Coriolus
Versicolor
[Two patients with
liver metastasis from gastric cancer who responded
remarkably to combined therapy of 5'-DFUR and PSK].
[Article in Japanese]
Kitamura M, Umekita N, Inoue S, Miyamoto Y, Maeshiro
T, Saiura A, Tanaka S, Kawahara Y, Arai K, Iwasaki
Y, Ohashi M, Takahashi T
Dept. of Surgery, Tokyo Metropolitan Bokutoh Hospital.
[Medline record in process]
Two patients with liver metastasis from gastric cancer
who responded remarkably to a combined therapy of
5'-DFUR and PSK are reported. The first patient had
liver metastases 8 months postoperatively. Her AFP
level was 513 ng/ml and CEA was 30 ng/ml. After the
combined therapy, all liver metastases showed a calcified
change. Tumor markers of AFP and CEA decreased remarkably
to the normal level within 3 weeks after the therapy.
The patient had no relapse as of December 1999. The
second patient with liver metastases was treated using
the same combined therapy for 14 days preoperatively.
The size of liver metastases had decreased remarkably
by the time of the operation. A small metastasis of
S8 (0.5 x 0.5 cm) was resected. No other liver metastasis
was detected by intraoperative ultrasonography. The
patient had no relapse as of February 2000. It is
reported that PSK produces several cytokines which
induce thymidine phosphorylase expression. The present
report suggests that the upregulation of PyNPase might
enhance the antitumor effect of 5'-DFUR.
PMID: 11057326, UI: 20511090
Long-term survival
after immunochemotherapy for juvenile colon cancer
with peritoneal dissemination. A case report.
Mukai M, Tokunaga N, Yasuda S, Mukohyama S, Kameya
T, Ishikawa K, Iwase H, Suzuki T, Ishida H, Sadahiro
S, Makuuchi H
Tokai University School of Medicine, Department of
Surgery, Bohseidai, Isehara, Kanagawa 259-1193, Japan.
[Medline record in process]
A 20 year-old man was hospitalized with an abdominal
mass and abdominal distension. Investigations resulted
in a diagnosis of ileus caused by advanced colon cancer
with peritoneal dissemination to the pouch of Douglas.
Palliative surgery was performed to relieve bowel
obstruction and debulk the tumor. Histopathological
examination showed that the tumor was a mucinous adenocarcinoma
invading the serosa without lymph node metastasis.
Ascites collected during the operation was diagnosed
as class V. Administration of PSK (3.0 g/day) and
UFT (600 mg/day) as adjuvant immunochemotherapy was
started postoperatively to achieve tumor dormancy.
He has been followed as an outpatient for 2.5 years
with no ascites or abdominal symptoms.
PMID: 11032941, UI: 20491469
Direct tumor growth
suppressive effect of melanoidin extracted from immunomodulator-PSK.
Kamei H, Hashimoto Y, Koide T, Kojima T, Hasegawa
M, Umeda T
Department of Surgery, Aichi-Gakuin University Hospital,
Nagoya, Japan. kamei@dpc.aichi-gakuin.ac.jp
Melanoidin, which belongs to the melanin group of
molecules, was extracted from the polysaccharide biological
response modifier PSK. Melanoidin was cultured together
with HCT-15 cells derived from human colon cancer
and with AGS cells derived from human gastric carcinoma.
After four days of culture, cell count was compared
with that of the control cells. Significant suppression
was observed, that is, 50% suppression was shown at
concentrations of melanoidin between 200 and 100 micrograms/ml.
A histogram generated by flow cytometry showed elevation
of the tetraploid peak and of that between diploid
and tetraploid peaks, suggesting blockage of S phase
and G2 to M phase of the cell cycle. Thus, melanoidins
contained in the immunomodulator PSK revealed to have
a direct tumor cell growth inhibitory effect.
PMID: 10851484, UI: 20310033
Susceptibility of
natural killer (NK) cells to reactive oxygen species
(ROS) and their restoration by the mimics of superoxide
dismutase (SOD).
Nakamura K, Matsunaga K
Department of Biochemistry, Kitasato University School
of Medicine, Kanagawa, Japan.
Natural killer (NK) cells are susceptible to reactive
oxygen species (ROS), and lose the activity by the
effects of ROS. Cancer bearing hosts usually suffer
from oxidative stress (OS), and the NK-activity decreases
to a significantly lower level than normal controls.
Superoxide dismutase (SOD)-mimicking substances, such
as protein-bound polysaccharide of Coriolus versicolor
(Fr) QUEL (PSK) and iron-chelating chlorine e6-Na
(FeCNa), can restore the NK-activity of cancer bearing
hosts, when collaborating with catalase. Incorporation
of 3H-thymidine by ROS-treated NK-cells is not affected,
indicating that these cells are still active in the
nucleic acid metabolism. Intraperitoneal administration
of anti-Asialo GM1 antibody extinguished the NK-activity.
NK-cells affected by ROS lost the adherence to target
cancer cells in both in vitro and in vivo. ROS may
change the surface charge of NK-cells to anionic,
resulting in an inability of adhesion to target cancer
cells which usually show the negative surface charge.
PMID: 10850363, UI: 20308909
Protein-bound polysaccharide
(PSK) induces cytotoxic activity in the NKL human
natural killer cell line.
Pedrinaci S, Algarra I, Garrido F
Departamento de Analisis Clinicos, Hospital Universitario
Virgen de las Nieves, Granada, Spain.
We studied the effect of protein-bound polysaccharide
PSK on the activation of the human natural killer
cell line NKL. We observed an increased natural killer
cytotoxic activity against different tumor cells (K562,
Daudi, and U937) when a standard 2- to 3-h 51chromium
release assay was performed. The results parallel
those obtained after treatment of the NKL cell line
with interleukin-2. The highest cytotoxic activity
was reached at a concentration of 100 microg/ml of
PSK. This natural killer activation was inhibited
when the PSK dose was 1,000 microg/ml. None of the
cell surface markers that were analyzed by fluorescence-activated
cell sorting showed variations after PSK or interleukin-2
treatment of NKL cells. These markers included CD2,
CD11b, CD11c, CD18, CD16, CD54, CD56, CD98, CD25,
CD122, HLA class I, HLA class II, CD94, ILT2, p58.1,
p70, and NKp46. One of these markers (NKp46) is a
major triggering receptor reported to be involved
in the natural cytotoxicity of fresh or cultured human
natural killer cells. In our study, another triggering
receptor must be implicated in PSK-induced natural
killer lysis. Our data suggest that PSK is an important
biological response modifier of natural killer cells
in vitro and may prove to be useful for the study
of human natural killer cell biology.
PMID: 10784373, UI: 20244959
The use of mushroom
glucans and proteoglycans in cancer treatment.
Kidd PM
Immunoceuticals can be considered as substances having
immunotherapeutic efficacy when taken orally. More
than 50 mushroom species have yielded potential immunoceuticals
that exhibit anticancer activity in vitro or in animal
models and of these, six have been investigated in
human cancers. All are non-toxic and very well tolerated.
Lentinan and schizophyllan have little oral activity.
Active Hexose Correlated Compound (AHCC) is poorly
defined but has shown early clinical promise. Maitake
D-Fraction has limited proof of clinical efficacy
to date, but controlled research is underway. Two
proteoglycans from Coriolus versicolor - PSK (Polysaccharide-K)
and PSP (Polysaccharide-Peptide - have demonstrated
the most promise. In Japanese trials since 1970, PSK
significantly extended survival at five years or beyond
in cancers of the stomach, colon-rectum, esophagus,
nasopharynx, and lung (non-small cell types), and
in a HLA B40-positive breast cancer subset. PSP was
subjected to Phase II and Phase III trials in China.
In double-blind trials, PSP significantly extended
five-year survival in esophageal cancer. PSP significantly
improved quality of life, provided substantial pain
relief, and enhanced immune status in 70-97 percent
of patients with cancers of the stomach, esophagus,
lung, ovary, and cervix. PSK and PSP boosted immune
cell production, ameliorated chemotherapy symptoms,
and enhanced tumor infiltration by dendritic and cytotoxic
T-cells. Their extremely high tolerability, proven
benefits to survival and quality of life, and compatibility
with chemotherapy and radiation therapy makes them
well suited for cancer management regimens.
Publication Types:
·
Review
·
Review, tutorial
PMID: 10696116, UI: 20161032
Contribution of
cytokines on the suppression of lung metastasis.
Ishihara Y, Iijima H, Matsunaga K
Department of Hygiene, School of Medicine, Tokyo Women's
Medical University, Japan.
Weekly injection of a protein-bound polysaccharide
PSK in mice with Lewis Lung Cancer (LLC) significantly
decreased the number of lung metastatic foci concomitant
with enhancement of cytostatic activity in the bronchoalveolar
lavage (BAL) cells. These effects were more marked
when the agent was given intratracheally, inducing
a larger number of pulmonary macrophages, lymphocytes
and neutrophils concomitant with increases in BAL
tumor necrosis factor-alpha (TNF-alpha), mouse inflammatory
protein-alpha (MIP-1alpha), mouse inflammatory protein-beta
(MIP-1beta), interleukin-1alpha (IL-1alpha) and interleukin-6
(IL-6), but not interleukin-2 (IL-2) and interleukin-4
(IL-4). Pre-treatment with anti TNF-alpha antibody
reduced these effects. The time course and production
of PSK-induced cytokines were similar between the
tumor-bearing mice and control mice. BAL neutrophils
in mice with LLC showed a tendency toward acceleration
of O2- production compared with circulating neutrophils.
Pulmonary macrophage phagocytosis was also significantly
higher in the LLC mice. These results suggest that
enhancement of cytostasis appears to be induced by
activation and/or improvement of function in inflammatory
and immune cells through cytokines under immunomodulator
treatment in lung metastasis, possibly via a TNF-alpha-dependent
mechanism.
PMID: 9950103, UI: 99133602
Polysaccharide K
induces Mn superoxide dismutase (Mn-SOD) in tumor
tissues and inhibits malignant progression of QR-32
tumor cells: possible roles of interferon alpha, tumor
necrosis factor alpha and transforming growth factor
beta in Mn-SOD induction by polysaccharide K.
Habelhah H, Okada F, Nakai K, Choi SK, Hamada J,
Kobayashi M, Hosokawa M
Laboratory of Pathology, Cancer Institute, Hokkaido
University School of Medicine, Sapporo, Japan.
Previously we reported the malignant progression of
QR-32, a regressor-type tumor clone, following co-implantation
with foreign bodies (gelatin sponge or plastic plate)
in normal syngeneic C57BL/6 mice. We also reported
that the progression of QR-32 cells by a gelatin sponge
was significantly inhibited in the mice administered
polysaccharide K (PSK) and that PSK induced an increase
of radical scavengers, especially manganese superoxide
dismutase (Mn-SOD), locally at the site of tumor tissues.
In this study, to reveal the possible mechanism by
which PSK induced Mn-SOD in the tumor tissues, we
examined the mRNA expression and protein levels of
inflammatory cytokines in the tissues. We found that
mRNAs of tumor necrosis factor alpha (TNFalpha) and
interleukin-1alpha (IL-1alpha) were considerably expressed
in both PSK-treated and phosphate-buffered-saline-treated
tumors, and that the mRNA expression and protein level
of interferon gamma (IFNgamma) increased in the tumor
tissues treated with PSK. In vitro treatment of QR-32
cells with IFNgamma did not significantly increase
the production of Mn-SOD; however, the combination
of IFNgamma with TNFalpha increased the Mn-SOD production
more effectively than did any of the cytokines used
singly. Furthermore, we observed the down-regulation
of the mRNA expression and protein level of transforming
growth factor beta (TGFbeta) in the tumor tissues
treated with PSK, and that in vitro treatment of QR-32
cells with TGFbeta decreased the production of Mn-SOD.
These results suggest that PSK suppresses the progression
of QR-32 cells by increasing Mn-SOD via the modulation
of inflammatory cytokines; that is, by decreasing
TGF-beta and increasing IFN-gamma.
PMID: 9756418, UI: 98427849
The role of neutrophils
as cytotoxic cells in lung metastasis: suppression
of tumor cell metastasis by a biological response
modifier (PSK).
Ishihara Y, Fujii T, Iijima H, Saito K, Matsunaga
K
Department of Hygiene and Public Health (I), Tokyo
Women's Medical College, Japan. ishihara@reserch.twmc.ac.jp
We aimed to determine the role of neutrophils and
the usefulness of a protein-bound polysaccharide (PSK)
in the suppression of tumor cell metastasis in the
lung in vivo. Circulating neutrophils collected frm
tumor-bearing animals (Line-10 hepatocarcinoma) induced
a marked decrease in the size and number of metastatic
foci in the lung. Although pulmonary macrophages (PAMs),
lymphocyte and eosinophil in bronchoalveolar lavage
(BAL) fluid increased following tumor cell inoculation,
in addition to these findings we found that PSK caused
an increase in BAL neutrophil levels causing increased
of target cell toxicity and a marked decrease in the
size and the number of lung metastatic foci. Superoxide
anion generation of blood neutrophils collected from
PSK-treated animals with metastasis showed forward
acceleration. The presence of neutrophil chemotactic
factors was confirmed in the BAL fluid of PSK-treated
animals with metastasis, but not leukotriene B4. The
results suggest that modulation of the tumor cell
microenvironment by activation of neutrophils may
prove to be an additional modality in treatment strategy
by combining PSK as a biological response modifier
with conventional therapies for lung metastasis.
PMID: 9627799, UI: 98291269
In vitro inactivation
of herpes simplex virus by a biological response modifier,
PSK.
Monma Y, Kawana T, Shimizu F
Department of Pediatric Dentistry, Tohoku University
School of Dentistry, Sendai, Japan.
Herpes simplex virus (HSV) causes herpes genitalis,
primary gingivostomatitis and recurrent herpes labialis.
In order to elucidate in vivo mechanisms by which
PSK, a biological response modifier, exerts a protective
effect against HSV infection, we used an in vitro
system to study whether PSK inactivated infectivity
of HSV-type 1 (HSV-1) and HSV-type 2 (HSV-2) isolated
from patients with herpes genitalis in addition to
a laboratory-cultured strain of HSV type 1 (HSV-1-GC+).
It was found that HSV-1-GC+ was inactivated by PSK
in a dose dependent fashion of concentrations of PSK
and virus titers. Concentrations of PSK as low as
0.31 mg/ml was shown to inactivate the infectivity
of HSV-1-GC+. Inactivation required at least 30 min
of incubation at 37 degrees C with maximal inactivation
observed at 60 min incubation time. Similar to HSV-1-GC+,
clinically isolated strains of HSV-2 were inactivated
by PSK although clinically isolated strains of HSV-1
were resistant to PSK, compared with HSV-2. It was
also shown that PSK-treated HSV retained the ability
to adsorb to the cell membrane, but did not synthesize
viral protein(s). These data illustrate that there
is a biological difference in the sensitivity to PSK
between HSV type 1 and type 2, and also suggest that
PSK could inactivate HSV in lesions at peripheral
sites of recurrent herpes.
PMID: 9298752, UI: 97442203
HLA antigen as predictive
index for the outcome of breast cancer patients with
adjuvant immunochemotherapy with PSK.
Yokoe T, Iino Y, Takei H, Horiguchi J, Koibuchi
Y, Maemura M, Ohwada S, Morishita Y
Department of Emergency and Critical Care Medicine,
Gunma University School of Medicine, Japan.
We demonstrated that the prognosis of breast cancer
patients who received adjuvant immunochemotherapy
with Krestin (PSK) showed a tendency to be better
than that of breast cancer patients receiving chemotherapy
only. We retrospectively investigated the usefulness
of HLA typing for selecting patients to receive adjuvant
immuno-chemotherapy with PSK. One hundred and thirty-four
patients with operable breast cancer were typed as
HLA-A, -B, -C by a lymphocytotoxicity test. Patients
without vascular invasion had no adjuvant therapy
(NA group). Patients with vascular invasion in the
tumor and/or in the metastatic lymph node were randomized
into two groups. In group 1 (FEMP only), a combination
chemotherapy of 100 mg of 5-fluorouracil (F), 50 mg
of cyclophosphamide (E), 2 mg of mitomycin C (M),
and 5 mg of predonisolone (P) was orally administered
daily for 28 days (one course). In group 2 (FEMP+PSK),
FEMP and 3.0 g of PSK were
orally administered for 28 days (one course).
Two courses a year of these agents were given for
five years in both groups. Each group (NA, FEMP, FEMP+PSK)
was stratified by the presence of HLA B40 type (B40(+))
or not (B40(-)). Five- and 10-year disease-free survival
(DFS) rates (93%, 80%, respectively) of patients with
B40(+) seemed to be better than those (83% and 51%)
of patients with B40(-). In the NA group, 5- and 10-year
DFS were 100% and 71% in patients with B40(+), 92%
and 76% in those with B40(-), respectively. In the
FEMP group (chemotherapy only), 5- and 10-year DFS
of patients with B40(+) were both 84%. These were
not statistically significant compared with those
(82% and 33%) of patients with B40(-). On the other
hand, in the FEMP+PSK group, 5- and 10-year DFS of
patients with B40(+) were both 100%, and those of
patients with B40(-) were 76% and 55%, respectively.
DFS of patients with B40(+) was significantly better
than that of patients with B40(-). It is concluded
that HLA typing may be a predictive index in determining
the use of immunochemotherapy combined with PSK for
patients with operable breast cancer.
Publication Types:
·
Clinical trial
·
Randomized controlled trial
PMID: 9252721, UI: 97396530
[A case of inoperable
advanced gastric cancer remarkably responding to combined
chemotherapy with UFT-E, MMC and PSK].
[Article in Japanese]
Kogure A, Ishii S, Kakefuda T, Aiura K, Arisawa
Y, Kitagawa Y, Nakagawa M, Shirasugi N, Noga K
Dept. of Surgery, Kawasaki City Hospital.
A 55-year-old male consulted a local doctor with the
complaint of epigastralgia. Examination of the upper
gastrointestinal tract revealed gastric cancer (Borrmann
Type II) and he was referred to our hospital for operation.
A few lymph nodes were palpable in the left supraclavicular
fossa, and the biopsy of those lymph nodes revealed
metastatic adenocarcinoma. The CT scan of the abdomen
showed enlargement of paraaortic lymph nodes. Then,
the patient was determined inoperable (T3, N4, H02
P01, M1 stage IVb). He was treated as an outpatient
with UFT-E (300 mg/day, orally), Krestin (PSK 3.0
g/day, orally) and Mitomycin C (MMC 6 or 8 mg once
a week, intravenously repeated interval of 4 weeks).
The total dose of UFT-E, PSK and MMC was 219 g, 1,095
g and 136 mg, respectively. One month later, lymph
nodes in the supraclavicular fossa disappeared, and
the lesion in the stomach completely responded. We
have followed the patient for more than one year.
He visits our the outpatient department and has kept
working until now.
PMID: 9170529, UI: 97314187
Effect of Krestin
as adjuvant treatment following radical radiotherapy
in non-small cell lung cancer patients.
Hayakawa K, Mitsuhashi N, Saito Y, Nakayama Y,
Furuta M, Nakamoto S, Kawashima M, Niibe H
Department of Radiology and Radiation Oncology, Gunma
University School of Medicine, Japan.
To evaluate the efficacy of Krestin (PSK) as adjuvant
treatment after radical radiation therapy (RT) for
non-small cell lung cancer (NSCLC), treatment results
of 225 patients with NSCLC treated with RT followed
by adjuvant administration of PSK between 1976 and
1989 were analyzed. Of these patients, 170 (76%) had
squamous cell carcinoma. In the patients with squamous
cell carcinoma of the lung, PSK was given only when
the tumor showed satisfactory shrinkage (complete
or partial response) after completion of RT. The treatment
outcomes were compared with those of the responders
to RT not receiving PSK. The 5-year survival rates
of patients with stages I-II and stage III disease
were 39 and 26%, respectively, while the non-administered
responder group's were 17 and 8%. These differences
are statistically significant. An improvement in the
treatment results with combined use of appropriate
immuno-modulating drugs is anticipated in the future.
When clinical trials of the efficacy of these drugs
are conducted, the agents should be given to the patients
with satisfactory tumor regression after RT, although
they still take much time and cost.
Publication Types:
·
Clinical trial
PMID: 9043766, UI: 97196677
