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Antitumor Effect of a Hot Water Extract of Agaricus blazei, "Himematsutake," Combined with an Organogermanium Compound, Ge-132
Abstract
The antitumor effect of extracts obtained from fluiting bodies of Agaricus blazei (Himematsutake) was examined in a double-grafted tumor system. Extracts of A. blazei significantly inhibited the growth of the right primary tumor but not the left metastatic tumor. Antimetastatic effect of an intratumoral administration of extracts of A. blazei was enhanced by an oral ad lib administration of the feed including 0.05% polytrans-[(2-carboxyethyl) germasesquioxane], Ge-132. Immunosuppressive acidic protein (IAP) was found to be produced by activated macrophages. IAP in serum was increased transiently soon after intradermal injection of the extracts of A. blazei. Combined treatment of extracts of A. blazei and Ge-132 increased CD4 positive helper T cells in the body.
... At the present time, research findings on the antitumoral metabolites are of the highest importance. The authors demonstrated Basidiomycota metabolites to be potential source of antitumoral agents particularly polysaccharides and more specificallypolysaccharides from fungal cell walls (Ebina et al ., 2004;Fuji et al . 1978;Kerrigan, 2005;Lu, 1995;Mizuno et al ., 1995;Yoshioka et al., 1985). ...
The widespread occurrence of biological activities within the fungal kingdom is now widely accepted. Since ancient times the so called mushrooms meaning Basidiomycota have been used for medicinal purpose. All major human body functions were considered to benefit from fungi intake. These positive effects include prophylactic as well as curative actions. Historically, Oriental countries first recognized mushrooms as an important source of medicines. Recently, Occidental research starts to really consider this almost untapped source of therapeutic drugs. Indeed, discovering new major medics is becoming a great challenge. The aim of the present review is to outline past and current major therapeutic interests and pharmacology of medicinal mushrooms, and their applications in human health care. Indeed, metabolites from Basidiomycota demonstrate verified pharmacological activity in major diseases such as chronic inflammation, oxidation associated pathologies, diabetes, infections (HIV, fungi, bacteria), immune system disorder and cancer.
Key words: Basidiomycota / biological activity / health care / pharmacology / therapeutics / metabolic and infectious diseases
... Poly-trans-[(2-carboxyethyl) germasesquioxane], Ge-132, is the most common water-soluble organogermanium compound (Fig. 1); it has very low toxicity. Ge-132 was first synthesized by Tsutsui et al. (1976), and its immunomodulation activities have been revealed (Aso et al., 1989;Ebina et al., 2004;Aso et al., 1985). In particular, the activation of natural killer cells and macrophages (Aso et al., 1985) has been reported; therefore, interferon gamma is induced in the serum of humans (Miyao and Tanaka, 1988) and mice (Brutkiewicz and Suzuki, 1987) after the administration of Ge-132. ...
Poly-trans-[(2-carboxyethyl) germasesquioxane], Ge-132 is a water-soluble organic germanium compound. Oral intake of dietary Ge-132 changes fecal color and we attempted to identify the fecal red pigment, which increased by the intake of dietary Ge-132. Sprague Dawley rats were given diets containing Ge-132 from 0 to 0.5% concentration. Fecal red pigment was extracted and purified for optical and structural studies. We examined the fecal red pigment content by high performance liquid chromatography (HPLC), and hepatic gene expressions relating to heme synthesis by reverse transcription polymerase chain reaction (RT-PCR). The purified red pigment had particular optical characteristics on the ultraviolet (UV)-visible spectrum (Soret band absorbance at 400 nm) and fluorescence emission at 600 nm by 400 nm excitation, and was identified as protoporphyrin IX by LC-MS analysis. Protoporphyrin IX significantly (P<0.05) increased 2.4-fold in the feces by the intake of a 0.5% Ge-132 diet. Gene expression analysis of the liver explained the increase of protoporphyrin IX by dietary Ge-132 as it enhanced (P<0.05) aminolevulinic acid synthase 1 (Alas1), a rate-limiting enzyme of heme synthesis, expression 1.8-fold, but decreased ferrochelatase (Fech) expression 0.6-fold (P<0.05). The results show that the intake of dietary Ge-132 is related to heme metabolism. Because protoporphyrin IX is used to treat chronic hepatitis, Ge-132 may be a beneficial substance to increase protoporphyrin IX in the liver.
PSK, a Coriolus preparation, inhibited the growth of not only the right but also the left, non-treated tumor in a double grafted tumor system. In order to examine the role of lymph nodes and the spleen in the antitumor activity of PSK, regional (axillary and inguinal) lymph nodes and spleen were resected. Since in resected mice the antitumor activity of PSK against the right and left tumors was weakened, the regional lymph nodes and the spleen probably have a very important role in the antimetastatic effect of intratumoral administration of PSK. TIL (tumor-infiltrating lymphocytes) obtained from left and right side tumors treated with PSK were examined by Winn assay for their antitumor activity against Meth-A sarcoma in BALB/c mice. TIL from both sides clearly inhibited the growth of admixed Meth-A cells, but control TIL did not. A primary growth of Meth-A sarcoma inoculated into the right flank resulted in the generation of concomitant immunity to the growth of a second graft of the same tumor cells in the left flank. A significant inhibitory effect on the proliferation of the tumor cells inoculated secondarily was shown in mice bearing a primary right tumor that had previously been inoculated with PSK 3 times. After surgical excision of the primary tumor on day 6, daily oral administration of PSK significantly inhibited the growth of the secondary tumor inoculated on day 21, that is, PSK treatment also enhanced sinecomitant immunity. These observations suggest that presurgical intratumoral injection and postoperative oral administration of PSK are highly effective in eradicating metastatic tumors.
The antitumor effects of three biological response modifiers (BRMs; PSK, IFN alpha A/D and OK432) and two chemotherapeutics (Mitomycin C and Neocarzinostatin) in a new experimental mouse model, the "double grafted tumor system," were evaluated. BALB/c mice received simultaneous inoculations of Meth A fibrosarcoma cells on right flank (1 x 10(6) cells) and left flank (2 x 10(5) cells) on day 0, and drugs were given intratumorally into the right-flank tumor on day 3. The growth of the left-flank tumor was the real target for the evaluation of a given drug after 21 days. All tested five agents successfully cured the drug-injected right tumor with a pre-determined optimum dose. In addition, PSK, OK432, IFN alpha A/D and MMC among the five, inhibited the left-flank tumor, whereas no inhibition was observed when treated with NCS. To understand the mechanism by which the antitumor effect of the above four agents is able to influence the growth of tumor on the other side, tumor cells (2 x 10(5) cells) inoculated only into the left flank were treated with drugs given subcutaneously to the right flank (single tumor system). Among the four, MMC exhibited an effect similar to that obtained in the double tumor system, and IFN alpha A/D showed a less pronounced but still definite antitumor effect. However, PSK and OK432 failed to express anti-tumor effect in the single tumor system. These results obtained with PSK, OK432 and IFN alpha A/D suggest that the effect of the drug on the left-tumor may be mediated by certain effector cells, which are specifically induced by injection of the drug, in the right-tumor tissues. When effector cell analysis was conducted with spleen cells obtained after PSK treatment by means of intratumoral adoptive transfer into 3-day Meth A bearing recipients, these cells were shown to be Lyt-1+2(-)-T and L3T4(+)-T cell.
Effects of the organogermanium compound Ge-132 (i.p.) were examined on the 3LL local tumor (1 X 10(5)/mouse, s.c.) and its pulmonary metastases in B6 mice. A characteristic feature of its action was the preferential antimetastatic effect under strictly defined conditions. Either inhibition or facilitation was observed depending on the treatment schedules; 7 daily doses of 100 mg/kg yielded the inhibition ratio 49% when started from day 1, whereas the treatment from day 8 resulted in the ratio -99%. The maximum inhibition was obtained at 100 mg/kg. The postsurgical-adjuvant treatment with Ge-132 was of no beneficial effect. The local tumor growth was affected only marginally and temporarily. When inoculum size was minimized (1 X 10(4)), a single dose of 300 mg/kg on day 1, but not on day 8, was effective in prolonging the latency before tumor take. The antitumor action of Ge-132 was discussed with reference to its interferon (IFN)-inducing activity.