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

BACK