Potential Application of Ganoderma Polysaccharides in the Immune
Surveillance and Chemoprevention of Cancer by Dr. Raymond Chang, M.D., F.A.C.P.
ABSTRACT
Chemoprevention of cancer is a means of cancer control by
preventing, the occurrence of disease using chemical compounds,
natural or synthetic. One hypothesized mechanism of cancer
prevention is by means of enhanced immune surveillance. Animal
studies suggest that immune protection against cancer is effected
primarily through cell-mediated immune mechanisms; and because
Natural Killer (NK) lymphocyte functional activity correlates with
the incidence of tumors, immune surveillance of cancer is believed
to be particularly dependent on NK cells. Ganoderma polysaccharides
(GP), particularly those of a B-1, 3 configuration, have been
extensively demonstrated to have broad immunopotentiating
properties, including the stimulation of NK activity. This is
supported by similar activity in other purified bioactive
polysaccharides of comparable configuration, and their effectiveness
in suppressing viral and chemical carcinogenesis in animal systems.
Although no animal or human studies have yet been carried out using
GP for cancer prevention, it is potentially an ideal agent based on
I) GP's effectiveness in immunostimulation, particularly its ability
to augment NK activity, 2) GP's oral efficacy, and 3) GP's proven
lack of toxicity.
1. INTRODUCTION
The concept of chemoprevention of cancer took form about 30 years
ago (wattenberg 1966). It originally referred to the prevention of
cancer by the use of pharmacological agents to inhibit or reverse
the process of carcinogenesis (Sporn and Newton 1979). Based on the
accumulation of laboratory, epidemiological, and clinical data that
indicate various natural and synthetic substances may halt or
reverse cancer progression in animals as well as reduce the risk of
cancer in humans, the definition can be broadened to encompass any
use of natural or synthetic substances for the purpose of reducing
cancer incidence.
Currently, there are over 600 potential chemopreventative agents
belonging to more than 25 classes of chemicals including retinoids.
selenium salts, protease inhibitors hormones and antihormones.
indoles. phenols, and tocopherols (Costa et al. 1990). Most
compounds are direct chemopreventative compounds since they either
interfere with the metabolic activation of carcinogens, prevent the
carcinogens from reaching or reacting with target tissue, or inhibit
the promotion of carcinogenesis after carcinogen exposure (Bertram
et al. 1987).
A newer category of indirect chemopreventative agents based on
immunostimulation to enhance the host's natural defense against
cancer has been proposed based on the concept of immune
surveillance, which hypothesizes that the immune system functions to
police and control the spontaneous development of cancers (Burnet
1971).
2. ENHANCED IMMUNE SURVEILLANCE AS INDIRECT
CHEMOPREVENTION
Our understanding of the role of the immune system in protecting
against the development and growth of cancer is yet incomplete, but
it is generally recognized as a role of the host immune system. So
far, a large number of studies on immune competence demonstrate
defective immune response to a variety of cancers, and other reports
document that stimulation of the immune system have been
successfully applied to cause regression in cancer.
Based on the premise that the host immune system plays a
surveillance role in controlling the development of cancer and the
observation of defective immune competence in some cancer patients,
it is postulated that an augmented immune system may prevent cancer.
This is the concept of immunoprevention of cancer, which stems from
the concepts of tumor immunity, host immunocompetence, and immune
surveillance.
Both humoral and cellular immune response can be heightened by
immune adjuvants which enhance the immune system against cancer.
Such stimulated immune response arc considered non-specific since
tumor-specific T cells that recognize tumor antigens, and B cells
that produce antibodies against tumor antigens are not involved,
Therefore, immune surveillance and immunoprevention primarily
involves an amplified overall immune response effected by
non-specific stimulation of macrophages, natural-killer (NK) cells
and T cells.
3. THE NK CELL AS A MAJOR EFFECTOR OF IMMUNE
SURVEILLANCE
The NK cell is a distinct form of lymphocyte with the unique ability
to spontaneously and rapidly destroy a variety of tumor cells
without deliberate or specific stimulation by antigen or arming with
antibody (Heberman 1980). It is of particular interest in immune
surveillance and cancer immunoprevention because it is he major
effector cell in the host's immune defense against cancer. So far, a
body of experimental evidence supports the role of NK cells in the
in vivo resistance to malignancy. Original studies (Heberman 1980)
in mice demonstrating impaired tumor growth in animals with high NK
cell activity and progressive tumor growth in animals with low NK
cytotoxicity were complemented by studios showing rapid in vivo
clearance of transplanted tumors in rats with high NK activity (Lotzova
1983). Furthermore, a direct correlation was observed between
augmentation of NK activity and increased resistance to tumor growth
in rodents (Warner and Dennert 1982). In humans, significantly lower
N K activity was detected in normal individuals with high familial
incidences of cancer compared to individuals with low incidences in
one study (Strayer et al. 1986), and treated disease-free cancer
patients with high NK activity have significantly longer
metastasis-free survival than those with low NK activity (Pross and
Lotzova 1993); thus it has been postulated that augmented NK
activity may contribute to immunoprevention against cancer.
Besides NK cell activity, other immune effectors such as activated
macrophages (Fidler and Raz 1981), cytotoxic T lymphocytes (McMichael
1992), and various other cytokines (Lattime and Stutman 1991) of the
immune system may also have a role in the surveillance and
prevention of cancer
4. IMMUNOSTIMULATION WITH GANODERMA
POLYSACCHARIDES
Almost two decades ago, Nakashima et al. (1979) demonstrated T-cell
activation by orally administered Ganoderma polysaccharides (GP).
Subsequently, activation of immune function including the activation
of cytotoxic NK cells (Won et al. 1989), and stimulation of
cytokines (Chang et al. 1988) has also been reported with GP. The
B-1,3 glucan polysaccharide fraction in particular, has been
demonstrated to have a broad-based adjuvant stimulatory activity on
T-cells and macrophages, and lead to the enhance production of IL-I
(Jia et al. 1993), IL-2 (Chang et al. 1988, Zhang et al. 1 993a),
and TNF (Zhang et al. 1993b) which have been reported to play a role
in antitumor immune surveillance (Lattime and Stutman 1991). Of
particular interest is the demonstrated activity of a crude
Ganoderma extract on NK cell activity in vitro (Zhang et al. 1993c).
and the effectiveness of a water soluble GP fraction derived from
mycelium given by intraperitoneal, intravenous, or oral route in
enhancing splenic NK activity in normal mice and restoring depressed
NK cytotoxicity in tumor-bearing mice (Won et al. 1989). Other
studies demonstrated the ability of GP in activating macrophages
(Zhang et al. 1 983d) and in markedly enhancing the cytotoxicity of
CTL (Lei and Lin 1.992), both established tumoricidal effector
pathways of the host immune system.
5. POTENTIAL OF GP IMMUNOSTIMULATION FOR
PREVENTION OF CANCER
Ganoderma has been recognized traditionally and scientifically as
potentially useful in the treatment of cancer (Chang 1993). Although
triterpenoid and other fractions of Ganoderma may have direct
cytotoxic activity (Toth et al. 1983, Lin et al. 1991). current
evidence supports the notion that major anti-tumor efficacy of
Ganoderma is host dependent and mediated through GP immune
stimulation (Xia et al. 1989, Mizuno 1995).
Since enhanced NK and CTL activity are both believed to be crucial
effector mechanisms in immune surveillance and cancer prevention,
and such effector pathways are demonstrably activated by GP, it is
logical to suggest the application of GP for the immune prevention
of cancer. This notion is further supported by the effectiveness of
similarly structured fungal polysaccharides in immunostimulation (Chihara
et al. 1987 ), NK activation, (Tani et al. 1992), and in inhibiting
both methylcholanthrene (Suga 1984) and adenovirus (Hamada 1981)
carcinogenesis in animals.
More specifically, Stavinoha (1993) had performed a study indicating
that slow Ganoderma consumption inhibited the development and growth
of microadenomatous lesions in the colon of rodents treated with the
carcinogen 1, 2-dimethylhydrazine.
6.CONCLUSION
It is apparent that immune stimulation, especially NK and CTL
activation, may be effective in the immune prevention of cancer by
enhanced immune surveillance. However, the ideal chemopreventative
agent should have minimal or no toxicity besides proven efficacy and
be convenient to use since chernoprevention is intended by and large
for the general healthy population (Bertram et al. 1 987). G P is
non-toxic, without long-term side-effects (Kim et al. 1986) and has
been demonstrated to enhance N K and CTL activity when administered
oral l y (Won et al. 1989), and is thus an ideal candidate for
chemoprevention. In the meantime, more specific s studies to
demonstrate its efficacy in animal models need to be performed, and
these should be confirmed by large scale population studies in
humans.
