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The New Role of Mushrooms in Traditional Medicine

Recent improvements in chemical technology have allowed the isolation and purification of the relevant compounds (especially the polysaccharides) which contain demonstrable anti-cancer activities.  Most species of mushrooms appear to act as immune system enhancers though some can have direct cytotoxic effects on cancer cells. Only a small number have progressed successfully to objective clinical assessment in trials.

The anti-tumor polysaccharides isolated from mushrooms (fruit-body, submerged, cultured mycelial biomass or liquid culture broth) are either water-soluble â-D-glucans, â-D-glucans with heterosaccharide chains of xylose, mannose, galactose or uronic acid or â-D-glucan-protein complexes -proteoglycans.  Some are orally bioavailable.

Methods of extraction and purification of the various polysaccharides are now well worked out. The main medically important polysaccharide compounds that have undergone clinical trials include Lentinan (Lentinus edodes), Schizophyllan (Schizophyllum commune), PSK and PSP (Trametes versicolor) and Grifron-D (Grifola frondosa). Compounds from other medicinal mushrooms with proven anti-cancer properties have been studied in pre-clinical models and will increasingly be submitted for clinical trials.

Mushroom-derived glucan and polysaccharo-peptides can act as immunomodulators.  The ability of these compounds to enhance or suppress immune responses can depend on a number of factors including dosage, route of administration, timing and frequency of administration, mechanism of action or the site of activity. Several mushroom compounds have been shown to potentiate the host's innate (non-specific) and acquired (specific) immune responses and activate many kinds of immune cells that are important for the maintenance of homeostasis, e.g. host cells (such as cytotoxic macrophages, monocytes, neutrophils, natural killer cells, dendritic cells) and chemical messengers (cytokines such as interleukins, interferon, colony stimulating factors) that trigger complement and acute phase responses. They can also be considered as multi-cytokine inducers able to induce gene expression of various immunomodulatory cytokines and cytokine receptors. Lymphocytes governing antibody production (â-cells) and cellmediated cytotoxicity (T-cells) are also stimulated.

Lentinan and Schizophyllan are T-cell oriented immunopotentiators and require a functional T-cell component for biological activity by way of increasing helper T-cell production, increased macrophage production leading to a stimulation of acute phase proteins and colony stimulating factors which in turn affect proliferation of macrophages, neutrophils and lymphocytes, and activation of the complement system.

PSK and PSP are potent immunostimulators with specific activity for T-cells and for antigen-presenting cells such as monocytes and macrophages. Their biological activity is characterized by their ability to increase white blood cell counts, interferon-y and interleukin-2 production and delayed type hypersensitivity reactions.

There have been extensive in vivo studies demonstrating the anti-cancer activity of the glucan polysaccharides and polysaccharide-peptides in animal models. These studies strongly suggest an immunomodulating mode of action. However, in in vitro studies on various cancer cell lines, there is strong evidence for direct cytotoxic effects on the cancer cells for some, but not all, of the polysaccharides.

While all of the proprietary mushroom polysaccharides successfully used in animal and human cancer treatments are effective by i.v.route, several can also be effective orally.

Many of the mushroom polysaccharides have proceeded through Phase I, II and III clinical trials mainly in Japan and China but now in US. Lentinan (L. edodes) has demonstrated strong anti-tumor activity in a wide range of xenographty and with human clinical trials where it has proved successful in prolonging the survival especially those patients with gastric and colorectal cancer. Lentinan has been approved as a drug in Japan and is considered an important adjuvant treatment for several cancers. Schizophyllan (S. commune) has proved useful for recurrent and inoperable gastric cancer, as well as increasing survival times of patients with head and neck cancers. Neither of these compounds show any significant side-effects.

There are several on-going clinical trials with Grifron-D, GD (G. frondosa) on breast, prostate, lung, liver and gastric cancers underway in Japan and US. Results to date are promising. In in vitro studies GD appears to inactivate glyoxalase I, an enzyme believed to metabolize chemotherapeutic compounds used against cancer cells thus potentially enhancing their bioavailability.

Two compounds, PSK and PSP (derived from mycelial cultures of T. versicolor) have shown worthwhile anti-cancer properties when given with traditional chemotherapeutic agents with no increases in side-effects. PSK has successfully been used in Phase I, II and III clinical trials with cancers of the stomach, oesophagus, nasopharynx, colon, rectum and lung, and with subsets of breast cancer. PSK gave protection against the immunosuppression that normally is associated with surgery and long-term chemotherapy. PSK continues to be used extensively in Japan as an adjunct to standard radio- and chemotherapy. PSP has been extensively studied by Chinese scientists and oncologists, with little evidence of side-effects.  Clinical trials have shown efficacy in gastric, oesophageal and non-small cell (NSCLC) lung cancers, and PSP has been recognized as a drug by the Chinese Ministry of Public Health.

A significant observation from these studies is the apparent ability of all of the above mushroom-derived polysaccharides when administered with radiotherapy and/or chemotherapy to significantly reduce the side-effects so often encountered by patients.

While the role of medicinal mushrooms in immunomodulation and anti-cancer activities represents the central theme of this Report it is pertinent to observe that many of the medicinal mushrooms have been highly valued for other medicinal properties including hypercholesterolemia, high blood pressure, diabetes, anti-viral, anti-bacteria, and antioxidant and free radical scavenging; each of these features is briefly discussed.

The safety criteria for mushroom-derived â-glucans have been exhaustively carried out in pre-clinical experiments. Acute, subacute and chronic toxicity tests have been carried out together with administration during pregnancy and lactation with no adverse effects. There were no anaphylactic reactions and no effects in mutagenicity and haemolysis tests, blood coagulation and a wide range of other regulatory tests. There was no evidence of genotoxicity.  Similar results have been obtained with other â-glucans. When applied to humans in Phase 1 clinical tests, the â-glucans demonstrate remarkably few adverse clinical reactions.

Current laws on dietary supplements in Europe, Japan and US are discussed with reference to herbal and mushroom products.

The safety of all medicinal mushrooms or their extracts cannot be guaranteed simply because they have been used for many centuries with apparent safety. Recent proposals have carefully examined historical usage and have set out reasons for adopting a more cautionary approach but at the same time indicating the way forward to ensure adequate safety and efficacy for an expanding use of mushroom dietary supplements and pharmaceutical products.

The main advantage of using mushroom products with respect to safety (when compared to herbal preparations) are:

  • The overwhelming majority of medicinal mushrooms are cultivated commercially (not gathered from the wild). This guarantees proper identification and relatively pure, unadulterated products.

  • Mushrooms are easily propagated vegetatively and, thus, kept to one clone. The mycelium can be stored for a long time and the genetic and biochemical consistency may be checked over time.

  • The ability to grow most medicinal mushrooms as mycelium in fermenters under controlled conditions with consequent improved product purity. This may well be an important future trend in medicinal mushroom product formation.

Several purified mushroom polysaccharides have been in clinical use in Japan, China and the US for several years with no reports of any significant short-term or long-term adverse effects.

In view of the great interest in medicinal mushrooms and the absence of a specialized journal in this field, a special journal dedicated to medicinal mushrooms - "The International Journal of Medicinal Mushrooms" (IJMM) was established in 1999 by Begell House (USA) (www.begellhouse.com). The IJMM highlights new perspectives in the field of mycology and medicine.  JES is a Senior Editor. In September 12-14, 2001, an International Conference "Perspectives of Medicinal Mushrooms in Health Care and Nutrition in the 21st Century" was held in Kiev, Ukraine.  Three hundred and forty eight scientists from 38 countries presented their results of this fascinating and growing science.