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.