Introduction
In Asian cultures, mushrooms are traditionally combined with herbal mixtures to treat cancer. Reports from the 1960’s have documented health benefits for stomach cancer when drinking “Saru-no-koshikake” tea containing “C. VERSICOLOR” mushroom. Research has found that this mushroom has antimicrobial, antiviral and anti-tumor properties. Nowadays C. versicolor is mainly used as an adjuvant in the treatment of cancer. It was demonstrated in vitro and clinically that extracts obtained from this mushroom are likely to exhibit stimulatory effects on the immune system and to inhibit the growth of cancer cells. Because of these properties, C. versicolor is called a biological response modifier (BRM). The growing popularity of C versicolor, as an adjuvant to conventional cancer treatment has generated commercial interest to develop oral proprietary products.

While limited information is available on the physical, chemical and pharmacodynamic properties of the active principles present in the extracts, there is sufficient scientific evidence to support the feasibility of developing at least some of these constituents into an evidence-based immunomodulatory agent. The background, pharmacological activities and clinical effects of C. versicolor mushroom extracts are reviewed in this paper.

Mushroom Description
The mushroom C. VERSICOLOR (alternatives names: Polyporus versicolor and Trametes versicolor) is a macrofungi belonging to the Basidiomycetes class which encompasses about 22,000 known species. Most of the conspicuous macrofungi of the fields and woods are Basidiomycetes. C. versicolor is in the Poriales order which includes important agents of timber decay. These mushrooms grow naturally on dead logs. They possess a wide array of enzymes that can digest the lignocellulose of wood. This characteristic makes them an interesting tool for the industrial breakdown of lignin (Arora et al, 1991; Carlile et al, 2001). Coriolus is characterized by a leathery skin and woody fruit bodies. Sometimes called «turkey tail», its shape and color shades are evocative of the bird ornament (fig. 1) (Chu et al, 2002). In China, C. VERSICOLOR is named Yun Zhi (meaning «cloud-like mushroom»).

Figure 1. Coriolus Versicolour

Over 120 strains of C. VERSICOLOR have been recorded in the Compendium of Chinese Materia Medica that was written during the Ming Dynasty. By then already, C. versicolor was considered useful in fighting adverse conditions such as infection and inflammation of the upper respiratory, urinary, and digestive tracts. It was also used for increasing energy, as well as enhancing the host’s immune functions. In the clinical practice of traditional Chinese medicine, C. versicolor is still recommended for various types of cancer, for chronic hepatitis, and for infections of the upper respiratory, urinary, and digestive tracts (Jong and Yang, 1999a). Among the myriad of commercially available mushroom products claimed to possess medicinal value, Yun Zhi is one of the most outstanding and well known. Research pertaining to PSP is reviewed in the next section.

Active Principle from C. VERSICOLOR: the Polysaccharopeptides (PSP)
The active principle derived from C. versicolor belongs to a new class of elements called biological response modifiers (BRM). BRM are defined as agents capable of stimulating the immune system and thereby express various therapeutic effects. Polysaccharides (complex sugar molecules) linked to a small protein (or a peptide) are at the basis of this immunomodulatory activity. This «polysaccharide-peptide» is termed polysaccharopeptide, or PSP in its abbreviated form. There are probably many PSP with closely similar physicochemical characteristics and isolation of a pure PSP is technically difficult. However, a few structural features of PSP have been identified to date. The average molecular weight is 100 000 Da. The protein core accounts for about 10% of this weight, the remaining being polysaccharides. The peptide moiety comprises 18 amino acids, mostly glutamic and aspartic acids. In addition to glucose, PSP contains small amounts of five other monosaccharides: galactose, mannose, xylose, arabinose and rhamnose. PSP does not contain fucose, unlike PSK, a similar compound derived from a different C. versicolor strain found in Japan (see below) (Chu et al, 2002; Jong et Yang, 1999; Yang, 1999a; Zhou et Yang, 1999).

Gas chromatography disclosed mainly b1-4, b1-2 and b1-3 glucose linkages. This structure is typical of b-glucans which consist of linear unbranched polysaccharides of glucopyranose units (figure 2). The b-glucans have an exciting potential for enhancing the immune system. Numerous studies have reported that b1-3 glucans are activators of the natural anti-cancer immune system in humans. Animal studies have shown that glucans can induce tumor shrinkage (di Luzio et al, 1980; Mansell et al, 1975; Morikawa et al, 1985). Moreover, PSP is not just an ordinary beta-glucan. DEAE-cellulose column chromatography and HPLC have revealed that the polysaccharides and peptides components of PSP are strongly bound and cannot easily be separated; with PSP, where there are polysaccharides, there are polypeptides. The scientific literature sustains that only those fungal polysaccharides that are bound with proteins can produce anti-tumor effects after oral administration to animals or humans.

Figure 2. Beta-glucan: structural unit

The strain used for PSP production is called Cov-1 and was obtained through careful selection of over 80 wild strains collected from various areas in China. While it is possible to obtain PSP from wild mushrooms, for mass production and quality control objectives C. versicolor intended for medical uses is usually produced by fermentation (raw material obtained from deep-layer cultivated mycelia). Since the anti-cancer components of Yun Zhi exist primarily in the mycelia, PSP uses the deep layer cultivated mycelia as its raw material instead of using the fruit bodies. The mycelia produced by modern biological engineering technology are not only pure but also of higher quality; the yield of extraction is only 5%; thus PSP is absolutely the essence of Yun Zhi. The mycelia grow on various nitrogen sources like maize pulp, bean cake powder, peptone and yeast extracts; the carbon source usually consists of glucose or starch. The ideal fermentation temperature is 26 oC, and the pH range from 5,0 to 7,0. After the production stage, PSP is usually obtained by extraction of the mycelia in hot water, followed by alcoholic precipitation; the precipitate is then freeze-dried to produce a light brown, hydrosoluble powder.

PSP is different from PSK
PSK is another protein-bound polysaccharide extract from C. versicolor with immunopotentiating and anti-tumor properties. PSK is a biological response modifier (BRM), similar to PSP, in chemistry and in medicinal properties. It is composed of 62% polysaccharide with b1-4 and b1-3 glucans as its main components and 38% protein. However, PSK is obtained from a different strain of C. versicolor (usually strain C-101) and is produced in Japan; the extraction is done by salting out with ammonium sulfate instead of using alcoholic precipitation. The polysaccharide fraction does not contain arabinose and rhamnose, but rather contains fucose. Glutamic acid, leucine and aspartic acid are the major amino acids (Jong et Yang, 1999; Yang, 1999a; Zhou et Yang, 1999).

PSK manufactured in Japan first received the commercial name of Krestin. It is currently used as a cancer treatment adjuvant in Japan, principally in conjunction with surgery, chemotherapy and/or radiation (Kobayashi et al, 1993; 1995; Tsukagoshi et al, 1984). Most importantly, PSK displays a less potent tumor inhibitory potential than PSP (Chen, 1990; Li and Xu, 1987; Zhou et al, 1988 Jong and Yang, 1999).

Toxicology
The first toxicological experiments conducted with a variety of animals (dogs, monkey and guina pigs) have shown negative results for acute and chronic toxicity. It appears that PSP does not harm normal cells, having the ability to distinguish between normal and cancer cells (Jong and Yang, 1999).

Acute and subacute toxicity of PSP are very low. The LD50 (the lethal dose required to kill 50% of a group of tested animals) ranges from 10 to 26 mg/kg in animals, according to the mode of administration (oral vs injection). With such a LD50, the daily oral dosage used in most human clinical trials, ranging from 2 to 6 grams of dried PSP (equivalent to 0,03 to 0,08 mg/kg for a 75 kg man), is very safe (Jin, 1999; Chu et al, 2002). Subchronic and chronic toxicity studies (designed to measure the medium- and long-term effects) were done by Jiang et al (1999) who continuously administrated 4 oral doses (1.5, 3,0 and 6,0 mg/kg) to 80 rats for 62 days. The results showed no toxic symptoms or death. Neither were there any obvious toxic changes in blood and serum biochemistry.

The possible effects on male and female reproductive physiology and embryonic development were also examined. Results from these studies suggested that PSP could not cause sperm aberration at a dosage 100 times higher than the usual clinical dose (Qian, 1993). The lack of deleterious effects on ovarian follicular development, ovulation, pregnancy and embryo development in mice was also demonstrated (Ng and Chan, 1997). Mutagenicity of PSP was assessed with the Ames test (based on the use of Salmonella thyphimurium mutant strains that have lost the ability to synthesize the amino acid histidine and that may regain this capacity if a mutation occur) and with the chromosome aberrations test of bone marrow cells in mice (Zhong et al, 1999). It was concluded that PSP showed no evidence of mutagenic or cytogenetic activity.

Negative findings resulting from toxicological tests proved that PSP is a very safe product. Although the anticancer effect of PSP is not as potent as that of chemotherapeutic drugs, PSP does not harm normal cells. It appears that PSP has the ability to distinguish between normal and tumorous cells; this ability is linked to the specific mode of action of C. versicolor extracts, as discussed in the next section.

Immunomodulatory Effects
The immunological activities of PSP have been extensively investigated both in vitro and in vivo. PSP strengthens the immunological functions. Its anti-tumor effect seems to be mediated more through immunomodulatory regulation rather than by direct cytotoxicity as is the case for most anticancer drugs currently used. To understand this immunomodulatory action of PSP, a short review of the immune system is however desirable.

Phagocytic cells (i.e. neutrophils, monocytes, and macrophages) and lymphocytes are the two major groups of cells in charge of the host defense system. Phagocytic cells are responsible for the innate immunity (non-specific cellular response). They kill infectious microbes and digest them with lysosomal enzymes. Macrophages can be activated by lymphokines (cytokines produced by lymphoctytes; see below), and other cell mediators, to kill microorganisms and tumor cells through the release of tumor necrosis factor (TNF), oxygen radicals, and reactive nitrogen intermediates (like nitrite oxide).

When innate immunity fails, specific (acquired or adaptive) immune responses are activated. Leukocytes (i.e., white blood cells), specifically B and T lymphocytes, are agents of the specific immunity. A group of T lymphocytes, called «T-helper cells» (which encompasses CD4 cells), produces protein messengers or effectors molecules, called cytokines; cytokines are a group of cell-derived proteins or peptides that transmit signals between cells of the immune system. Cytokines can stimulate, inhibit, upregulate or downregulate the immune system. They are similar to hormones in the fact that they act at sites distant from their site of synthesis. Cytokines are divided in many categories which include interferons IFN-a, -b and -g, and interleukins (IL-1 through IL-15). Another process involving antibodies exists for killing infected or tumor cells. In this process, circulating antibodies bind to epitopes (specific antigens) exposed on the surface of the «foreign» cell (a micro-organism or a tumor cell). These antibody-tagged cells are next recognized by granular lymphocytes, called natural killer cells (NK) whose job is to eliminate them. In some types of cancer, NK cells do not work properly.

It appears that the basic mechanisms for PSP to inhibit tumor cells include the activation of 1) macrophages; 2) natural killer cells and 3) T-helper cells (CD4+) which induce T-killer cells, antibody production, and interleukins (Jong and Yang, 1999). The mechanisms of such an immune stimulation have yet to be completely elucidated. Nevertheless, natural killer (NK) and lymphocyte activation have been demonstrated in vitro and in vivo, and recent studies support the induced expression of cytokines by PSP(Fisher and Yang, 2002).

In vitro tests were conducted with numerous cell lines to investigate the immunomodulatory effects of PSP. It has been demonstrated that PSP promoted the proliferation of T cells both in human and mouse and also increased the population of CD4+ T helper cells (Li, 1999). Interleukin-2 (IL-2) is recognized to play a critical role in immune defense against tumor, because it is a potent inducer of activation of NK cells. In a study designed to evaluate the anti-tumor potential of IL-2 and PSP, it was demonstrated that the combination of the two agents had the most dramatic anti-tumor effect (Mao et al, 1996). Moreover, PSP could effectively stimulate the generation of Interferon-a (IFN-a) and markedly improve the yields of IFN-g (Yang et al, 1999b). Liu et al (1999) demonstrated that PSP does not exert a direct cytotoxic effect on tumor cell lines but rather stimulates macrophages, thus strengthening the hypothesis that C. versicolor anti-tumor effects are mediated by an immunomodulatory mechanism. Peritoneal macrophages cultured in vitro, obtained from mice which had received PSP in the drinking water for 2 weeks, showed an increase in the production of reactive nitrogen intermediates, reactive oxygen intermediates (like superoxide anions) and tumor necrosis factor (Liu et al, 1993).

In vivo studies have revealed that PSP generally has no significant immunological effects on a normal host, but can restore a depressed immunological responsiveness as seen in cancer or with chemotherapy (Chu et al, 2002). PSP promotes the expression of the IL-6 gene of peripheral blood lymphocytes, hence inducing the production of interleukin 6. PSP also activates white blood cells to increase the production of IFN-a and IFN-g up to 2 to 4 times. PSP also activates the proliferation of T-lymphocytes and pre-T cells in the thymus and spleen (Li et al, 1990). When mice were pretreated with PSP, the production of tumor necrosis factor (TNF), oxygen radicals, and reactive nitrogen intermediates were stimulated (Liu et al, 1993). Like those of human, mouse lymphocytes and macrophages could also be activated by preparations of polysaccharopeptides from cultured C. vesicolor (Wang et al, 1996).

PSP can also counteract the depressive effect of cyclophosphamide on white blood cell count and interleukin-2 production. Cyclophosphamide (CPA) has become the leading drug in the clinical treatment of cancer, particularly for lymphomas, leukemia and solid tumors. This drug is cytotoxic, kills rapidly dividing neoplasic and normal cells, but has deleterious effect on the immune system. Research has demonstrated that PSP can antagonize the immunosuppression caused by such chemotherapeutic agents. For instance, the administration of PSP (at a dosage of 2 grams/kg.day) on cyclophosphamide-induced immunosuppressed rats demonstrated that the mushroom extract was effective in restoring their immune system. It did so by stimulating lymphocytes proliferation, NK cells functions, and the growth of spleen and thymus where lymphocytes mature and transit (Qian et al, 1997). Lu et al (1995) demonstrated that under the immunosuppressive condition of cyclophosphomidium treatment, the levels of lymphocyte maturation and antibody production in mice were maintained near normal with PSP administration (dosage of 500 mg/kg).

Anti-tumor Effects on Animals
Many studies were done since the 1980’s to demonstrate the effectiveness of PSP, and its counterpart PSK. Most of these studies have been done with tumor-induced animals. Research works report that PSK and PSP can suppress pulmonary metastasis from induced sarcomas, induced prostate cancer, lymphatic metastasis of mouse leukemia P388, and that both could prolonge the survival period in spontaneous metastasis models. The mushroom extracts also appeared to be effective for the prophylaxis against esophageal, colon, breast, liver, lung and bladder cancers. Oral administration of PSK reduced the incidence of tumor and/or prolonged the survival period in the following chemical carcinogen-induced, radiation-induced, or spontaneously developped animal cancer models: rat gastrointestinal cancer (by dimethylhydrazine), rat hepatoma (by methyl-dimethylaminobenzene), mouse thymic lymphoma (by whole body irradiation) and mouse spontaneous mammary tumor.

Polysaccharopeptides from C. versicolor influence cancer metastasis in a number of ways: 1) by suppression of intravasation through the inhibition of tumor cells infiltration, 2) by suppression of tumor cell attachment to endothelial cells through the inhibition of tumor cell-induced platelet aggregation, 3) by suppression of tumor cell migration after extravasion through the inhibition of tumor cell motility, and 4) by suppression of tumor growth after extravasation through the inhibition of angiogenesis, the modulation of cytokine production and the augmentation of effector cell functions.

Some selected references in connection with animal anti-tumor effects are presented here:

PSP administrated orally at 1-2 grams/kg/day for 15 to 20 days to mice inhibited growth of human lung adenocarcinoma by 50-70%. PSP administrated intraperitoneally at 50 mg/kg.day for about 3 weeks inhibited the growth of Lewis lung cancer by nearly 45% (Zeng et al, 1993; Wang et al, 1993). Dong et al (1996) demonstrated that a refined polysaccharide peptide isolated from cultivated C. versicolor, and administrated i.p. for two weeks in mice, was effective in decreasing the incidence of tumor growth (2 out of 5 mice in control group, all 5 mice in tested group); the tumor size of control group was about 3-5 times bigger than that of the tested group. PSK significantly prolonged the survival period of mammary tumor-bearing rats when given at a dose of 150 mg/kg twice a week for 3 weeks (Fujii et al, 1995). PSK could also act as an antiangiogenesis compound as demonstrated by the suppression of a mouse hepatoma-induced angiogenesis (Kanoh et al, 1994). A protein-bound polysaccharide obtained from C. versicolor prolonged significantly the life span of tumor-bearing mice (syngeneic plasmacytoma) when administrated at 100 mg/kg daily, starting the day after tumor inoculation; it appears that the polysaccharopeptide restored the cytokine-producing capacity of spleen cells previously suppressed in tumor-bearing mice (Matsunaga et al, 1992). Nakajima et al (1990) investigated the effect of a protein-bound polysaccharide from a strain of C. versicolor on chemically-induced tumor rats (with methyl-dimethylaminoazobenzene); after 24 weeks, the survival rate was significantly higher in the group given PSK than in the control group. Results indicated that PSK had a suppressive effect on the chemically-induced hepatocarcinogenesis. PSP could also inhibit the growth of tumors. Oral administration of PSP (2,5 grams/kg) daily for 4 weeks resulted in tumor (nasopharyngeal carcinoma inoculated in mice) growth inhibition rate of 77 and 63% in treated groups with no adverse influence on blood system and body weight (Zeng et al, 1999).

However, some animal experiments have not been able to demonstrate a specific effect of polysaccharopeptides extracted from the mushroom C. versicolor. Thus, for the long-term control of brain tumors, intraperitoneal injection of 2mg of PSP with radiotherapy did not increase radiation efficacy (Mao et al, 2001). Mao et al (1996) evaluated the effect of low-dose administration of interleukin-2 (IL-2) and PSP in a herpes virus type-2 transformed murine tumor in mice. Results indicate that Il-2 or PSP alone can slow down tumor progression, but the combination of the two modalities had no synergistic effects on tumor growth. Collectively these results warrant further investigation to determine if PSP could be effectively used for all types of tumors, or cancers, in which immunosuppression is a prominent feature.

In summary, it appears that oral administration of PSP reduced the incidence of tumor/or prolonged the survival period, following chemical carcinogen-induced, radiation-induced and spontaneously developed animal cancer models. PSP does not interact and/or inhibit drug-metabolizing enzymes. On the other hand, this agent scavenges active oxygen through the induction of superoxide dismutases (metalloenzymes which have a potential in preventing oxygen toxicity, in the form of free radicals). PSP also regulates cytokine production and enhances the anti-tumor activity of effector cells such as killer T-cells and natural killer cells, suggesting a possible effect on the growth process after the establishment of malignancy. Thus, this agent seems to act at multiple steps during carcinogenesis rather than at a particular step. The main mechanisms might be an antiteratogenic effect attributed to free radical trapping and prevention of chromosome injury, coupled to an immunomodulating effect linked to the modulation of cytokines production and effector cell functions.

Human Clinical Studies
Encapsulated PSP was subjected to Phase I, II and III clinical trials in Shanghai (China), as an adjuvant in the treatment of many types of human cancer. Phase II and III trials were carried out between 1991 and 1997 for the treatment of stomach, primary lung and esophagus cancers. Results showed that addition of PSP to radiotherapeutic or chemotherapeutic protocols can greatly improve the quality of life of cancer patients, since PSP alleviated weakness, anorexia, vomiting, dryness of throat, spontaneous sweat and pain symptoms. Importantly, although PSP itself is not an analgesic drug, phase II and III clinical trials all confirmed that PSP could alleviate cancer-related pain to some extent. PSP also antagonized the reduction of appetite, noted in many cancer patients, increased their dietary intake, strengthened their physical constitution and favored an increase in therapeutic efficacy. The overall effective rate was significantly higher in the treatment group (85,8%) than in the control group (42%) (Liu et al, 1999). Moreover, cancer patients treated with PSP experienced relatively low toxic side effects (Liu et al, 1999)

In addition to symptoms improvement, polysaccharopeptides from C. versicolor also impact on the survival rate of different types of cancer. PSK used in Japanese trials significantly extended the survival rate at five years for stomach, colorectal, esophagus, nasopharynx, breast and lung (non-small cell types) cancers. Selected results are presented here, by type of cancer.

Breast cancer
As early as 1970, breast cancer patients received long term combination chemotherapy along with C. versicolor extract immunotherapy. Addition of the extract to the regimen significantly extended the survival rate. In a large trial done in 1995 in Japan, the survival rate at 10 years was 81% for the PSK plus chemotherapy group while the rate fell to 64% for the group that used chemotherapy alone. The study concluded that immuno-chemotherapy with mushroom extract could improve the prognosis of patients with resectable breast cancer with vascular invasion. Mild and well tolerated side effects such as leukopenia and nausea were observed in 5 out of the 227 patients (Iino et al, 1995).

Colorectal cancer
C. versicolor extract was assessed for its potential anticancer activity in patients with advanced colorectal cancer (stages III and IV) by Torisu et al (1990). PSK was given at 3 grams/day for two months after surgery, followed by 2 grams/day until the end of the second year and 1 gram/day thereafter. This study found that the leucocyte activity of the PSK group was remarkably enhanced. Notably, polymorphonuclear leukocytes from PSK-treated patients showed enhancement in their activities, such as random and/or chemotactic locomotion, and phagocytic activity, when compared with those of the control group. The survival rate of the PSK group reached 40%, a net improvement over the 25% rate registered for the placebo group. From this study, it was concluded that PSK could be useful as a maintenance therapy for patients after their curative surgical operations for colorectal cancer.

Gastric and esophageal cancer
Stomach cancer is a major cause of mortality in Japan and China and, for that reason, has been the object of many clinical trials with polysaccharopeptides from C. versicolor. Trials done in the 1970s and 80s have evidenced a better survival rate at two or three years. More recent clinical studies, done in the 1980s and 90s, established that PSK could improve the survival rate at five years and beyond in stomach cancer patients, including some patients with advanced Stage III and IV cancer with metastasis (Kidd, 2000).

In a randomized clinical trial including 579 patients with gastric cancer receiving chemotherapy, C. versicolor extract was administrated orally as an adjuvant to surgery in a combination therapy to part of the group, at a daily dose of 3 grams for 1 year. Results from this study showed a significant increase in the 5 years survival rate for the PSK-treated group when compared with the other groups (Niimoto et al, 1988).

In an additionnal study involving more than 260 patients who underwent surgery for stomach cancer at 46 hospitals in Japan, those who received PSK along with chemotherapy experienced a higher 5-year disease free rate and a better 5-year survival rate than subjects who underwent chemotherapy alone (73% vs 60%). The two regimens had slight toxic effects, consisting of nausea, leucopenia, and liver functions impairment but no characteristic toxic effects were linked to PSK administration (Nakazato et al,1994).

Trials with PSP indicated that this C. versicolor extract has the potential to alleviate the side effects normally associated with chemotherapy (lassitude, inappetance, spontaneous perspiration, etc.) in patients with stomach cancer classified as stage I to IV (Zhang et al, 1999). Moreover, an increase in the immunological functions and a concomitant decrease of the adverse hematological side effects of chemotherapeutic drugs was demonstrated for stomach cancer patients following the administration of PSP (1 gram three times a day for 8 weeks) (Wu et al, 1999a).

Results from a prospective multi-center study including 158 esophageal cancer patients, showed that those who received PSK (3 grams/day for three months after surgery) had a significantly better survival rate at five years (55% and 58%) as compared with those without PSK supplementation (26 and 31%) (Ogoshi et al, 1995a). Ogoshi et al (1995b) also reported the results of another study with 174 patients who underwent esophagectomy and were then assigned to receive radiotherapy or chemotherapy with or without PSK. There was a tendency for longer survival on PSK, but statistical significance was not reached. However, regression analysis indicated that C. versicolor extract may have beneficial effect on esophageal carcinoma when combined with radiotherapy and chemotherapy.

Better survival rates were also achieved with PSP. A hundred patients with esophageal carcinoma were randomly divided into two groups; one was treated with radiotherapy alone while the other one received radiotherapy plus PSP (3 grams daily for a total dose of 190 grams during the period of radiation time). The results showed that patients treated with radiotherapy plus PSP had higher one, three and five year survival rates (67%, 38% and 19% respectively) versus the control group (47%, 21% and 14%) (Yao, 1999). Addition of PSP to the regimen improved the relief of major symptoms commonly associated with esophageal cancer, such as change of weight, alteration in the hemogram profile and in immunological functions. The relief of these symptoms was quantified to reach 61% in the PSP-treated group, while it was 31% in the control group (Wu and Wang, 1999b).

Leukemia
A study with PSK as an adjuvant to chemotherapy done in the early 1980’s (with 28 patients) found that remission and survival were significantly prolonged for patients who received PSK plus chemotherapy over those who received chemotherapy alone (Nagao et al, 1981). In another multi-center trial including 67 patients in remission of acute non-lymphocytic leukemia (ANLL) in Japan, patients who received a maintenance chemotherapy plus immunotherapy with PSK tended (but not significantly) to have longer survival over the group that received chemotherapy alone. However, when data analysis was focused on a sub-group of patients that maintained complete remission for more than 270 days, it became clear that immunotherapy with PSK had a beneficial effect (P = 0.105), prolonging the 50% remission period by 418 days (885 vs 467 days) (Ohno, et al, 1984). It was concluded that PSK may help in the treatment of adult ANLL when used for maintenance therapy in combination with chemotherapy especially in patients with an initial good prognosis.

Lung cancer
A Japanese clinical trial was done with patients having different lung cancers (of severity up to stage IIIB); a group was selected to receive 3 grams of PSK daily after cessation of radiation therapy. PSK was given in repeating cycles of two weeks on and two weeks off. After 5 years, 27% of the patients treated with PSK were alive compared to 7% for those not given the mushroom extract (Hayakawa et al, 1993). The study also demonstrated that patients with stage III disease who received PSK had a better prognosis than those with stage I and II without PSK. The effects of PSP as an accessory treatment for lung cancer was evaluated by Ke et al (1999) who administrated the mushroom extract to 30 patients receiving chemotherapy. The symptoms (side effects) improvement for PSP-treated patients was over 87%, while it was 47% for the control group.

Taking together, the findings from Phase II and Phase III clinical trials established that PSP benefits cancers of the stomach, esophagus, and lung and PSP. As a consequence, PSP was recognized for these applications by the China’s Ministry of Public Health (Yang, 1999c). The percentage of patients who experienced benefits from PSP in the Phase II and Phase III trials ranged from 90 to 97% for stomach, 82-87% for esophageal, and 70-86% for lung cancer (data statistically significant when compared to control data). Clearly, PSP can benefit the majority of patients afflicted with such cancers, and has the potential to be therapeutic against other cancers as well (Chen et al, 1993).

Other Effects of PSP
Besides its documented anti-cancer effects, polysaccharopeptides from C. versicolor could be useful for other conditions as well. Antiviral and hepatoprotective benefits have been reported for C. versicolor extracts. PSP is currently being investigated in animal model for application in the treatment of viral infection and hepatitis.

PSP has the potential to be a useful agent in the fight against human immunodeficiency virus type 1 infection (HIV-1 – which has a worldwide distribution). Reports point out the potential of PSP to interfere with the binding of the HIV-1 virus to cellular target. This effect could be mediated by the carbohydrate moiety of PSP binding to HIV-1 and affecting the binding of the virus to the CD4 lymphocyte receptors. PSP also has a very potent inhibitory effect against HIV-1 reverse transcriptase (a viral step following attachment to CD4 lymphocytes) in vitro. The multivalent manner in which PSP acts to inhibit HIV life cycle makes it an ideal candidate for more advanced studies (Collins and Ng, 1999; Jong and Yang, 1999; Xu, 1999).

In China, C. versicolor is also considered useful in the treatment of hepatitis. Preliminary studies have shown that PSP is effective in protecting the liver from hepatotoxins in laboratory animals. Several mechanisms have been proposed for this particular protective effect, including direct conjugation of PSP to toxic agents. PSP can also promote reconstitution of hematopoietic functions in irradiated mice and could also act on hepatic reduced glutathione (GSH) as demonstrated with animal studies using acetaminophen; the conjugation of GSH to xenobiotics serves as a protective mechanism to facilitate the disposition of reactive or toxic compounds. As with antiviral action, the multivalent manner in which PSP acts to protect liver cells and detoxification mechanisms, demonstrate the potential usefulness of C. versicolor extracts to prevent damages from reactive compounds which could be carcinogenic agents (Jong and Yang, 1999; Yeung, 1999; Yeung et al, 1999; Wang et al, 1999)

Regulatory Status and Dosage
In Asia, C. versicolor extract is available as a health supplement and can be purchased without a prescription. In both China and Japan, health authorities regard C. versicolor extract as a valuable adjunct for combination chemotherapy or radiotherapy in the treatment of various cancers (Chu et al, 2002). In the United States, PSP has been put on record as a fungous anticancer substance by the American National Cancer Research Center (Applied Microbiology, vol 34: 183-264, 1989). However, PSP has not been evaluated by the Food and Drug Administration and is sold as a dietary supplement not specifically intended to treat, cure or prevent any disease.

C. versicolor extract can be taken in capsules, as an extract, or as a tea. However, the most practical administration form is encapsulated PSP containing intracellular mycelium extract. For encapsulated extract, 2 to 6 grams is the daily oral dosage used in most clinical trials (see clinical research reports in Yang, 1999). It is recommended that the daily dose be split between morning, noon and evening, taking between 500 mg to 2 grams each time, on an empty stomach or with a light meal. For general preventative purposes, one might use about 500 mg to 600 mg capsule twice daily.

Additional PSP Product Data

Available PSP Products

References
Arora, D.K., R.P. Elander and K.G. Mukerji, editors (1991) Handbook of Applied Mycology. Volume 4: Fungal Biotechnology. Marcel Dekker, 1114p.

Carlile, M.J., S.C. Watkinson et G.W. Gooday (2001) The Fungi. Academic Press, 2nd editon, 588p.

Chen, R.T. and B. Xu (1990) Study of anti-tumor effect of polysaccharopeptide of C. VERSICOLOR. J. of the Shanghai Teachers Univ., 19(2) 1-84

Chen, Z., M. Yang et P. Zhu (1993) Research and application of the anticancerous mechanism of the purified PSP (PCV). In: Yang, Q. and C. Kwok (eds), PSP International Symposium 1993, Hong Kong. Fudan University Press, 151-152.

Chu, K.K.W., S.S.S. Ho and A.H.L. Chow (2002) C. VERSICOLOR; A Medicinal Mushroom with Promising Immunolotherapeutic Values. J. Clin. Pharmacol., 42: 976-984.

Collins, R.A. and T.B. Ng (1999) Polysaccharopeptide from C. VERSICOLOR has potential for use against human immunodeficiency virus type 1 infection. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 181-186), Hong Kong Association for Health Care Ltd.

Di Luzio, N.R., D.L. Williams et al (1980) Comparative evaluation of the tumor inhibitory and antibacterial activity of solubilized and particulate glucan. Recent Results Cancer Research, 75: 165-172.

Dong, Y., C.Y. Kwan, Z.N. Chen et M.M. Yang (1996) Anti-tumor effects of a refined polysaccharide peptide fraction isolated from C. VERSICOLOR: in vitro and in vivo studies. Research Communications in Molecular Pathology & Pharmacology, 92: 140-148.

Fisher, M. and L.X. Yang (2002) Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res., 22: 1737-1754.

Fujii, T., K. Sasito, K. Matsunaga et al, (1995) prolongation of the survival period with the biological response modifier PSK in rats bearing N-methyl-N-nitrosourea-induced mammary gland tumors. In Vivo, 9: 55-57.

Iino, Y., T. Yokoe, M. Maemura et al (1995) Immunochemotherapies versus chemotherapy as adjuvant treatment after curative resection of operable breast cancer. Anticancer Research.., 15: 2907-2912.

Jong, S.C. et Yang, X.T. (1999) PSP- a powerful biological response modifier from the mushroom Coriolus vesicolor. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 16-28, Hong Kong Association for Health Care Ltd.

Hayakawa, K., N. Mitsuhashi, Y. Saito et al (1993) Effect of Krestin (PSK) as adjuvant treatment on the prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer Res., 13: 1815-1820.

Jian, X.Z, L.M. Huang, Y.F. Zhou and M.M. Wang (1999) Subchronic toxicity test of polysaccharopeptide of Yun Zhi (PSP). In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 272-284, Hong Kong Association for Health Care Ltd.

Jin, T.Y. (1999) Toxicological research on Yun Zhi polysaccharopeptide (PSP). In: Yan, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 76-79, Hong Kong Association for Health Care Ltd.

Kanoh, T., K. Matsunaga, K. Saito et T. Fujii (1994) Suppression of in vivo tumor-induced angiogenesis by the protein-bound polysaccharide PSK. In Vivo, 8: 247-250.

Ke, L., P.Y. Yao, Z.M. Gao and S.T. Fan (1999) An observation on the effect of polysaccharide peptide (PSP) as an accessary treatment for lung cancer. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 331, Hong Kong Association for Health Care Ltd.

Kidd, P.M. (2000) The use of mushrooms glucans and proteoglycans in cancer treatment. Altern. Med. Rev., 5: 4-27.

Kobayashi, H., K. Matsunaga, M. and Fujii (1993) PSK as a chemopreventive agent. Cancer Epidemiology, Biomarkers & Prevention, 2: 271-276.

Kobayashi, H., K. Matsunaga, M. and Y. Oguchi (1995) Antimetastasic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview. Cancer Epidemiology, Biomarkers & Prevention, 4: 275-281.

Li, X.Y. (1999) Advances in immunomodulating studues of PSP. In: Yan, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 39-46, Hong Kong Association for Health Care Ltd.

Li, X.Y., J.F. Wang, P.P. Zhu, L. Liu, J.B. Ge and S.X. Yang (1990) Immune enhancement of a polysaccharides peptides isolated from C. VERSICOLOR. Chung Kuo Yao Li Hsueh Pao, 11: 542-545.

Li, X.M. and L.Z. Xu (1987) A study of anti-cancer effects of PSP and PSK on human tumor cell lines in vitro. Acta Acad. Med., Shanghai, 14(5) 23-24.

Liu, J.X., J.Y. Zhou and T.F. Liu (1999) Phase III clinical trial for Yun Zhi polysaccharopeptide (PSP) capsules. In: Yang, Q.Y. (ed), International Symposium on Traditiional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 295-303. Hong Kong Association for Health Care Ltd.

Liu, W.K., T.B. Ng, S.F. Sze and K.W. Tsui (1993) Activation of peritoneal macrophages by polysaccharopeptide from the mushroom, C. VERSICOLOR. Immunopharmacology, 26: 139-146.

Liu, W.K., T.B. Ng, S.F. Sze and K.W. Tsui (1999) Evidence that C. VERSICOLOR polysaccharopeptide acts on tumor cells through an immunomodulatory effect on macrophages. In: Yang, Q.Y. (ed), International Symposium on Traditiional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 187-191, Hong Kong Association for Health Care Ltd.

Liu, J.X, J.Y Zhou and T-F Fei (1999) Phase III clinical trial for Yun Zhi polysaccharopeptide (PSP) capsules. In: Yang, Q.Y. (ed), International Symposium on Traditiional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 295-303, Hong Kong Association for Health Care Ltd.

Lu, J., H. Wan, Y. Tian, Z. Xu, J. Tan and H. Chen (1995) Effect of C. VERSICOLOR polysaccharide on murine immunologic function. Chinese Pharmaceutical Journal, 30: 10-13.

Mao, X.W., J.O. Archambeau, D.S. Gridley (1996) Immunotherapy with low-dose interleukin-2 and polysaccharopeptide derived from Coriolus vesicolor. Cancer Biother. Radiopharm., 11: 393-403.

Mao, X.W., L.M. Green et D.S. Gridley (2001) Evaluation of polysaccharopeptide effects against C6 glioma in combination with radiation. Oncology, 61: 243-253.

Mansell, P.W., H. Ichinose et R.J. Reed et al (1975) Macrophages-mediated destruction of human malognant cells in vivo. Journal of the National Cancer Institute, 54(3): 571-580.

Matsunaga, K., H. Iijima, M. Aota et al (1993) Enhancement of effector cell activities in mice bearing syngeneic plasmacytoma X5563 by a biological response modifier, PSK. Journal of Clinical & laboratory Immunology, 37: 21-37.

Mitomi, T., S. Tsuchiya, N. Iijima et al (1992) Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. Diseases of the Colon and Rectum, 35: 123-130.

Morikawa, K. R. Takeda, M. Yamazaki et al (1985) Induction of tumoricidal activity of polymorphonuclear leucocytes by a linear beta-1,3 D-glucan and other immunomodulators in murine cells. Cancer Research, 45(4) 1496-1501.

Nagao, T., M. Komatsuda, K. Yamauchi, H. Nozaki, K. Watanabe and S. Arimori (1981) Chemo-immunotherapy with Krestin (PSK) in acute leukemia. Tokai Journal of Experimental & Clinical Medicine, 6: 141-146.

Nakajima, T., S. Ichikawa, S. Uchida et T. Komada (1990) Effects of aa protein-bound polysaccharide from a basidiomycetes against hepatocarcinogenesis induced by 3’-methyl-4-dimethylaminobenzene in rats. Clinical Therapeutics, 12: 385-392.

Nakazato, H., A. Koite, S. Saji, N. Ogawa and J., Sakamoto (1994) Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet, 343: 1122-1126.

Ng, T.B. and W.Y. Chan (1997) Polysaccharopeptide from the mushroom C. VERSICOLOR possesses analgesic activity but does not produce adverse effects on female reproductive or embryonic development in mice. Gen. Pharmacol., 29: 269-273.

Niimoto, M., T. Hattori, R. Tamada, K. Sugimachi, K. Inokuchi and N. Ogawa (1988) Postoperative adjuvant immunochemotherapy with mitomycin C, futraful and PSK for gastric cancer; an analysis of data on 579 patients followed for five years. Japanese Journal of Surgery, 18: 681-686.

Ogoshi, K., H. Satou, K. Isono, T. Mitomi, M. Endoh and M. Sugita(1995a) Possible predictive markers of Immunotherapy in esophageal cancer: retrospective analysis of a randomized study. Cancer Investigation, 13: 363-369.

Ogoshi, K., H. Satou, K. Isono et al, (1995b) Immunotherapy for esophageal cancer: a randomized trial in combination with radiotherapy and radiochemotherapy. American Journal of Clinical Oncology, 18: 216-222.

Ohno, R., K. Yamada, T. Masaoka et al (1984) A randomized trial of chemoimmunotherapy of acute nonlymphocytic leukemia in adults using a protein-bound polysaccharide preparation. Cancer Immunology Immunotherapy., 18: 149-154.

Qian, Z.B., L.F. Zhou, Z.D. Zhang, B.Xu, P.J. Xin, L.Y. Zhou, R.T. Chen and Z.G. Li (1993) The test of PSP on the cause of the abnormal fetus in two generations of rats. In: Yang, Q. and C. Kwok (eds), Proceedings of PSP International Symposium, Shanghai, Chinam Fudan University Press, pp. 157-158

Qian, Z.M., M.F. Xu and P.L. Tang (1997) Polysaccharide peptide (PSP) restores immunosuppression induced by cyclophosphamide in rats. Am. J. Chin. Med., 25: 27-35.

Torisu, M., Y. Haayashi, T. Ishimitsu et al (1990) Significant prolongation of disease-free period gained by oral polysaccharide K (PSK) administration after curative surgical operation of colorectal cancer. Cancer Immunology, Immunotherapy, 31: 261-268.

Tsukagoshi, S., Y. Hashimoto, G. Fujii, H. Kobayashi, K. Nomoto et K. Orita (1984) Krestin (PSK). Cancer Treatment Reviews, 11: 131-155

Wang, C.A., A.L. Ma, T.H. Zhang, and H. Yu (1993) The effect of Yun Zhi essence and schizophyllan in activating the lymphocytes of the peripheral blood to kill stomach liver and lung cancerous cells and leukocytes. In: Proceedings of PSP International Symposium, pp. 139-142, Fundan University Press.

Wang, H.X., T.B. Ng, W.K. Liu, V.E. Qoi and S.T. Chang (1996) Polysaccharide-peptide complexes from the cultured mycelia of the mushroom C. VERSICOLOR and their culture medium activate mouse lymphocytes and macrophages. Int. J. Biochem. Cell. Biol., 28: 601-607.

Wu, C.P., J. Wu and W.H. Sun (1999a) The curative effect of Yun Zhi polysaccharopeptide (PSP) on stomach cancer. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 322-325, Hong Kong Association for Health Care Ltd.

Wu, Z. and Z. Wang (1999b) Clinical curative effects observation on NSCLC and esophageal cancer by radiotherapy and chemotherapy combined with PSP. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 326, Hong Kong Association for Health Care Ltd.

Xu, L.Z. (1999) The anti-tumor and anti-virus activity of polysaccharopeptide (PSP) In: yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 62-67, Hong Kong Association for Health Care Ltd.

Yang, Q.Y. (1999a) Yun Zhi polysaccharopeptide (PSP) and the general aspects of its research. In: yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 29-38, Hong Kong Association for Health Care Ltd.

Yang, J.C., Y. Zhang, J.D. Tian, J.S. Lu et W.H. Sheng (1999b) The stimulative and inductive effects of C. VERSICOLOR polysaccharopeptide (PSP) on interferon. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 164-167, Hong Kong Association for Health Care Ltd.

Yang, Q.Y. (1999c) History, present status and perspectives of the study of Yun Zhi polysaccharopeptide. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 5-15, Hong Kong Association for Health Care Ltd.

Yao, W.Q. (1999) Prospective randomized trial of radiotherapy plus PSP in the treatment of esophageal carcinoma. In: Yang, Q.Y. (ed), International Symposium on Tradiiional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 310-313, Hong Kong Association for Health Care Ltd.

Yeung, J.H.K. (1999) Metabolic studies to investigate the protective effects of polysaccharide peptide (PSP) on paracetamol-induced hepatotoxicity in the rat. In: Yang, Q.Y. (ed), International Symposium on Tradiiional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 126-127, Hong Kong Association for Health Care Ltd.

Yeung, H.K., L.C.M. Chiu and V.E.C. Ooi (1999) Effect of poylsaccharide peptide (PSP) on glutathione and protection against paracetamol-indiced hepatotoxicity in the rat. In: Yang, Q.Y. (ed), International Symposium on Tradiiional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 126-127, Hong Kong Association for Health Care Ltd.

Zeng, S.J., S.L. Shen and L.-s. Wen (1999) The anticancerous effects of PSP compound on human nasopharyngeal carcinoma inoculated on nude mice. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 201. Hong Kong Association for Health Care Ltd.

Zeng, S.J., S.L. Shen, L.Z. Weng and Y.P. Wu (1993) The anticancerous effects of Yun Zhi essence on human lung adenocarcinoma inoculated in nude mice. In: Yang, Q. et C. Kwok C. (eds), Proceedings of PSP International Symposium, pp. 97-103, Fundan University Press.

Zhang, L.Y., Y. Zhong and J. Zhou (1999) The observation of PSP decrease 60 cases chemotherapeutical stomach cancer’s side effect. In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 328. Hong Kong Association for Health Care Ltd.

Zhong, B.Z. et al (1989) Chromosome aberration test. Recent Advance in Cancer, pp. 42-43.

Zhong, B.Z., Y.G. Zhou, L.F. Zhou et Q.Y. Yang (1999) Genetic toxicity test of Yun Zhi polysaccharopeptide (PSP). In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 285-294. Hong Kong Association for Health Care Ltd.

Zhou, J.X., X.Y. Li and X.T. Shen (1988) The anti-tumor and immunomodulating activity of Ps-P in mice. J. Shanghai Teachers Univ., 17(3): 72-77.

Zhou, Y.L and Q.Y Yang (1999) Active principles from Coriolus sp. . In: Yang, Q.Y. (ed), International Symposium on Traditional Chinese Medicine and Cancer: Development and Clinical Validation – Advances Research in PSP 1999, pp. 111-124. Hong Kong Association for Health Care Ltd.