Fractionation and purification of the polysaccharides with marked antitumor activity, especially lentinan, from Lentinus edodes (Berk.) Sing. (an edible mushroom).
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Animals↗
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The ability of polymorphonuclear leukocytes to produce active oxygen in a model of peritonitis in rats.
To elucidate the mechanism of enhancing survival in peritonitis rats treated with lentinan, a fully purified beta-1,3-glucan, we measured the active oxygen-producing ability of polymorphonuclear leukocytes (PMNs). Four groups of rats (group I, fecal peritonitis control; II, rats receiving 3 mg/kg lentinan intraperitoneally at the same time as peritonitis induction; III, rats receiving 1 mg/kg gentamicin intramuscularly; and IV, rats receiving combined lentinan-gentamicin treatment) were used. The survival period was significantly longer in group IV than in the other three groups. The ability of ascitic PMNs to produce active oxygen (superoxide, H2O2, myeloperoxidase) was significantly more than that of blood PMNs in each group at 20 h after peritonitis induction. The increase in active oxygen production in ascitic PMNs was higher in group IV compared with that in the other three groups. The concentration of lentinan in the blood was high at 24 h after administering lentinan intraperitoneally to both the normal and peritonitis rats. In the in vitro study, the superoxide production in normal rat blood PMNs was significantly higher in the presence of cytokines (IL-1 beta, IL-6, TNF-alpha) without dose-dependence but was not higher for the lentinan group than in the control. This study therefore suggests that lentinan activated the peritoneal macrophage secretory activity and produced cytokines which thus enhanced the ability of PMNs to produce active oxygen, which possesses a bactericidal ability in PMNs.
Animals↗
Cancer cell progression and chemoimmunotherapy--dual effects in the induction of resistance to therapy.
To determine whether resistance to chemoimmunotherapy is acquired during therapy, we investigated the effects of chemotherapeutic agents and anti-tumour polysaccharide, lentinan, on the progression of Rous sarcoma virus-induced S908.D2 fibrosarcomas. The chemoimmunotherapy was effective against the parental S908.D2-bearing mice. Nearly all the mice that were treated with cyclophosphamide (CY) and lentinan achieved complete tumour regression. Only a few of the mice that achieved complete regression of the primary tumours showed a recurrence of the tumour in regional lymph nodes. S908.D2-vp.1 was established from metastatic tumours that developed in the regional lymph nodes of parental S908.D2-bearing mice during therapy. S908.D2-vp.2-or vp.3 cells were sequentially derived in a similar way from S908.D2-vp.1-or-vp.2-bearing mice respectively, in which complete tumour regression at each primary site was achieved during therapy. These lines acquired resistance to CY and lentinan and also to 5-fluorouracil (5-FU)/5'-deoxy-5-fluorouracil and lentinan. No significant difference in either the sensitivity to 5-FU or 4-deoxycyclophosphamide in vitro or in the susceptibility to immune effector cells was observed between the parental and progressed lines (S908.D2-vp1 -vp3). There was an increase in the level of prostaglandin E2 (PGE2) in the progressed lines during repeated therapy (parental, 1171 pg ml(-1); vp.1, 2199 pg ml(-1); vp.2, 5500pg ml(-1); vp3, 16187 pg ml(-1)). There was no significant increase in the production of transforming growth factor beta (TGF-beta). The amount of interleukin-2 (IL-2) produced by spleen cells isolated from the S908.D2-vp.2-bearing mice was decreased compared with the amount produced by the parental S908.D2- bearing mice. Furthermore, combination therapy with lentinan and IL-2 achieved complete tumour regression in all the mice transplanted with S908.D2 progressed tumour lines, although IL-2 alone did not show any anti-tumour effects in either the S908.D2 parental or progressed lines. The findings suggest that the reduced production of IL-2 induced an increase in the production of the PGE2 by progressed tumour lines is involved in the acquisition of resistance.
Animals↗
Synthesis of an inhibitor of human immunodeficiency virus infection.
Anti-HIV effects of lentinan sulfate were investigated by using an HTLV-I-carrying cell line, MT-4, in vitro. Lentinan, a fungal branched (1----3)-beta-D-glucan, was sulfated to various degrees by means of two kinds of procedures using piperidine N-sulfonic acid in dimethyl sulfoxide or chlorosulfonic acid in pyridine. Lentinan sulfate with a sulfur content of more than 13.9% effectively prevented HIV-induced cytopathic effects (CPE) at concentrations of more than 3.3 micrograms/ml. However, low-substituted lentinan sulfate did not prevent HIV-induced CPE at any concentration tested. When the countercation was 50% Na+ and 50% pyridinium ion, the inhibitory capacity was low. Anticoagulant activity of the lentinan sulfate was also assessed.
Anticoagulants↗
Modification of septic processes by beta-glucan administration.
The effect of glucan (lentinan), beta(1----3)-glucan derived from Lentinus edodes, was evaluated in a clinically relevant septic model. Male, Japanese, white rabbits were intravenously injected with lentinan (1 mg/body) just before septic insult, induced by injecting fecal suspension into the ligated choledochus. In septic animals without lentinan treatment, platelet counts dropped serially following the septic insult and a paracoagulation test, measured by protamine gelation, turned positive. Plasma bilirubin and creatinine elevated significantly in comparison with control animals injected with saline, at 9 h and at 6 and 9 h. respectively. In lentinan-treated septic animals, platelet counts did not decrease and a significant difference was found at 9 h, compared to the untreated septic animals. The degree of positive paracoagulation was less prominent. The elevation of plasma bilirubin and creatinine levels was also less prominent and a significant difference was found at 9 h. Plasma endotoxin elevated significantly at 9 h in the untreated septic animals in comparison with lentinan-treated septic and control animals. The findings suggest a modification of the septic processes by the administration of glucan.
Animals↗
[Potentiation of combination effect of cisplatin and radiation--application of biological response modifiers].
The combination antitumor effect of three kinds of biological response modifiers (lentinan, PSK and juzentaiho-to) was evaluated in the treatment of IMC solid carcinoma with CDDP (9 mg/kg) and/or radiation (1000 rad). Remarkable antitumor effects were observed in the lentinan (2 mg/kg, daily) group to which a single dose of CDDP was given 24 hours before irradiation. On the other hand, combined therapy with CDDP and radiation alone showed less antitumor effect. No antitumor effect was observed in the groups treated with biological response modifiers (BRM) alone. Winn's test was performed to investigate the level of immunity on each treatment group. Mice were inoculated with the admixtures of immunized spleen cells and IMC carcinoma cells at a ratio of 200:1. Tumor growth was completely suppressed in the groups of CDDP and lentinan with or without radiation even on the 41st day after inoculation. These results are strongly suggestive of potentiation of the immunity of tumor bearing mouse by the combined use of lentinan. Histopathological evaluation also revealed a potent antitumor effect of combined use of lentinan. Since host immunity is known to be suppressed in the tumor bearing state, combined use of BRM in chemo-radiotherapy must play an important role in the treatment of malignant tumor.
Adjuvants, Immunologic↗
[Modulation of the anti-tumor effect of BRM under various nutritional or endocrine conditions].
Immuno-chemotherapeutic effects on the growth of MM-48 mammary tumor were studied in syngeneic C3H/He mice fed diets containing a low (D), normal (N) or arginine-supplemented (NA) protein content. The serum protein levels were 5.7 g/dl in N-mice and 3.7 g/dl in D-mice, respectively. On the other hand, no difference was seen between the two groups, with regard to intra-tumoral protein concentrations. The natural killer (NK) activity of spleen cells was significantly lower in D-mice than in N-or NA-mice. Augmentation of NK activity was detected following the i.p. injection of OK-432 or LENTINAN, while no augmentation was recognized in D-mice. Interferon production of cultured spleen cells was significantly reduced in D-mice, and significantly increased in NA-mice compared with N-mice. NK activity was markedly augmented at 7 days after bilateral oophorectomy in N-mice. Both NK and IFN titers were significantly reduced following administration of estradiol every 7 days. The growth of MM-48 tumor was inhibited by daily administration of OK-432 or LENTINAN in N-mice. However, the tumor growth was paradoxically accelerated after administration of the same drugs in D-mice. These findings indicated that the nutritional or endocrine environment of cancer-bearing mice plays an important role in the effect of some kinds of BRMs. A clinical randomized study of advanced and recurrent gastric cancer patients treated with MMC and FT (MF) with or without LENTINAN, was then performed. We recognized excellent end-point results only in LENTINAN-administered patients with normal protein levels, while no effect of LENTINAN was seen in patients with low protein levels (below 6.0 g/dl).
Animals↗
[Experimental studies on growth inhibition and regression of cancer metastases].
The most important target in pharmaceutical therapy against cancer is complete suppression of metastases and recurrence after curative surgical operation. It is fundamentally, a growth inhibition and regression of small number of autochthonous tumors scattering in the host, and coexistence between tumor and host is also important. As immunosuppressive anticancer drugs have detrimental effects for patients in such cases, application of strong immunopotentiators such as lentinan should be expected. Lentinan showed a prominent effect on suppression of metastases in experimental systems of clinical models using MH-134 hepatoma, Madison-109 lung carcinoma and DBA/2.MC.CS-1 fibrosarcoma. Suppression of carcinogenesis may be considered as one of experimental methods to prevent metastases in a viewpoint of regression of small number of autochthonous tumor cells. Lentinan given at suitable timing and schedule showed marked prophylactic effect on chemical and viral carcinogenesis. Mode of action of lentinan as T-oriented adjuvant in its antitumor and metastases-inhibitory effects is also discussed. Considering excellent end-point results of Phase III with advanced and recurrent gastrointestinal cancer, lentinan is the most hopeful substance to prevent micrometastases.
Animals↗
T-cell mediated vascular dilatation and hemorrhage induced by antitumour polysaccharides.
Antitumour polysaccharide lentinan, capable of potentiating T-cell dependent reactions and some other antitumour polysaccharides such as pachymaran, carboxymethyl-pachymaran and zymosan were found to induce vascular dilatation and hemorrhage(VDH) in CD-1 normal mice starting the following day after a single injection. Polysaccharides which do not have the tumour-regressing activity, several immunopotentiators such as BCG, lipopolysaccharide, dextran sulfate and concanavalin A, and chemical mediators of inflammation such as histamine, serotonin and prostaglandin E1 did not induce VDH in mice. This response seems to be mediated by T-cells and macrophages, because VDH was not observed in CD-1 nu/nu mice treated with lentinan, and carrageenan, an antimacrophage drug, inhibited the appearance of VDH by lentinan. Furthermore, carrageenan inhibited the production of the VDH-inducing serum which was caused by lentinan, capable of passively transferring VDH to another mouse.
Adjuvants, Immunologic↗
Recent progress in immunopharmacology and therapeutic effects of polysaccharides.
Lentinan, a (1----3)-beta-D-glucan with (1----6)-beta-D-glucopyranoside branches and its related polysaccharides have marked antitumour activity in allogeneic, syngeneic and autochthonous primary hosts, suppress chemical and viral oncogenesis, and prevent cancer recurrence or metastasis after surgery. Results of the clinical application of lentinan have proven prolongation of life-span of the patients with advanced and recurrent stomach, colorectal and breast cancer with only little toxic side effect. These polysaccharides also increase host resistance to various kinds of bacterial, viral and parasitic infections including AIDS. Lentinan appears to represent Host Defence Potentiators (HDPs), which can restore or augment the ability of responsiveness of the host to lympho-cytokines or other intrinsic bioactive factors through maturation, differentiation or proliferation of the important cells for host defence mechanisms. That is, HDPs might make the physiological constitution highly cancer and infection-resistant, which may be a concept in Oriental Medicine, the fundamental principle of which is to regulate homeostasis of the whole body and to bring the diseased person to his normal state. HDPs such as lentinan are the most appropriate drugs to prevent cancer recurrence, or the manifestation of AIDS symptoms in HIV carriers.
Acquired Immunodeficiency Syndrome↗
[Two case reports of complete regression of liver metastases from colorectal cancer after locoregional immunochemotherapy].
Hepatic arterial infusion (HAI) with pharmacokinetic modulating chemotherapy (PMC) has been well known to be one of the most effective protocols for unresectable liver metastases from colorectal cancer. PMC is a combination of oral UFT and continuous hepatic arterial 5-FU infusion. We present herein the cases of two patients with multiple liver metastases from colorectal cancer in whom complete regression (CR) was achieved by HAI with PMC in combination with Lentinan (immunostimulator). These patients received HAI via an implantable port system with a 4-24-hour continuous perfusion of 5-FU at 1,000 mg/m2 plus Lentinan at 2 mg/body once a week, and oral administration of UFT at 200-300 mg/m2/day everyday. CR of all metastatic lesions in the liver was achieved 4 months after the initiation of the treatment in both patients. One patient maintained CR for 3 months, but he died due to a recurrence of liver metastases and peritoneal dissemination 19 months after the initiation of the treatment. The other patient has been well without recurrence for 21 months. Because the liver is the largest immunologic organ, Lentinan could have activated lymphocytes and macrophages in the liver. Judging from the clinical experience of these two cases, HAI with PMC in combination with Lentinan could be one of the most promising treatment strategies for unresectable liver metastases from colorectal cancer.
Adjuvants, Immunologic↗
[TS-1/CDDP/Lentinan combination chemotherapy for inoperable advanced gastric cancer].
It is reported that TS-1 administered orally shows a significant anti-neoplasm effect on advanced gastric cancer, and, furthermore, approximately 70% or greater effectiveness is reported for combination chemotherapy with cisplatin (CDDP). Lentinan is reported to extend the survival period in advanced cancer, and in combination with Tegafur. In the present study, combination chemotherapy with TS-1/CDDP/Lentinan was conducted for patients with inoperable advanced gastric cancer, and the validity, safety and resultant QOL of the treatment were evaluated. TS-1 was administered for 3 weeks at 80 mg/m2, followed by withdrawal for 2 weeks, and CDDP was prescribed once for patients at 70 mg/m2 on the 8th day after starting TS-1 administration. For patients aged 80 or above, however, the dose was reduced, and given separately to the patients. Lentinan was administered at 2 mg/week. The rate of effectiveness for the 9 registered patients was 100%. This high rate was obtained regardless of changes in the histopathological findings. Critical side effects (grade three or above) were anemia and pigmentation, in one case each. An improvement in QOL was also observed for combination therapy including Lentinan. In cases of inoperable advanced gastric cancer, TS-1/CDDP combination chemotherapy showed higher efficacy regardless of the pathological alterations, and higher and sustained improvement of QOL was also observed with the addition of Lentinan to the protocol.
Adult↗
[Analysis of immunological response of regional lymph node lymphocytes from patients with gastric cancer after endoscopic local injection of biological response modifier (BRM)].
Local injection of BRM (OK-432 or Lentinan) around the cancer lesions via endoscope was performed on 66 gastric cancer patients preoperatively, and the regional lymph node lymphocytes in the surgical specimens were examined on T-cell subset, production of IL-2, and responsiveness to IL-2. The results were as follows: 1) In the metastatic lymph nodes, proportions of T-lymphocyte subsets, production of IL-2 and responsiveness to IL-2 did not change after local administration of OK-432 or Lentinan. 2) In the non-metastatic lymph nodes, percentage of CD4+4B4+ cells were significantly increased and production of IL-2 was markedly augmented after local injection of OK-432. On the other hand, percentage of CD8+CD11- cells were significantly increased and production of IL-2 was markedly enhanced after the local injection of Lentinan. These data suggested that the antitumor response of the non-metastatic lymph node lymphocytes was augmented after the local injection of OK-432 or Lentinan.
Adult↗
Combination antitumor therapy with rabbit tumor necrosis factor and chemo- and immuno-therapeutic agents against murine tumors.
The antitumor activity of partially purified rabbit tumor necrosis factor (TNF) in combination with lentinan or chemotherapeutic agents was tested. Partially purified TNF was obtained from TNF-containing rabbit sera by salt precipitation and ion-exchange chromatography. Its specific activity, determined in vitro as its cytotoxic activity against L929 cells in the presence of actinomycin D, was 10(5) U/mg protein or about 30-fold that of the crude rabbit sera. The growths of MH134 hepatoma in C3H/He mice and Lewis lung carcinoma in C57BL/6 mice were partially inhibited by intratumoral administration of a suboptimal dose of the TNF preparation. Additional treatment with lentinan, actinomycin D, mitomycin C or adriamycin significantly increased the antitumor activity. In particular, combination therapy with TNF and lentinan was very effective against MH134 hepatoma without having detectable side-effects, showing that lentinan expanded the therapeutical potential of TNF. These results are discussed in relation to our previous results on combination antitumor therapy.
Animals↗
Current status and perspectives of immunomodulators of microbial origin.
The chemical structure and characteristics, the antitumour activity, the antibacterial, antiviral, antifungal, antiparasitic activities, immunological properties and mode of action of immunomodulators of microbial origin, especially antitumour polysaccharide lentinan, have been discussed immunopharmacologically in comparison with pachymaran, schizophyllan, DiLuzio's yeast glucan, Coriolus preparation PS-K, Streptococcal preparation OK-432, Nocardia rubra cell wall skeleton N-CWS together with BCG and Corynebacterium parvum. Lentinan exerts its inhibitory action not only on allogeneic tumours but also on syngeneic and autologous tumours, and prevents chemical and viral carcinogenesis. The phase III randomized control study of lentinan in cancer patients with gastric and colo-rectal cancer showed the clinical efficacy of lentinan in prolonging the life span and improving host immune responses. Experimental and clinical application demonstrated the advantage of N-CWS over BCG-CWS, and a recent study on OK-432 showed similar results to those obtained with C. parvum. In future work on microbial immunomodulators, it will be essential to find a parameter of the host-tumour relationship which will indicate the protocol for application of immunomodulators, and to find a new-type of selective immunostimulant. For this purpose, exhaustive studies on lymphokines, monokines and lymphocyte tropic hormones are indispensable.
Adjuvants, Immunologic↗
Adoptive cellular immunotherapy to the endometrial carcinoma cell line xenografts in nude mice.
The present study was designed to examine the immunotherapeutic properties of lymphokine-activated killer (LAK) cells against uterine endometrial cancers. Three endometrial cancer cell lines, ISHIKAWA, SNG-M, and HHUA, were shown to be specifically lysed in short-term 51Cr-release assay, although the susceptibility was different among the cell lines. The xenograft tumors of ISHIKAWA and SNG-M exhibited high susceptibility to LAK cells in the in vitro assay and responded well to the adoptive transfer of LAK cells in nude mice. On the other hand, the xenograft of HHUA showed low reactivity to LAK cells and showed no response to the adoptive immunotherapy. However, the adoptive transfer of LAK cells combined with intraperitoneal administration of both recombinant interleukin-2 (rIL-2) and lentinan markedly inhibited the growth of HHUA xenografts in nude mice, while no response was observed in nude mice treated with LAK cells plus either rIL-2 or lentinan, or treated with rIL-2 plus lentinan alone. These results suggest the clinical application of adoptive immunotherapy in association with LAK cells, rIL-2, and lentinan as a treatment of gynecologic cancers.
Adenocarcinoma↗
The influence of Lentinus edodes (Shiitake mushroom) preparations on bacteriological and morphological aspects of the small intestine in piglets.
Among substances intended to replace growth promoting antibiotics in pig nutrition, non-digestible oligosaccharides or polysaccharides could be potential alternative compounds. Therefore, the influence of beta-1,3-1,6 glucans on bacteriological, biochemical and morphological aspects of the small intestine in weaned piglets was investigated. As sources of beta-glucans, Lentinan (extract of Lentinus edodes mycelium) or dried L. edodes mycelium were added to the diet. Four homogenous groups of 5 newly weaned piglets (4 weeks of age) received one of four diets: control diet (C), C supplemented with Avilamycin (50 mg/kg, positive control), C supplemented with 0.1% of Lentinan and C supplemented with 5% of dried L. edodes mycelium powder. A first group of 10 piglets was euthanized after 11 days and the remaining 10 on day 12 of the experiment. The gastrointestinal tract was divided in segments and samples taken from digesta (stomach, proximal and distal jejunum, caecum), mucosal scrapings (jejunum) and ring shaped tissue samples (1 cm) of proximal and distal jejunum. Bacterial counts were made with digesta and mucosal samples, and short-chain fatty acids (SCFA), lactic acid and ammonia concentrations were determined. Tissue samples of both jejunal sites were embedded in paraffin wax for morphometrical (villus length, crypt depth) and histological observations (numbers of intraepithelial lymphocytes (IEL), goblet cells, apoptotic enterocytes on villi, mitotic cells in crypts). Only the diet containing 5% of dried L. edodes consistently resulted in lower viable counts (ca. 1-2 log10 CFU) of total bacteria, E. coli, streptococci and lactic acid bacteria, and luminal and mucosal effects agreed very well. With this diet, acetate and butyrate concentrations in the distal jejunum were doubled, which is favourable in view of the trophic effect on enterocytes and colonocytes. Villus length (V) was increased with both diets containing beta-glucans while crypt depth (C) was not altered, but V/C was higher. IEL counts were decreased by both diets although bacterial numbers, which is only one parameter of bacterial load, were only diminished with the L. edodes feed. The three supplemented feeds lowered the number of apoptotic enterocytes on the villi, but these numbers were very low (control diet : 44 cells per 100 villi), making clear interpretation difficult. The mitotic index was slightly lower with the L. edodes feed, although not statistically significant. Decreased viable counts observed with the latter diet is a favourable effect as it is accepted that a lower bacterial load causes lower turnover rates of the intestinal epithelial cells, while there is also less competition for specific substrates. A higher V/C ratio, a smaller number of IEL in the epithelium and a lower apoptotic index also indicate slower turnover rate of the mucosa when Lentinan and L. edodes diets were fed. The inconsistent effects observed with Lentinan were probably due to the low amount added to the diet. It should be taken into account that the influence of L. edodes mycelium powder was more likely due to the presence of antibacterial compounds (eg. lenthionine, lentinamycin, terpenoids, polyphenols), rather than to an immunostimulating action of beta-glucans with increased release of IgA onto the mucosa surface.
Adaptation, Physiological↗
Analysis of immunomodulating cytokine mRNAs in the mouse induced by mushroom polysaccharides.
The immunomodulating action of two mushroom antitumor polysaccharides, polysaccharide-protein complex (PSPC) and lentinan, was elucidated through analysing the expression profile of cytokines during a time course (0 h to 48 h) after their administration. Among the 5 cytokine genes, the induction of a marked increase in the mRNA levels of IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma and M-CSF by PSPC and lentinan was observed in the peritoneal exudate cells and splenocytes. However, the time point of their increased production was different after PSPC and lentinan administration.
Adjuvants, Immunologic↗