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Executive summary
A
EXECUTIVE SUMMARY
1. This literature study commissioned by the Cancer Research Campaign in
November 2000, entailed searching computerized databases of published
literature (e.g. Medline, BIDS/WOS, Embase, Science Citation Index, British
Library Net) and searching of relevant specialised journals (as outlined in the
proposal), many of which are not included in the computerized databases.
Many original and peer-reviewed papers were obtained from the Document
Supply Centre of British Library Net and scanning reference lists of
appropriate review articles, books and other relevant publications (including
symposia and conference proceedings). Consultations were achieved with
key informants in the field, nationally and internationally. In addition to writing
to many internationally-leading scientists in this field, Prof Smith spoke to a
number of these scientists at an international conference held recently in Kiev
where he presented an invited paper on this particular topic. However, while
most of the aforementioned strategies proved successful, we were
disappointed at the lack of response from some key scientific and medical
centres in China and Japan who have specialised knowledge in this particular
field.
We believe that this seminal literature study does contain the best up to date
information on the therapeutic properties and current medical usage of
medicinal mushrooms with special emphasis given on cancer treatment. It is
proposed that the critical information in this report will be used to write
reviews for appropriate journals. As a closing qualifying remark, while every
effort was made to ensure that the best-published-data was gathered on the
aforementioned, it must be appreciated that this particular field is enormous
and a limited number of interesting papers may have been missed.
Executive summary
B
2. Scientific evidence supports the view that diet controls and modulates many
functions of the human body and, accordingly, participates in the
maintenance of the state of good health or homeostasis.
3. Arising from this awareness of the relationship between diet and disease has
evolved the concept of functional foods and the development of functional
food science. Foods as medicine underpins the paradigm of functional foods.
The primary objectives of functional food science are to maintain good health,
improve homeostasis and to create the conditions for disease reduction. It is
seen to be quite distinct from the medical and pharmaceutical sciences where
the objectives are mainly to cure or control diseases.
4. Mushrooms have long been valued as highly flavoursome and nutritional
foods by many societies. In the Orient, there has long been the recognition
that certain edible and non-edible mushrooms can have profound health
benefits. When used as tonics the medicinal mushrooms are consumed
whole or preferably as concentrated extracts and act as dietary supplements.
A limited number of highly purified compounds derived from certain medicinal
mushrooms are now being used in the Orient and the US as pharmaceuticalgrade
products in medicine – especially, but not exclusively, for cancer
treatment.
5. Mycology is concerned with the study of the fungi, the term being derived
from the Greek word mykes. They are heterotrophic, requiring organic
carbon compounds of varying degrees of complexity for growth and
reproduction. Most fungi exist as microscopic filaments or hyphae which form
a complex mycelium or network. In some cases the mycelia form large
complicated structures as exemplified in the mushrooms. This report deals
Executive summary
C
exclusively with large fleshy mushrooms, especially the medicinal
mushrooms.
6. The use of psychotropic mushrooms by man dates far back into antiquity with
the earliest records dating back to Palaeolithic times. There is an extensive
literature implicating certain mushrooms in ancient religious beliefs and
practices.
7. Consistent production of successful mushroom crops is built upon scientific
knowledge and practical experience. To date about 35 mushroom species
have been cultivated commercially with about 20 cultivated on an industrial
scale. Most of these species are both edible and possess medicinal
properties.
8. Mushroom cultivation involves several different operations each of which
must be performed accurately if the enterprise is to be successful, viz. strain
selection and maintenance, spawn production, mushroom production (log
culture and enriched sawdust culture), and crop management for production.
Mycelium production by liquid tank fermentation is now increasingly being
used for the production of more uniform medicinal products. The ability to
use pure substrates and controlled growth environments will aid in the final
purity of the products.
9. The practice of using fungi, especially mushrooms, in Chinese Traditional
Medicine (TCM), dates back into antiquity and has been recorded in ancient
Chinese manuscripts. Increased scientific and medical research in recent
decades, especially in Japan, Korea and China and more recently US, is
confirming efficacy and identifying the bioactive molecules.
10. The main medicinal mushrooms both edible and non-edible are briefly
depicted to identify their historical usage and their current commercial and
Executive summary
D
medical acceptance, viz. Ganoderma lucidum (Reishi or Ling Zhi), Lentinus
(Lentinula) edodes (Shiitake), Phellinus linteus, Porio cocos, Auricularia
auricula, Hericium erinaceus, Grifola frondosa (Maitake), Flammulina
velutipes, Pleurotus ostreatus (Oyster mushroom), Trametes (Coriolus)
versicolor, Tremella fuciformis, Schizophyllum commune and the nonmushroom
Cordyceps sinensis (the caterpillar fungus).
11. 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 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.
12. The anti-tumour polysaccharides isolated from mushrooms (fruit-body,
submerged, cultured mycelial biomass or liquid culture broth) are either
water-soluble β-D-glucans, β-D-glucans with heterosaccharide chains of
xylose, mannose, galactose or uronic acid or β-D-glucan-protein complexes -
proteoglycans. Some are orally bioavailable.
13. 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.
14. Mushroom-derived glucan and polysaccharo-peptides can act as
immunomodulators. The ability of these compounds to enhance or suppress
Executive summary
E
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 (β-cells) and cellmediated
cytotoxicity (T-cells) are also stimulated.
15. 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.
16. 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 characterised by their ability to increase white blood cell
counts, interferon-y and interleukin-2 production and delayed type
hypersensitivity reactions.
17. There have been extensive in vivo studies demonstrating the anti-cancer
activity of the glucan polysaccharides and polysaccharide-peptides in animal
Executive summary
F
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.
18. 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.
19. 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-tumour 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.
20. 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 metabolise chemotherapeutic
compounds used against cancer cells thus potentially enhancing their
bioavailability.
21. 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
Executive summary
G
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 recognised as a drug by the
Chinese Ministry of Public Health.
22. A significant observation from these studies is the apparent ability of all of the
above mushroom-derived polysaccharides when administerded with
radiotherapy and/or chemotherapy to significantly reduce the side-effects so
often encountered by patients.
23. 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.
24. The safety criteria for mushroom-derived β-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.
Executive summary
H
Similar results have been obtained with other β-glucans. When applied to
humans in Phase 1 clinical tests, the β-glucans demonstrate remarkably few
adverse clinical reactions.
25. Current laws on dietary supplements in Europe, Japan and US are discussed
with reference to herbal and mushroom products.
26. 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.
27. 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.
Executive summary
I
28. 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.
29. In view of the great interest in medicinal mushrooms and the absence of a
specialised 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.
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