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Dose intensity of uracil and tegafur in postoperative chemotherapy for patients with poorly differentiated gastric cancer

Keizo Sugimachi, Yoshihiko Maehara, Michio Ogawa, Teruo Kakegawa, Masao Tomita

A retrospective analysis of postoperative chemotherapy had shown the continuous administration of UFT, an oral preparation of 1-(2-tetrahydrofuryl)-5-¯uorouracil (tegafur) and uracil at a molar ratio of 1:4, to be e€ective for poorly di€erentiated gastric cancer. We therefore sought to determine prospectively the effective dose of postoperative chemotherapy with UFT for patients with poorly di€erentiated gastric cancer following a curative resection. We determined the e€ect of the combined intravenous administration of mitomycin C (MMC) and oral treatment with protein-bound polysaccharide Kreha (PSK), extracted from the basidiomycete Coriolus versicolor, and UFT at a dose of either 8 mg/kg or 12 mg/kg daily for 1 year. A total of 224 patients with poorly di€erentiated stage II±IV gastric cancer were entered into this study after undergoing a curative resection. No di€erences were observed between the two treatment groups in terms of prognostic factors, the toxicity rate or the doses of the drugs prescribed, other than UFT. The higher dose of UFT in maintenance therapy led to a decrease in the recurrence rate (P < 0.05), and increases in disease-free survival and cause-speci®c survival (P < 0.05). UFT at 12 mg/ kg in postoperative chemotherapy was thus found- to improve the postoperative results with no increase in toxicity for poorly di€erentiated gastric cancer, and is also cost-e€ective for outpatients.

Differential effect of Coriolus versicolor (Yunzhi) extract on cytokine production by murine lymphocytes in vitro

C.Y. Hoa, Clara B.S. Laua, C.F. Kima, K.N. Leungb, K.P. Fungb, T.F. Tsec, Helen H.L. Chanc, Moses S.S. Chowa

Being one of the commonly used Chinese medicinal herbs, Coriolus versicolor (CV), also named as Yunzhi, was known to possess both anti-tumor and immunopotentiating activities. The present study aimed to investigate the in vitro immunomodulatory effect of a standardized ethanol–water extract prepared from CV on the proliferation of murine splenic lymphocytes using the MTT assay, and the production of six T helper (Th)-related cytokines using the enzyme-linked immunosorbent assay (ELISA) technique. The results showed that the CV extract significantly augmented the proliferation of murine splenic lymphocytes in a time- and dose-dependent manner, maximally by 2.4-fold. Moreover, the production of two Th1-related cytokines, including interleukin (IL)-2 and IL-12, in culture supernatants from the CV extract-activated lymphocytes was prominently upregulated at 48 and 72 h. Positive correlations were found between the levels of these two cytokines and the MTT-based proliferative response. In contrast, the production of two other Th1-related cytokines, including interferon (IFN)-g and IL-18, was significantly augmented only at 24 h, but not at 48 and 72 h. On the other hand, the levels of two Th2-related cytokines such as IL-4 and IL-6 were undetectable in the culture supernatants of lymphocytes treated with the CVextract. The CVextract was suggested to be a lymphocyte mitogen by differentially enhancing the production of Th1-related cytokines.

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Differential anti-tumor activity of coriolus versicolor (Yunzhi) extract through p53- and/or Bcl-2-dependent apoptotic pathway in human breast cancer cells.

CY Ho, CF Kim, KN Leung, KP Fung, TF Tse, H Chan, CB Lau.

Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells, but the underlying mechanism has not been fully elucidated. The present study aimed to evaluate the in vitro anti-tumor activity of a standardized aqueous ethanol extract prepared from CV on four breast cancer cell lines using MTT assay, and test whether the mechanism involves apoptosis induction and modulation of p53 and Bcl-2 protein expressions using cell death detection ELISA, p53 and Bcl-2 ELISAs respectively. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of three breast tumor cell lines, with ascending order of IC50 values: T-47D, MCF-7, MDA-MB-231, while BT-20 cells were not significantly affected. Tumoricidal activity of the CV extract was found to be comparable to a chemotherapeutic anti-cancer drug, mitomycin C. Nucleosome productions in apoptotic MDA-MB-231, MCF-7 and T-47D cells were significantly augmented in a time-dependent manner and paralleled the anti-proliferative activity of CV extract. Expression of p53 protein was significantly upregulated only in T-47D cells treated with the CV extract in a dose- and time-dependent fashion, but not in MCF-7 (except at 400 mug/ml after 16 h) and MDA-MB-231 cells. The CV extract significantly induced a dose-dependent downregulation of Bcl-2 protein expression in MCF-7 and T-47D cells, but not in MDA-MB-231 cells. These results suggested that apoptosis induction, differentially dependent of p53 and Bcl-2 expressions, might be the possible mechanism of CV extract-mediated cytotoxicity in human breast cancer cells in vitro.

Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis

C.B.S. Laua, C.Y. Hoa, C.F. Kima, K.N. Leungb, K.P. Fungb, T.F. Tsec, H.H.L. Chanc, M.S.S. Chowa

Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used Chinese medicinal herbs. Although recent studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the objective of this study was to examine the in vitro cytotoxic activities of a standardized aqueous ethanol extract prepared from Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. Cell death ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis. The present results demonstrated that CV extract at 50 to 800 Ag/ml dose-dependently suppressed the proliferation of Raji, NB-4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC50 values: HL-60 (147.3 F 15.2 Ag/ml), Raji (253.8 F 60.7 Ag/ml) and NB-4 (269.3 F 12.4 Ag/ml). The extract however did not exert any significant cytotoxic effect on normal liver cell line WRL (IC50 > 800 Ag/ml) when compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon the treatment of CV extract, while no significant nucleosome production was detected in extract-treated WRL cells. The CV extract was found to selectively and dose-dependently inhibit the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway.

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Coriolus versicolor: a medicinal mushroom with promising immunotherapeutic values.

KK Chu, SS Ho, AH Chow.

Coriolus versicolor (CV) is a medicinal mushroom widely prescribed for the prophylaxis and treatment of cancer and infection in China. In recent years, it has been extensively demonstrated both preclinically and clinically that aqueous extracts obtained from CV display a wide array of biological activities, including stimulatory effects on different immune cells and inhibition of cancer growth. The growing popularity of aqueous CV extracts as an adjunct medical modality to conventional cancer therapies has generated substantial commercial interest in developing these extracts into consistent and efficacious oral proprietary products. While very limited information is available on the physical, chemical, and pharmacodynamic properties of the active principles present in these extracts, there has been sufficient scientific evidence to support the feasibility of developing at least some of these constituents into an evidence-based immunodulatory agent. In this article, the background, traditional usage, pharmacological activities, clinical effects, adverse reactions, active constituents, and regulatory aspects of CV are reviewed. Presented also in this review are the current uses and administration, potential drug interactions, and contraindication of aqueous extracts prepared from CV.

Coriolus versicolor (Yunzhi) extract attenuates growth of human leukemia xenografts and induces apoptosis through the mitochondrial pathway


Coriolus versicolor (CV), also called Yunzhi, has been demonstrated to exert anti-tumor effects on various types of cancer cells. Our previous studies have demonstrated that a standardized aqueous ethanol extract prepared from CV inhibited the proliferation of human leukemia cells via induction of apoptosis. The present study aimed to evaluate the underlying mechanisms of apoptosis through modulation of Bax, Bcl-2 and cytochrome c protein expressions in a human pro-myelocytic leukemia (HL-60) cell line, as well as the potential of the CV extract as anti-leukemia agent using the athymic mouse xenograft model. Our results demonstrated that the CV extract dose-dependently suppressed the proliferation of HL-60 cells (IC50=150.6 ?g/ml), with increased nucleosome production from apoptotic cells. Expression of pro-apoptotic protein Bax was significantly up-regulated in HL-60 cells treated with the CV extract, especially after 16 and 24 h. Meanwhile, expression of anti-apoptotic protein Bcl-2 was concomitantly down-regulated, as reflected by the increased Bax/Bcl-2 ratio. The CV extract markedly, but transiently, promoted the release of cytochrome c from mitochondria to cytosol after 24-h incubation. In vivo studies in the athymic nude mouse xenograft model also confirmed the growth-inhibitory activity of the CV extract on human leukemia cells. In conclusion, the CV extract attenuated the human leukemia cell proliferation in vivo, and in vitro possibly by inducing apoptosis through the mitochondrial pathway. The CV extract is likely to be valuable for the treatment of some forms of human leukemia.

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Comparsion of Anti-cancer Effect between two kinds of Polysaccharide Peptide of Coriolus versicolor on Human Tumor Cell Lines in Vitro

L.Z. Xu

In the present study the anti-cancer effect of polysaccharide peptide of Coriolus versicolor Cov-1 (PSP) was compared with polysaccharide peptide of Coriolus versicolor CM-101 (PSK) on four human tumor cell line targets (SGC 7901, stomach cancer cell; SPC, human lung adenocarcinoma cell; SLY, human monocytic leukemia cell and Mei, human skin histiocytic lymphoma cell) in Vitro.
PSP had similar cytotoxic effects upon human tumor cells as PSK, both inhibiting cell growth. In comparison with control specimens, the SPC cell line treated with PSP (1000ug/ml) for 72 hours at 37oC showed marked morphological changes such as cell swelling, chromatin aggregation, formation of polynuclear cells and sawtooth on the surface of cell nuclei.
PSK as a new immunomodulative drug had been widely used for clinical anticancer therapy in Japan. When combined with chemotherapy, radiotherapy and surgical operation, PSK is found to be able to improve the therapeutic effects. In 1983, a polysaccharide peptide of Coriolus versicolor Cov-1 was isolated from the mycelia by Qing-yao Yang. It is possessed of physio-chemical characteristics similar to PSK and designated as PSP. In the present study the anti-cancer effect of PSP was compared with PSK using four human tumor cell line targets in vitro.

Combined effect of prophylactic lymphadenectomy and long term combination chemotherapy for curatively resected carcinoma of the stomach.

Kodama Y, Kano T, Tamada R, Kumashiro R, Okamura T, Inokuchi K.

Effectiveness of prophylactic extensive lymph node dissection (PELD) plus postoperative long term combination chemotherapy (PLCC) for patients with curatively resected gastric carcinoma was assessed in terms of the degree of serosal invasion and lymph node metastasis. Either the Group 1 and Group 2 lymph nodes were eradicated by PELD. PLCC included intermittent intravenous administration of mitomycin C (0.4 mg/kg intraoperatively followed by 0.2 mg/kg every 3 months) and oral administration of Tegafur (600-800 mg/day) and PSK (3.0 g/day), an immunostimulator, for as long a period as possible. PELD alone resulted in a cure when the malignancy was confined to the mucosal and muscular layers of the stomach as well as to the Group 1 lymph nodes. In cases when the carcinoma involved the serosa and/or the Group 2 lymph nodes, the 5 year survival rate was about 55 per cent the PELD and PLCC groups, such being significantly higher than about 27 per cent in the PELD alone group. Therefore, PELD plus PLCC is highly effective for advanced gastric carcinoma, under a condition of curative resection.


Kunitaka Hirose, Michinori Hakozaki, Kenichi Matsunaga, Chikao Yoshikumi, Tetsuya Hotta, Masaaki Yanagisawa, Mikio Yamamoto, Hideya Endo.

To elucidate the effects of PSK, a protein-bound polysaccharide from Coriolus versicolor, on gene expression in tumor cells, we prepared cDNA clone libraries from PSKtreated and untreated cells of a rat ascites hepatoma line, AH66, which was previously shown to be susceptible to the antitumor action of this compound. Two PSK-induced and one suppressed cDNA clones were selected from these libraries by using a differential colony hybridization and RNA blot hybridization. PSK was thus shown to have a direct effect on the transcription and consequently on the translation of tumor cells.

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Clinical study of biological response modifiers as maintenance therapy for hepatocellular carcinoma.

Suto T, Fukuda S, Moriya N, Watanabe Y, Sasaki D, Yoshida Y, Sakata Y.

We conducted a randomized, controlled trial comparing 5-fluorouracil (5-FU) with or without biological response modifiers (BRMs) as a maintenance therapy for hepatocellular carcinoma (HCC) after treatment with percutaneous ethanol injection (PEI), transcatheter arterial embolization (TAE) or arterial infusion of antitumor agents (AI). A total of 58 cases of HCC were classified into 4 groups as follows: group I, PSK with 5-FU (n = 15); group II, lentinan with 5-FU (n = 15); group III, OK-432 with 5-FU (n = 12); and group IV, 5-FU alone as the control (n = 16). The mean survival time, mortality rate, time to progression, and T4/T8 ratio of lymphocytes in the peripheral blood were compared among the four groups. There was no significant difference in the background factors among the groups. In group I, the T4/T8 ratio of lymphocytes was reduced after the therapy. No significant difference was found among the groups in terms of the mean survival time, mortality rate, or time to progression. PEI for initial therapy was superior to the other therapies in terms of the mean survival time and mortality rate. These results suggest that the addition of BRM to maintenance therapy with 5-FU exerts no prognostic benefit on HCC patients treated with PEI, TAE, or AI.