molecular sizes. I’m-Yunity (PSP) is used as a dietary supplement by cancer patients and by individuals diagnosed with various chronic diseases. Laboratory studies have shown that I’m-Yunity (PSP) enhances immune functions and also modulates cellular responses to external challenges. Recently, I’m-Yunity (PSP) was also reported to exert potent anti-tumorigenic effects, evident by suppression of cell proliferation and induction of apoptosis in malignant cells. We investigate the mechanisms by which I’m-Yunity (PSP) elicits these effects.

METHODS: Human leukemia HL-60 and U-937 cells were incubated with increasing doses of aqueous extracts of I’m-Yunity (PSP). Control and treated cells were harvested at various times and analyzed for changes in: (1) cell proliferation and viability, (2) cell cycle phase transition, (3) induction of apoptosis, (4) expression of cell cycle, apoptogenic/anti-apoptotic, and extracellular regulatory proteins.

RESULTS: Aqueous extracts of I’m-Yunity (PSP) inhibited cell proliferation and induced apoptosis in HL-60 and U-937 cells, accompanied by a cell type-dependent disruption of the G1/S and G2/M phases of cell cycle progression. A more pronounced growth suppression was observed in treated HL-60 cells, which was correlated with time- and dose-dependent down regulation of the retinoblastoma protein Rb, diminution in the expression of anti-apoptotic proteins bcl-2 and survivin, increase in apoptogenic proteins bax and cytochrome c, and cleavage of poly(ADP-ribose) polymerase (PARP) from its native 112-kDa form to the 89-kDa truncated product. Moreover, I’m-Yunity (PSP)-treated HL-60 cells also showed a substantial decrease in p65 and to a lesser degree p50 forms of transcription factor NF-kappaB, which was accompanied by a reduction in the expression of cyclooxygenase 2 (COX2). I’m-Yunity (PSP) also elicited an increase in STAT1 (signal transducer and activator of transcription) and correspondingly, decrease in the expression of activated form of ERK (extracellular signal-regulated kinase).

CONCLUSION: Aqueous extracts of I’m-Yunity (PSP) induces cell cycle arrest and alterations in the expression of apoptogenic/anti-apoptotic and extracellular signaling regulatory proteins in human leukemia cells, the net result being suppression of proliferation and increase in apoptosis. These findings may contribute to the reported clinical and overall health effects of I’m-Yunity (PSP).

PMID: 16965632 [PubMed – indexed for MEDLINE]PMCID: PMC1574346Free PMC Article

http://www.ncbi.nlm.nih.gov/pubmed/16965632

Effects of polysaccharide peptides from COV-1 strain of Coriolus versicolor on glutathione and glutathione-related enzymes in the mouse.

Yeung JH, Or PM.

Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. johnyeung@cuhk.edu.hk

Abstract

The effects of polysaccharide peptide (PSP), an immunomodulator isolated from Coriolus versicolor COV-1, on glutathione (GSH) and GSH-related enzymes was investigated in C57 mouse. Administration of PSP (1-4 micromole/kg, i.p.) produced a transient, dose-dependent depletion (10-37%) of hepatic GSH, with no effect on serum glutamic-pyruvic transaminase (SGPT) activity. Blood GSH was depleted (6-25%) at 3 h, followed by a rebound increase above the control GSH level (20%) at 18 h. The GSSG/GSH ratio, a measure of oxidative stress, was increased 3 h after PSP treatment but returned to normal levels at 24 h. Sub-chronic treatment of PSP (1-4 micromole/kg/day, i.p.) for seven days did not produce any significant changes in hepatic GSH levels and the GSSG/GSH ratio when measured 24 h after the final dose of PSP. PSP had little effect on glutathione transferase (GST), glutathione reductase (GSSG reductase) and glutathione peroxidase (GPX) activities in the liver. However, a dose-dependent increase in blood GPX activity (30-48%) was observed at 3h, which coincided with the increase in the GSSG/GSH ratio. The increase in blood GPX activity may be a responsive measure to deal with the transient oxidative stress induced by PSP treatment. The results showed that PSP only caused a transient perturbation on hepatic glutathione without affecting the GSH-related enzymes such as GST, GSSG reductase and GPX. The observed changes in blood GSH simply reflected the intra-organ translocation of glutathione, as the glutathione-related enzymes were not significantly affected by PSP treatment.

PMID: 17240508 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/17240508

The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis.

Jiménez-Medina E, Berruguilla E, Romero I, Algarra I, Collado A, Garrido F, Garcia-Lora A.

Servicio de Análisis Clínicos e Inmunologia, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Av, de las Fuerzas Armadas 2, 18014 Granada, Spain. evajimenez@fundacionhvn.org

Abstract

BACKGROUND: Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated.

METHODS: The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells.

RESULTS: PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation.

CONCLUSION: These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells.

PMID: 18366723 [PubMed – indexed for MEDLINE]PMCID: PMC2291471Free PMC Article

http://www.ncbi.nlm.nih.gov/pubmed/18366723

Evaluation of widely consumed botanicals as immunological adjuvants.

Ragupathi G, Yeung KS, Leung PC, Lee M, Lau CB, Vickers A, Hood C, Deng G, Cheung NK, Cassileth B, Livingston P.

Laboratory of Tumor Vaccinology, Melanoma and Sarcoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States. ragupatg@mskcc.org

Abstract

BACKGROUND: Many widely used botanical medicines are claimed to be immune enhancers. Clear evidence of augmentation of immune responses in vivo is lacking in most cases. To select botanicals for further study based on immune enhancing activity, we study them here mixed with antigen and injected subcutaneously (s.c.). Globo H and GD3 are cell surface carbohydrates expressed on glycolipids or glycoproteins on the cell surface of many cancers. When conjugated to keyhole limpet hemocyanin (KLH), mixed with an immunological adjuvant and administered s.c. the magnitude of the antibody responses against globo H, GD3 and KLH depend largely on the potency of the adjuvant. We describe here the results obtained using this s.c. immunization model with seven botanicals purported to have immune stimulant effects.

METHODS: Groups of 5-10 mice were immunized with globo H-KLH or GD3-KLH mixed with botanical, saline or positive control immunological adjuvant, s.c. three times at 1 week intervals. Antibody responses were measured 1 and 2 weeks after the 3rd immunization. The following seven botanicals and fractions were tested: (1) H-48 (Honso USA Co.), (2) Coriolus versicolor raw water extract, purified polysaccharide-K (PSK) or purified polysaccharide-peptide (PSP) (Institute of Chinese Medicine (ICM)), (3) Maitake extract (Yukiguni Maitake Co. Ltd. and Tradeworks Group), (4) Echinacea lipophilic, neutral and acidic extracts (Gaia Herbs), (5) Astragalus water, 50% or 95% ethanol extracts (ICM), (6) Turmeric supercritical (SC) or hydro-ethanolic (HE) extracts (New Chapter) or 60% ethanol extract (ICM) and (7) yeast beta-glucan (Biotec Pharmacon). Purified saponin extract QS-21 (Antigenics) and semisynthetic saponin GPI-0100 (Advanced BioTherapies) were used as positive control adjuvants. Sera were analyzed by ELISA against synthetic globo H ceramide or GD3 and KLH.

RESULTS: Consistent significant adjuvant activity was observed after s.c. vaccination with the Coriolus extracts (especially PSK), a 95% ethanol extract of Astragalus and yeast beta-glucan, and (to a lesser extent) Maitake. Antibodies against KLH in all cases and against globo H in most cases were induced by these botanicals. Little or no adjuvant activity was demonstrated with H-48 or Echinacea extracts or the Astragalus water extract. Experiments with GD3-KLH as immunogen confirmed the adjuvant activity of the Coriolus, yeast beta-glucan and Astragalus extracts. While extraction with ethanol concentrated the active ingredients in Astragalus, it had no impact on Coriolus where the 90% ethanol precipitate and solute were equally active.

CONCLUSIONS: Some, but not all, botanicals purported to be immune stimulants had adjuvant activity in our model. PSK and Astragalus were surprisingly active and are being further fractionated to identify the most active adjuvant components.

PMID: 18640165 [PubMed – indexed for MEDLINE]PMCID: PMC2565601

http://www.ncbi.nlm.nih.gov/pubmed/18640165

Immune System Genes Show Links to Type 1 Diabetes – By Serena Gordon, HealthDay Reporter

WEDNESDAY, Sept. 8 (HealthDay News) — The exact cause of type 1 diabetes is still unknown, but international researchers have found a link between the blood sugar disorder and a network of immune system genes.

Using a genome-wide association study, the researchers found that a certain group of genes that react in response to viral infections were present in both rats and humans, and that those same genes were also associated with a susceptibility to type 1 diabetes.

“Diseases arise as a result of many genetic and environmental factors through gene networks that cause tissue damage,” explained study senior author Dr. Stuart Cook, the group head of molecular and cellular cardiology at the Medical Research Council Clinical Sciences Centre, and a professor of clinical and molecular cardiology at Imperial College in London.

“We used an approach to identify the major control points’ central command of an inflammatory gene network. This led us to uncover hundreds of new genes that might cause diabetes and one major control gene that controls the whole network,” said Cook.

He added that one of the genes belongs to a class of genes that might make a good target for drug therapy in the future.

Results of the study are published in the Sept. 9 issue of Nature.

Each year, more than 30,000 people are diagnosed with type 1 diabetes, formerly known as juvenile diabetes, according to the Juvenile Diabetes Research Foundation (JDRF). People with type 1 diabetes no longer produce enough of the hormone insulin to effectively use the sugars found in carbohydrate-containing foods. To survive, people with type 1 diabetes must take insulin injections or use an insulin pump for the rest of their lives.

Experts believe the disease is an autoimmune disease, which means that the body’s immune system mistakenly turns against healthy cells, such as the insulin-producing cells in the pancreas, and destroys them. People who develop type 1 diabetes are believed to have a genetic susceptibility to the disease that’s then triggered by something in the environment, possibly a virus.

In the current study, the researchers didn’t initially set out to look for type 1 diabetes genes. They started out by looking at a certain group of genes in rats, in this case a network of genes controlled by a gene called interferon regulatory factor 7 (IRF7). IRF7 is like a master switch that controls the genes in its network. The entire network of genes controlled by IRF7 is called the IRF7-driven inflammatory network (IDIN).

The researchers discovered that when there were differences in IRF7, there were also differences in the way other genes expressed themselves.

Cook and his colleagues then searched for a network of genes in humans that might behave the same way. They found an area on chromosome 13q32 that is controlled by a gene called the “Epstein-Barr virus induced gene 2” (Ebi2). This gene appeared to be the human equivalent of the IRF7 gene in rats.

Within this human version of the IDIN, research found a gene called IFIH1, which has been found in other research to be associated with the development of type 1 diabetes.

“Usually, research starts from the genetics and goes to function. Here, they started with a function — [an immune system reaction] — and were looking for a gene,” explained Marie Nierras, director of research and scientific affairs for the JDRF.

“The value of such a result is that if you can get to the same place using more than one pathway, it tends to support the hypothesis,” she said.

In this case, the hypothesis supported is the idea that type 1 diabetes may be triggered by an immune system response to a virus. However, Nierras stressed that this study doesn’t conclusively prove that a virus is the trigger for type 1 diabetes.

“We know better today that this network of genes is involved, and with a network, you have many targets you can test. This research invites us to plan experiments going forward, and opens up many more questions, like ‘If I disrupt this branch of the network, do I disrupt diabetes?’ Or, ‘If you look back at previous research knowing this study’s results, does that help to better explain previous results?'” said Nierras.

Cook said this type of genome-wide association study can be used for other diseases as well, and that his team is hoping to eventually develop a new drug based on the genetic target they discovered.

More information

Learn more about type 1 diabetes and its causes from the U.S. National Library of Medicine.

SOURCES: Stuart Cook, M.D., Ph.D., group head, molecular and cellular cardiology, the Medical Research Council Clinical Sciences Centre, and professor, clinical and molecular cardiology, Imperial College, London; Marie Nierras, Ph.D., director, research and scientific affairs, Juvenile Diabetes Research Foundation, New York City; Sept. 9, 2010, Nature

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