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Cancer Therapy Vol 6, page 117

Cancer Therapy Vol 6, 117-130, 2008

General review of polysaccharopeptides (PSP) from


C. versicolor: Pharmacological and clinical studies
Review Article

King-Fai Cheng, Ping-Chung Leung*


Institute of Chinese Medicine, The Chinese University of Hong Kong

__________________________________________________________________________________
*Correspondence: Prof. Ping-Chung LEUNG, DsocS(Hon), D.Sc, M.S, Director, Centre for Clinical Trials on Chinese Medicine 5/F,
The CUHK Hong Kong Jockey Club School of Public Health Building, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR; Tel:
(852) 2632 2723/ 2252 8872; Fax: (852) 2686 8463/ 2632 5441; E-mail: pingcleung@cuhk.edu.hk
Key words: Coriolus Versicolor (Yunzhi); polysaccharopeptide (PSP); immunomodulation; anti-tumor
Abbreviations: biological response modifiers (BRM); Coriolus versicolor (CV); cyclophosphamide (CPA); human immunodeficiency
virus (HIV); Interleukine-2 (IL-2); intraperitoneal (i.p.); National Center for Complementary and Alternative Medicine (NCCAM);
Natural Killer Cells (NK cells); Office of Dietary Supplements (ODS); polysaccharopeptide (PSP); polysaccharopeptide Krestin (PSK)
Received: 20 December 2007; Revised: 30 January 2008
Accepted: 5 February 2008; electronically published: February 2008

Summary
In China, C. versicolor is named Yun Zhi (meaning cloud-like mushroom). C. versicolor is mainly used as an
adjuvant in the treatment of cancer. The active principle derived from C. versicolor belongs to a new class of
elements called biological response modifiers (BRM) which are defined as agents capable of stimulating the immune
system and thereby, they express various therapeutic effects. The best know commercial polysaccharopeptide
preparations of C. versicolor are polysaccharopeptide Krestin (PSK) and polysaccharopeptide (PSP). One of the
most important functions of PSP and PSK is their immunomodulatory and anti-cancer actions. The present paper
reviewed and summarized the pharmacological and clinical properties, as well as its background of Coriolus
versicolor or PSP.

According to the record of Ben Cao Gang Mu


(!"#$) written during the Ming Dynasty (1368-1644),
there were over 120 strain of C. versicolor (Hyde and
Adams, 1960). Recent literatures report that more than 270
medicinal fungi are used in traditional Chinese medicine
for their preventive and/or curative effects (Ding, 1987;
Ying et al, 1987). In the clinical practice of traditional
Chinese medicine, C. versicolor is recommended for
various types of cancers, chronic hepatitis, and infections
of the upper respiratory, urinary, and digestive tracts (Jong
and Yang, 1999; Li, 2003).
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 adjuvant for combination
chemotherapy or radiotherapy in the treatment of various
cancers (Mizuno, 1999; Yan et al, 2000; Chu et al, 2002).
The present paper reviews and summarizes the
pharmacological and clinical properties, as well as its
background of Coriolus versicolor or PSP.

I. Introduction
Mushrooms have an established history of use in
traditional oriental therapies. In Asian cultures,
mushrooms are combined with herbal mixtures to treat
cancer. The mushroom Coriolus Versicolor (C. versicolor)
is a macrofungi belonging to the Basidiomycetes class,
which encompasses about 20,000 and 25,000 known
species (Gregory and Hirst, 1957; Hyde and Adams,
1960). In China, C. versicolor is named Yun Zhi (meaning
cloud-like mushroom). Researches have found that this
mushroom has antimicrobial, antiviral and anti-tumor
properties (Jong and Birmingham, 1993; Ulrike et al,
2005). Nowadays C. versicolor is mainly used as an
adjuvant in the treatment of cancer (Tsang et al, 2003;
Hattori et al, 2004). It has been demonstrated that extracts
obtained from this mushroom are likely to show
stimulatory effects on the immune system and to inhibit
the growth of cancer cells. Because of these properties,
Yun Zhi is called a biological response modifier (BRM)
(Leung et al, 2006).

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Cheng and Leung: General review of polysaccharopeptides (PSP) from C. versicolor


PSP and PSK are light or dark brown powders that
are soluble and stable in hot water. They are chemically
similar and posse similar physiological activity profiles,
PSK and PSP differ mainly in the presence of fucose in
PSK and rhamnose and arabinose in PSP (Table 1).

II. Composition of C. versicolor


The composition of the polysaccharopeptide is
depending on the source of the material and the method of
extraction used. For example, polysaccharopeptide Krestin
(PSK) is obtained from the extraction of C. versicolor
(CM-101) strains, while polysaccharopeptide (PSP)
obtained from the extraction of C. versicolor (Cov-1)
strains (Chu et al, 2002; Zhou et al, 2007).
The active principle derived from C. versicolor
belongs to a new class of elements called BRM. BRM are
defined as agents capable of stimulating the immune
system and thereby, they express various therapeutic
effects (Leung et al, 2006). Polysaccharides linked to a
small protein (or peptide) are at the base of this
immunomodulatory activity. This polysaccharidepeptide is termed polysaccharopeptide, or PSP in its
abbreviated form. 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.

IV. Safety studies


The toxicological experiments conducted with a
variety of animals (dogs, monkey and guinea pigs) had
shown negative results for acute, genetic, reproductive and
chronic toxicity.

A. Acute toxicity
The LD50 value of PSP is 26-300.36mg/kg for mice
administered by intraperitoneous injection. The highest
daily tolerant dose was over 18-20g/kg for mice (Jin,
1999; Ze et al, 2003). According to the Procedures for
Toxicological Assessment on Food Safety Acute Toxicity
Test (GB15193.3-94), PSP is considered to be non-toxic
(Procedures for Toxicological Assessment on Food Safety
Acute Toxicity Test GB15193.3-94).

III. The difference between PSP and


PSK

B. Long-term toxicity

The best know commercial polysaccharopeptide


preparations of C. versicolor are PSK and PSP. Both
products are obtained from extraction of C. versicolor
mycelia (Figure 1). PSK is a Japanese product, while PSP
is Chinese product which was first isolated in 1986 (Yang
and Van, 1986). Both products have similar physiological
activities but are structurally different. PSK is produced
from CM-101 strain of C. versicolor, the extraction is done
by salting out with ammonium sulfate from the hot water
extract. PSP is produced from Cov-1 strain of C.
versicolor (Figure 2), the extraction is done by using
alcoholic precipitation from the hot water extract.

Subchronic and chronic toxicity studies were done by


Jian et al who continuously administrated 4 oral doses (0,
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 (Jian, 1999). Rats and monkeys were
administrated with PSP by oral at a dose of higher than
200 and 100 times of human dose separately daily for 6
months, no abnormal changes in development,
hematology, blood chemistry, and electrocardiography
were observed (Zou et al, 2003).

Figure 1. Trametes (Coriolus) versicolor (http://www.alohamedicinals.com/chapt3_c.pdf).

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Cancer Therapy Vol 6, page 119

Figure 2. Typical partial structures of polysaccharide portions of the polysaccharide peptide (PSP) of COV-1 strain of Coriolus
versicolor (Zhou and Yang, 1999).

Table 1. The differences of PSP and PSK

Source
Produced in
Appeared on the market in
Extract method

Physicochemical properties

Chemical composition

Biological properties

References

PSP
Mycelia of Coriolus versicolor
Cov-1 strain
China
1987
Recovered by alcoholic
precipitation from hot water
extract
Brown in color; soluble in water;
insoluble in organic solvents;
stable to heat; mean
MW=100kDa
(1!3) !-glucan branched at 4
and 6 positions

PSK
Mycelia of Coriolus versicolor
CM-101 strain
Japan
1977
Recovered from hot water
extracts of the biomass by salting
out with ammonium sulfate
Brown in color; soluble in water;
insoluble in organic solvents;
stable to heat; mean
MW=100kDa
18%--38% w/w protein
(1!3) !-glucan branched at 4
and 6 positions
rhamnose, arabinose
fucose
In vitro and in vivo
In vitro and in vivo
immunorestorative and antiimmunorestorative and antitumor activities
tumor activities
Sakagami and Takeda, 1993; Ng et al, 1999; Kidd, 2000; Cui and
Yusuf, 2003

Accumulating evidence suggested that the


polysaccharopeptides were nontoxic even when
administered at several times the therapeutically effective
dosage and over extended periods. Extended use of PSP at
100-fold the normal clinical dose had not induced acute
and chronic toxicity in animals (Ng et al, 1997).

The results of chromosomal aberration tests and


cytogenetic lesions in mice showed that the number of
chromosomes had not changed in PSP treated groups even
at the high dose rate 126 mg/kg.

D. Reproductive test
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 that the usual clinical dose (Qian et al, 1993). The
lack of deleterious effects on ovarian follicular
development, ovulation, pregnancy and embryo
development in mice was also demonstrated (Ng et al,
1997). Polysaccharopeptides appear to be safe during
pregnancy. No adverse effects of PSP had been observed
in female reproductive and embryonic development in
mice (Ng et al, 1997).

C. Genetic toxicity (Zhong et al, 1999)


Mutagenicity of PSP was assessed with the Ames
test and with the chromosomal aberration test of bone
marrow cells in mice. It was concluded that PSP showed
no evidence of mutagenic or cytogenetic activity.
Cytotoxicity tests of PSP with V79 Chinese hamster
cells in vitro also showed no toxic effects against the V79
cell line.
In vivo micronucleus tests to assess the cytogenotoxicity on mammalian somatic cells, the results indicated
that PSP showed no evidence of mutagenic potential.

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Cheng and Leung: General review of polysaccharopeptides (PSP) from C. versicolor


Researches demonstrated that PSP can antagonize the
immunosuppression caused by such chemotherapeutic
agents (Qian et al, 1997; Li, 1999). The administration of
PSP (at a dosage of 2 grams/kg day) on
cyclophosphamide-induced
immunosupressed
rats
demonstrated that the mushroom extract was effective in
restoring their immune system. It did so by stimulating
lymphocytes proliferation, NK cell functions, and the
growth of spleen and thymus where lymphocytes mature
and transit (Qian et al, 1997).

V. Pharmacological actions
A. Immunomodulatory effects
The immunological activities of PSP and PSK have
been extensively investigated both in vitro and in vivo.
PSP strengthening the immunological functions was
studied. Its anti-tumor effect seemed to be mediated more
through immunomodulatory regulation rather than by
direct cytotoxicity as was the case for most anticancer
drugs currently used. Numerous reports had demonstrated
the ability of PSK and PSP to active cellular and humoral
components of the host immune system. In addition, these
polysaccharides had been shown to inhibit the growth of
tumor cell lines and to have in vivo anti-tumor activity
(Tzianabos, 2000).
The effect of PSP on the phagocytic functions had
been tested in normal ICR mice. It was determined that the
carbon clearance rate of the groups given oral doses of
0.5-1.5g PSP/kg or intraperitoneal (i.p.) injections of 100,
200, 400mg/kg was similar to that of groups treated with
acanthopanax (300mg/kg). Regardless of the route of
administration, PSP increased the carbon clearance rate in
mice and it suggested that PSP could increase the
phagocytic function of normal animals (Yang et al, 1993).
It was reported that PSP in different concentrations
promoted the proliferation of T-lymphocytes both in
human peripheral blood and mouse splenocytes (Li, 1999).
PSP augmented T-helper cell (CD4+) activation, and also
increased the ratio of CD4+/T suppressor (CD8+)
production (Li, 1999). It appeared that the basic
mechanisms for PSP to inhibit tumor cells included the
activation of 1) macrophages, 2) natural killer cells and 3)
T-helper cells (CD4+) which induce T-killer cells,
antibody production, and interleukins (Li, 1999). Studies
were conducted in vitro with numerous cell lines to
investigate the immunomodulatory effects of PSP. It was
recognized that Interleukine-2 (IL-2) plays a critical role
in immune defense against tumors, 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-" (IFN-") and markedly improve the
production of IFN-# (Yang et al, 1999). A study
demonstrated that PSP did not exert a direct cytotoxic
effect on tumor cell lines but rather stimulated
macrophages, thus strengthening the hypothesis that C.
versicolor anti-tumor effects were mediated by an
immunomodulatory mechanism (Liu et al, 1999). In vivo
studies had revealed that PSP usually had no significant
immunological effects on a normal host, but could restore
a depressed immunological responsiveness as seen in
cancer or with chemotherapy (Chu et al, 2002).
PSP can also counteract the depressive effect of
cyclophosphamide (CPA) on the white blood cell count
and interleukin-2 production. 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.

B. Anti-tumor effects in vivo


Many studies have been done since 1980s to demonstrate
the effectiveness of PSP, and its counterpart PSK (Table
2). The anti-tumor actions are predominantly considered to
be host-mediated. The preliminary determination of antitumor activity is usually assessed by a bioassay system
normally using Sarcoma 180 in mice and B16 melanomabearing mice through transplantable animal tumor (Yang
et al, 2007). Several hundreds of polysaccharides or
polysaccharide-protein complexes have been screened for
their anti-tumor activity, and three of them, namely
schizophyllan, lentinan and protein-bound polysaccharides
(PSK and PSP), have been used clinically (Kobayashi et
al, 1993). PSK has been successful in postoperative
treatment of respectable cancer in humans, increasing
survival rates (Ito et al, 2004). Protein-bound
polysaccharide (PSK) prepared from the cultured mycelia
of Coriolus versicolor in Japan demonstrated a significant
anti-tumor effect against allogeneic tumors such as
Sarcoma 180 and Ehrlich carcinoma of experimental
animals by both intraperitoneal and oral administration
(Taniguchi et al, 1984; Kobayashi et al, 1993). Researches
indicated that PSK and PSP can suppress pulmonary
metastasis from induced sarcomas, induced prostate
cancer, lymphatic metastasis of mouse leukemia P388, and
that both could prolong the survival period in spontaneous
metastasis model (Xu, 1999).
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 cellinduced platelet aggregation, 3) by suppression of tumor
cell migration after extravasation through the inhibition of
tumor cell mobility, and 4) by suppression of tumor
growth after extravasation through the inhabitation of
angiogenesis, the modulation of cytokine production and
the augmentation of effector cell function (Liu et al, 2004).
In addition to anti-cancer effect, animal study also
demonstrated that PSP had central analgesic effect (Yin et
al, 2002).
In vitro antitumour study, the C. versicolor extract
was also found to tumour-selectively and dosedependently inhibit the proliferation of lymphoma and
leukemic cells possibly via an apoptosis-dependent
pathway (Lau et al, 2004; Zhou et al, 2007). However,
both immune property and anticancer potency of
polysaccharopeptide-Coriolus versicolor were affected by
the fermentation duration of the fungi (Lee et al, 2006).

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Cancer Therapy Vol 6, page 121


Table 2. Some animal anti-tumor studies.

1
2

Animal
Mice

Test article
PSP

Administration
By oral

Dosage
1-2g/kg/day

Duration
15-20 days

Nude mice

PSP

Intraperitoneal

50mg/kg/day 3 weeks

Mice

PSP

Intraperitoneal

2 weeks

Rats

PSK

oral

150mg/kg
3 weeks
twice a week

Mice

PSP

Oral

2, 5 g/kg
daily

4 weeks

Mice

CVP1

Intraperitoneal

5-20mg/kg

3-15 days

Rats

PSP

Oral

1.2g/day

21 days

Results
Inhibited growth of
human lung
adenocarcinoma by
50-70%
Inhibited the growth
of Lewis lung cancer
by nearly 45%
Decreased the
incidence of tumor
growth, tumor size in
control group about 35 times bigger than the
PSP group
Prolonged the survival
period of mammary
tumor-bearing rats
Tumor inhibition rate
of 77 and 63% in
treated groups
Exerted inhibitory
effects on
experimental and
clinical tumors
Oral PSP did not
prevent CTX2-induced
cytopenia in rats

Reference
Zeng et al, 1993

Wang et al, 1993

Dong et al, 1996

Fujii et al, 1995

Zeng et al, 1999

Wei et al, 1996

Kanoh et al,
1994

Coriolus versicolor polysaccharides


Cyclophosphamide

When PSK, obtained from cultured mycelia of


Coriolus versicolor, was administered in mice, in vivo
tumor-induced angiogenesis was suppressed (Mao et al,
2001).
However, some animal experiments could not
demonstrate a specific effect of polysaccharopeptides
extracted from the mushroom C. versicolor. For example,
for a long-term control of brain tumors, intraperitoneal
injection of 2mg of PSP with radiotherapy did not increase
radiation efficacy (Mao et al, 1996). Another study
investigated the effect of low-dose administration of IL-2
or PSP alone in a herpes virus type-2 transformed murine
tumor in mice. The results indicated that IL-2 or PSP alone
could slow down tumor progression, but the combination
of the two modalities had no synergistic effects on tumor
growth (Liu, 2001). These results warranted further
investigation to determine if PSP could be effectively used
for all types of tumors, or cancers, in which
immunosuppression was a prominent feature.
In general, it seemed that oral administration of PSP
reduced the incidence of tumor or prolonged the survival
period, following chemical carcinogen-induced, radiationinduced and spontaneously developed animal cancer
models. Coriolus versicolor (CV) regulated cytokine
production and possessed both anti-tumor and
immunopotentiating activities (Ho and Lau, 2004). The

main mechanism might be an anti-teratogenic effect


attributed to free radical trapping and prevention of
chromosome injury, coupled to an immunomodulating
effect linked to the modulation of cytokines production
and effect cell function. Table 3 summaries the possible
mechanisms of anticancer effects of PSP (Hobbs, 2004).

C. Antimicrobial effects
Besides its documented anti-cancer effects,
polysaccharopeptides from C. versicolor could be useful
for other conditions as well.
PSK has been demonstrated to have antiviral
activities against ectromelia virus (Taniguchi et al, 1984)
and cytomegalovirus infections (90) and human
immunodeficiency virus (HIV) (Zou and Zhu, 2003).
In China, C. versicolor is also considered useful in
the treatment of hepatitis. Preliminary studies had
indicated that PSP was effective in protecting liver from
hepatotoxins in laboratory animals (Song and Liang, 2000;
Zou et al, 2003). As with antiviral action, the multivalent
manner in which PSP acts to protect liver cells and
detoxification mechanisms, demonstrates the potential
usefulness of C. versicolor extracts to prevent damages
from reactive compounds which could be carcinogenic
agents (Jong and Yang, 1999; Yeung, 1999).

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Cheng and Leung: General review of polysaccharopeptides (PSP) from C. versicolor


Table 3. Mechanisms of anticancer effects of extracts of C. versicolor.
Inhibition of DNA of tumour cells
Enhancement of cytokine production
Antitumour activity in wide range of animal systems
Tumour cell killing effect
Inhibition of carcinogen-induced cancers in rats
Antioxidant effects in tumour-bearing rats
Induction of apoptosis
Antiproliferative effect on many cancer cell lines
Anti-invasion effects
Angiogenesis effects
Tumouricidal and cytotxicity effects
Antimetastic activity
Immunoprotective effects during radiation and chemotherapy

have an 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 cancers. Study
also showed that PSP has effect of cancer prevention and
development (Zhou et al, 2001). The following were the
clinical trial results selected from research papers
conducted in Japan (Table 4, 5).

D. Anti-nociceptive effects
In an animal study, two different mice pain models
were used to investigate the anti-nociceptive effects of
PSP. The results demonstrated that PSP could induce
hyperalgesia. PSP-induced hyperalgesia was related the
activation of peritoneal macrophages and mast cells and,
hence, increased the release of inflammatory mediators
(Chan and Yeung, 2006).

A. Breast cancer

VI. Clinical studies

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 which 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 227 patients
(Iino et al, 1995).

The therapeutic use of PSP or PSK as an adjuvant


therapy in cancer treatment has been substantiated by
numerous clinical trials. Table 6 summarizes the
methodological parameters and the results of some these
trials. As an adjuvant in the treatment of many types of
cancers, Yun Zhi (PSP) was subjected to Phase I, II and III
clinical trials in Shanghai, China. The results showed that
addition of PSP to radiotherapeutic or chemotherapeutic
protocols can greatly improve the quality of life of cancer
patients and reduce chemotherapy-induced side effects
(Zhong et al, 2001), because PSP alleviated weakness,
anorexia, vomiting, dryness of throat, spontaneous sweat
and pain symptoms. In addition to symptoms
improvement, polysaccharopeptides from Yun Zhi also
Table 4. Randomized controlled trials for breast cancer.
Patients
914 cases Standard
or Radical
mastectomy

Stage
IIA, IIB, III

227 cases operable


breast cancer with
v+ and/or n+
involvement
134 cases Typed
as HLAA, HLA-B
and HLA-C

Treatment
1.Patients(ER+tumours)
chemo +/- tamoxifen
2.Patients (ER- tumour)
Chemo +/- PSK
Chemo (n=77)
Chemo +LMS (n=76)
Chemo +, PSK (n=74)

Operable with
v+ and/or nv+

Previously randomised
into two groups(ref 23):
1. Chemo
2. Chemo +PSK
Each group stratified by
HLA type B40+ or
B40-.

122

Outcome
Longer overall survival for patients in
Stage IIA T2N1 cancer ER- and
node-negative treated with chemo +
PSK compared with other ERsubgroups without PSK.
Risk ratio lower in the chemo+ PSK
group. Overall and diseasefree
survival rates not significant for all
groups.

Refs
Toi et al, 1992

Years for chemo + PSK group:


HLA-B40+ : 100%;
HLA-B40- : 76% and 55%,
respectively.
Significant difference at p =0.05.

Yokoe et al,
1997

Iino et al, 1995;


Yokoe et al,
1997

Cancer Therapy Vol 6, page 123


Table 5. Selected randomized controlled trials for colorectal cancer.
Patients
55 cases
56 controls

Multicentre
221 cases
227 controls
Total 207
134 cases
67 controls
6 withdrew

Stage
Advance
(II/III)

Primary
(II/III)

Total 205
137 cases
68 controls

Primary
(II/III)

Colon cancer
with lymph
node
metastasis
Total 441
220 cases
221 controls

Dukes
A:7%
B:45.5%
C:47.3%

202 primary colon


cancer patients
5-FU + PSK:99
5-FU alone:103

Primary
colon
cancer

Treatment
1. Surgery + placebo
2. Surgery + PSK
(3gm/day for 2 months;
2g/day for 24 months;
1 gm/day thereafter)
1.Chemo
2.Chemo+ PSK
(3g/day for 3 years)
1. Chemo
2.Chemo+ PSK (3g per
day for >2 yrs)

All patients received


Mitomycin-C postsurgery.
1. Chemo
2. Chemo + PSK (3g/
day) Both treatments for
2 yrs
All patients received
chemo after surgery for
3-4 weeks, then 10
courses of treatment.
1. PSK 4 weeks then 4
weeks chemo.
2. 4 weeks rest then 4
weeks chemo.
99 underwent adjuvant
treatment with PSK and
5-FU (PSK group),
103 were treated with 5FU alone (5-FU group).

Outcome
8-yrs survival rate significant in the
PSK group( p<0.05);
Disease-free interval
(p<0.05)

Refs
Torisu et al, 1990

Disease-free interval and survival


significantly better for PSK in the
colon group (p<0.05 in both)
Overall survival rate higher in the
PSK group but not significant
(p=0.21).
3-year disease-free survival rate
significantly higher in the PSK
group (p=0.02).
Stage III. Patients 3-year overall and
disease-free survival rates in the
PSK significant (p=0.02; p =0.01)
5-year overall survival rate
significantly higher in the PSK
group (p<0.016, p <0.056
respectively).
Stage III patients: Overall and
5-year disease-free survival in PSK
group (p <0.003; p<0.002).
Seven- year survival rate
Significantly higher in the PSK
group (p=0.019).
Overall survival or disease-free
rates not significant.

Mitomi et al, 1992

The presence of diffuse nuclear


accumulation-type !-catenin
activation identifies patients
with colon cancer who respond
better to immunotherapy
with polysaccharide K.

Yamashita et al,
2007

Ohwada et al, 2003

Ohwada et al, 2004

Ito et al, 2004

5-FU = 5-fluorouracil

patients in three clinical trials. The aim of the metaanalysis was to evaluate the effect of PSK as adjuvant
immunochemotherapy for patients with curatively resectal
colorectal cancer. The results suggested that adjuvant
immunochemotherapy with PSK can improve both
survival and disease-free survival of patients with
curatively resectal colorectal cancer.

B. Colorectal cancer
C. versicolor extract was assessed for its potential
anticancer activity in patients with advanced colorectal
cancer (stages III and IV) (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
leukocyte 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.
Sakamoto and colleagues performed in 2006 a metaanalysis of colorectal cancer, which involved 1094

C. 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 had 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).

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Cheng and Leung: General review of polysaccharopeptides (PSP) from C. versicolor


Table 6. Assessment of methodological parameters on clinical trials of PSP or PSK.
Reference

Mitomi et al,
1993

Jadad
Study design
Score (max
= 5)
2
Randomized
control, followup study

Nakazato et al, 3
1989

Ichihashi et al, 3
1987

Sample size

Inclusion/Exclusion
criteria

Patients younger than 75


years of age with stage III
or IV colorectal cancer and
consented form obtained
were included
Patients with
WBC<4000/mm3,
PLT<100,000/mm3,
TP<6.0g/dl, Alb<3.0g/dl,
A/G<1,
SGOT/SGPT>100U, urine
protein (+), Crea>1.5mg/dl
were excluded
Randomized
262 gastric
Patients with age<75
control, follow- cancer patients years, PPD(+), diagnose
up trial
with radical
confirmed by pathology
surgery
were included.
Patients who underwent
any radiotherapy,
chemotherapy, or
immunotherapy or having
multiple cancers, or any
abnormal hematological
findings were excluded
Randomized
168 patients with Inclusions included: age
control follow- stomach cancer <75 years, without
up study
multiple cancers, normal
hematological findings and
diagnosis confirmed by
post-operation pathology

Guo, 2000

Double-blind
placebocontrolled
randomized
study

Ze et al, 2003

Randomized
controlled trial

Ebihara and
2
Minamishima,
1984

Randomized
controlled trial

448 colorectal
cancer patients
treated with
chemotherapy

34 patients with Completed conventional


non-small cell
treatment for advanced
lung cancer
NSCLC

Treatment
schedule

Results

227/221 patients
were randomly
assigned to control
(chemotherapy for 6
months) and
treatment
(chemotherapy 6
months plus PSK
3g/day for 3 years)

The disease-free
survival and the
survival of the PSK
group were better
than those of the
control group
(Disease-free
survival: p=0.0214,
Survival: p=0.0272)

129/124 were
randomly assigned
to control
(chemotherapy) and
treatment
(chemotherapy plus
PSK 3g/day for 4
weeks)

The disease-free
survival curves and
overall survival
curves of PSK
treatment group were
significant (p=0.018
and p=0.045) better
than those of control
group.

49/47/28 patients
were randomly
assigned to receive
chemotherapy (CQ),
PSK (3g/50kg) plus
CQ for 13 months
and no CQ and PSK
treatment (as
control).
Patients received
28-day
administration of
PSP

Overall 7 year
survival rate in PSK
group higher than
chemotherapy group
but no significant
difference.

After 28-day
treatment, there was a
significant
improvement in blood
leukocyte and
neutrophil counts,
serum IgG and IgM,
and percent of body
fat among the PSP,
but not the control,
patients (p<0.05)
201 patients with Age < 75 year and
137/68 patients
The three-year,
stage II or III
historical confirmed
treated with 3g PSK disease-free survival
colorectal cancer colorectal cancer. Exclude: plus 300mg tegafur rate was 80.6% in
underwent any
/uracil or 300mg
PSK group (p=0.02)
radiotherapy,
tegafur/uracil alone compared with 68.7%
chemotherapy or
for 2 years
in the control group.
immunotherapy.
25 advanced
Advanced malignant
Treatment group
Quality of life and
malignant cancer cancer patients without
orally taken PSP 5g symptoms were
patients
immunotherapy
each time 3 times a improved in PSPday for 2 months
treated group
plus symptoms
compared with
control treatment
control group (p<0.01
Control group only and p< 0.05)
gave symptoms
control treatment

124

Cancer Therapy Vol 6, page 125


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-year survival rate for the
PSK-treated group when compared with the other groups
(Niimoto et al, 1988).
In an additional 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 function impairment but no
characteristic toxic effects were linked to PSK
administration (Nakazato et al, 1994).
Trials with PSP indicated that C. versicolor extract
has the potential to alleviate the side effects normally
associated with chemotherapy (lassitude, inappetence,
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 chemotherapeutical drugs was demonstrated for
stomach cancer patients following the administration of
PSP (1 gram three times a day for 8 weeks) (Wu et al,
1999).
Results from a prospective multi-centre study
including 158 esophageal cancer patients, indicated 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%) compared with those without PSK
supplementation (26% and 31%) (Ogoshi et al, 1995a).
Another study reported the results of 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
might have a beneficial effect on esophageal carcinoma
when combined with radiotherapy and chemotherapy
(Ogoshi et al, 1995b).
Better survival rates were also achieved with PSP. A
hundred patients with esophageal carcinoma were
randomly divided into two groups: one group was treated
with radiotherapy alone while other one received
radiotherapy plus PSP (3 grams daily for a total dose of
190 grams during the period of radiation time). The results
demonstrated that patients treated with radiotherapy plus
PSP had higher one, three and five 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,
1999).

A Meta-analysis study was performed to evaluate the


effect of immunochemotherapy on survival in patients
with curative resections of gastric cancer. The metaanalysis included 8,009 patients from eight randomized
controlled trials after central randomization. The results
suggest that adjuvant immunochemotherapy with PSK
improves the survival of patients after curative gastric
cancer resection (Oba et al, 2007).

D. Leukemia
A study with PSK as an adjuvant to chemotherapy
done in the early 1980s (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 to have longer
survival over the group that received chemotherapy alone
but without significance. However, analysis of the data of
patients who had maintained complete remission for more
than 270 days revealed that immunotherapy had a
suggestive beneficial effect (p=0.105), prolonging the 50%
remission period by 418 days (885 vs. 467 days). 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 a good
prognosis.

E. Lung cancer
A clinical trial conducted in Japan was done with
patients having different lung cancers at stages I-III; 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 stages I and II without
PSK. A study investigated the effects of PSK as an
accessory treatment for lung cancer (Ke et al, 1999), 30
patients were administered the mushroom extract while
they received chemotherapy. The symptoms (side effects)
improvement for PSP-treated patients was over 87%,
while it was 47% for the control group.
Thirty-four patients, with no significant difference in
their baseline demographic, clinical or tumor
characteristics, or previous treatment regimes (p>0.05),
were recruited into each of the PSP and control arms.
After 28-day treatment, there was a significant
improvement in blood leukocyte and neutrophil counts,
serum IgG and IgM, and percent of body fat among the
PSP, but not the control patients (p<0.05) (Tsang et al,
2003).

VII. Discussion and Conclusion


Since 1970s numerous mushroom fungi have been
increasingly used as a source of medicinal compounds and

125

Cheng and Leung: General review of polysaccharopeptides (PSP) from C. versicolor


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therapeutic adjutants or health food supplements. PSP has


been previously shown to have immuno-stimulatory,
antitumour and analgesic effects (Zhong et al, 2001) in
animal models. When used as an adjunct in cancer
chemotherapy in clinical trials carried out in China, PSP
improved the quality of life in the patients by improving
appetite and alleviating symptoms associated with cancer
chemotherapy. Cancer chemotherapy and radiotherapy are
standard treatments of cancer in the past 30 years, often
associated with side effects such as immuno-suppression,
poor appetite, and vomiting, which seriously affected the
therapy. Studies in Japan and China have suggested
mushroom proteoglycans may provide a possible solution,
with Polysaccharide Krestin and PSP being systemically
studied as adjunct to cancer chemotherapy (Kidd, 2000).
Nowadays the biological activities of PSP and PSK have
received much attention in biomedical sciences. One of the
most important functions of PSP and PSK is their
immunomodulation and anti-cancer actions. Various
experimental evidences demonstrated that the anti-tumor
action of mushroom polysaccharides is due to the
enhancement and potentiation of cell-mediated immune
system through the regulation of immunomodulatory
cytokines and activation of the complement system and
Natural Killer Cells (NK cells) (Ohwada et al, 2006).
However the mechanism of anti-tumor actions of PSP and
PSK from most fungi is still not clear. It is accepted that
anti-tumor polysaccharides enhance various immune
responses, and act as biological response modifiers
(Ohwada et al, 2006). PSK/PSP are nonspecific
immunopotentiators and exert immunomodulatory actions
by promoting the proliferation of T-lymphocytes, the
activation of macrophages, natural killer cells, and Thelper cells, thereby inducing the production of antibody
and interleukins (Mao et al, 1996; Li, 1999). PSK also has
favorable effect on the activation of leucocyte chemotactic
locomotion and phagocytic activity (Torisu et al, 1990).
However further studies on the mechanisms behind
anticancer, immunostimulatory, and biological response
modifying effects of PSK or PSP are needed.

Acknowledgments
This project was made possible by Grant Number 1
P50 AT002779-01 from the National Center for
Complementary and Alternative Medicine (NCCAM) and
the Office of Dietary Supplements (ODS). Its contents are
solely the responsibility of the authors and do not
necessarily represent the official views of the NCCAM,
ODS or the National Institute of Health.

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From left to right: King-Fai Cheng, Ping-Chung Leung

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