JP4422881B2 - Anti-cancer side effect reducing composition - Google Patents

Description

【００４９】
上記表１によれば、制癌剤のシスプラチンを投与する際に、通常の飼育飼料のみを与えた（Ｃ）群では、マウスの生存率は４３．７５％であるが、椎茸菌糸体エキスを添加した飼料を与えた（Ａ）群、（Ｂ）群では、マウスの生存率が９０％前後と著しく向上していることが分かる。なお、シスプラチン投与による腎障害由来のＢＵＮ値は、何れの飼料を与えた群においても変化が見られなかった。
【００５０】
椎茸菌糸体エキスに代えて、山伏茸菌糸体エキス、エノキタケ菌糸体エキスを用いた場合にも、上記と同様な効果が得られる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a side effect-reducing composition for an anticancer agent (a side effect reducing agent for an anticancer agent), and more particularly to a side effect reducing composition for an anticancer agent containing a basidiomycete mycelium extract such as shiitake mycelium extract.
[0002]
[Prior art]
Since ancient times, basidiomycete moths such as shiitake mushrooms, matsutake mushrooms and enoki mushrooms have been edible, and some of them have been used as traditional Chinese medicines, such as moths belonging to the family Basidiomycetes sarnococcidae.
On the other hand, various methods for extracting active ingredients from such basidiomycetes have been proposed. For example, (1) Japanese Patent Application Laid-Open No. 54-46859 discloses that basidiomycetes are inoculated into a medium mainly composed of bagasse, and the mycelium is propagated, and then the mycelium propagation medium is squeezed to collect the active ingredient. A method for producing health foods is disclosed.
[0003]
The applicant of the present application (2) in Japanese Patent Application No. 62-34123 includes "mycelium obtained by inoculating enoki bacillus on a solid medium based on bagasse and then growing the mycelium. The solid medium is unbundled so that the 12-mesh passage is 30% by weight or less, and water and one or more enzymes selected from cellulase, protease, or glucosidase are added to the unbundled solid medium. And crushing and crushing the solid medium in the presence of the enzyme so that at least 70% by weight or more of the bagasse fiber is passed through 12 mesh and then heating to a temperature up to 95 ° C. to inactivate the enzyme. And a method for extracting useful components from enoki mycelium and bagasse medium, which is characterized by being sterilized.
[0004]
(3) In Japanese Examined Patent Publication No. 60-23826, the applicants of the present application manufactured health drinks by the same method as described in Japanese Patent Application No. 62-34123, except that Shiitake was used as an inoculum. Proposed method to do. In this publication, it is described that the obtained health drink has blood pressure lowering action, diuretic action, fatigue recovery action and the like.
[0005]
(4) In JP-A-57-170173, a material containing a large amount of raw sugar and plant fiber such as sugar cane or sugar radish is used as a culture medium, and this is inoculated with an inoculum of edible mushrooms such as shiitake mushrooms. After the mycelium is cultured, the culture medium immediately before or after the fruiting body is pulverized, hydrolyzed, and heated to cause self-digestion of the mycelium, and the active ingredients contained in the mycelium are leached into the culture medium. A method for producing a powdered food containing an active ingredient of edible mycelium and dietary fiber, which is then dried and then finely pulverized is disclosed. The publication describes that the powdered food obtained by this method is effective for colorectal cancer, arteriosclerosis, diabetes and the like.
[0006]
Further, the applicant of the present invention inoculated (5) Japanese Patent No. 2519785 (Japanese Patent Laid-Open No. 2-107171) inoculated enokitake mushroom mycelia into a solid medium containing plant fiber made of corn, bran and rice bran and water. And then cultivating the culture medium and crushing the medium after completion of the culture and drying it, and proposes a method for producing a dietary fiber-containing food. It is described that prevention of obesity, diabetes, arteriosclerosis, promotion of elimination of toxic substances in foods, improvement of self-protection ability and the like can be expected.
[0007]
In addition, (6) JP-A-2-134325 describes an AIDS therapeutic agent comprising a component extracted from a mycelium culture of shiitake mushroom, which is a kind of basidiomycete.
In addition, (7) “Mushroom Chemistry / Biochemistry” (Mizuno, edited by Kawai, published by Academic Publishing Center), mushroom dietary fiber can be expected to have pharmacological action, colon cancer, and rectal cancer prevention effects. In the extract, it is described that the carcinogenesis preventing effect has been proven in animal experiments.
[0008]
(8) In “20 years of mushroom antitumor research” (Ikegawa et al., Published by Nagano Prefectural Rural Industrial Research Institute, published on March 1, 1989), proflamin isolated from enokitake mushroom mycelium functions as an anticancer agent. It is described that it is not toxic even after oral administration and that no other side effects are observed.
Furthermore, the present inventors have found that shiitake mycelium extract obtained by the same method as described in (9) Japanese Examined Patent Publication No. Sho 60-23826 has an inhibitory effect on HIV virus activity. No. 7-173070 (Patent No. 3017630) proposes an HIV type virus activity inhibitor obtained by this method.
[0009]
Thus, conventionally, shiitake mycelium extract, enokitake mycelium or its extract, etc., have anticancer effects, constipation prevention, obesity, diabetes, prevention of arteriosclerosis, promotion of elimination of toxic substances in food, self-protection It has been reported that there are various effects effective for maintaining and improving health, such as improving performance.
However, in addition to the effects described above, what other effects can be obtained from basidiomycete mycelium extracts such as shiitake mycelium extract extracted from basidiomycete shiitake (mycelium culture) and the like? Many points are not yet known.
[0010]
Therefore, the present inventor conducted extensive research on the pharmacological action of mycelia extracts of basidiomycetes that have been edible and used in traditional Chinese medicine, such as shiitake mycelium extract. The body extract surprisingly found that it can significantly reduce the side effects of anticancer drugs represented by cisplatin and can significantly increase the survival rate of humans and other animals administered these anticancer drugs. It came to do.
[0011]
In addition, (10) Japanese Patent Laid-Open No. 6-321792 discloses a traditional Chinese medicine (Toki, licorice, purple hu or soft purple root), or its original plant or other related plants, and is about 10 times the amount of an aqueous solvent. A side effect reducing agent for pharmaceuticals containing a polysaccharide component as an active ingredient, which is obtained by performing an operation such as ethanol precipitation and dialysis on the filtrate obtained by extraction with the above and filtering the extract is disclosed. The publication also shows an embodiment in which the side effect is caused by administration of platinum, the platinum complex is cisplatin, and the type of side effect is nephrotoxicity or hematologic toxicity.
[0012]
However, there is no teaching what kind of medicinal effect the basidiomycete mycelium extract has.
[0013]
OBJECT OF THE INVENTION
The present invention is intended to solve the problems associated with the prior art as described above, which can reduce the side effects of anticancer drugs, and has no fear of side effects, and is excellent in safety. Another object of the present invention is to provide a composition for reducing side effects of an anticancer drug that can be expected to significantly improve the survival rate of humans and animals.
[0014]
SUMMARY OF THE INVENTION
The composition for reducing side effects of an anticancer agent according to the present invention (the side effect reducing agent of an anticancer agent) includes a basidiomycete mycelium extract extracted from a mycelium culture of basidiomycetes.
Examples of the anticancer agent include cisplatin.
[0015]
Examples of the basidiomycetes include shiitake, yamabushi, and enokitake, and particularly preferably shiitake.
In the present invention, the mycelium extract of the above basidiomycetes,
Inoculating basidiomycetes and other basidiomycetes on a solid medium based on Bacus, then bundling the solid medium containing the mycelium obtained by growing the mycelium,
To this unbound solid medium, water and one or more enzymes selected from cellulase, β-glucanase or protease are added while keeping the solid medium at 30 to 50 ° C., and the solid medium is added to the enzyme. Pulverized and crushed in the presence of an extract of basidiomycetous mycelium extract such as shiitake mycelium extract, and then heated to a temperature up to 95 ° C. to inactivate and sterilize the enzyme desirable.
[0016]
If such an anticancer drug side effect-reducing composition is taken orally, for example, the side effects of the anticancer drug, particularly cisplatin, can be significantly improved, and the survival rate of the anticancer drug-administered patient can be expected to be significantly improved. No safety at all.
[0017]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the side effect reducing composition of the anticancer drug according to the present invention will be specifically described.
[Production of side-effect reducing composition of anticancer drug]
The anticancer drug side effect reducing composition (anticancer drug side effect reducing agent) according to the present invention contains a mycelium extract of basidiomycetes.
[0018]
Basidiomycota has been edible as an edible fungus in Japan since ancient times, or used in Chinese medicine.
As a spider of the pine moth or agaricales,
Matsutake (Tricholoma Matsutake Ito et Imai),
Shiitake (Lentinula edodes (Berk.) Sing.),
Enoki mushroom (Flammulina Velutipes (Fr.) Sing.),
Pleurotus ostreatus (Jacq.Ex Fr) Kummer,
Nameko (Pholiota nameko (I.Ito) S.Ito et IMAI),
Iguchi (Boletus Dill.ex Fr.),
Shimeji (Lyophyllum shimeji (Kawam.) Hongo),
Chichitake (Lactarius volemus (Fr.) Fr.),
Examples include erurogi (pleurotus eryngii).
[0019]
In addition, as moths of the order of Sarnochoshika or Aphyllophorales,
(Elfvingia applanatus (Pers.) Karst.),
Fomitopsis pinicola (Fr.) Karst.
Kawaraki mushroom (Coriolus versicolor (Fr.) Quel.),
Ganoderma lucidum (W.Curt.ex Fr.) Karst.),
Maiko (Grifola frondosa (Fr.) SFGray),
Meshimakobu (P.yucatensis (Murr.) Imaz.,) And the like.
[0020]
As moths of the order Auriculariales or Tremellales,
Jellyfish (Auricularia auricula (Hook.) Underw.),
Examples include Tremellinea fuciformis Berk.
As a moth of cantharellales,
Examples include the Yamabushi Pass of Hydnaceae, that is, Hydnum.
[0021]
In the present invention, among these basidiomycetes, shiitake mushroom (Lentinula edodes (Berk.) Sing.), Enoki mushroom (Flammulina Velutipes (Fr.) Sing.), And Yamabushi mushroom, that is, hydnum, are preferred. Used.
In the present invention, these basidiomycetes can be used alone or in combination of two or more. Many of these basidiomycetes are “Mushroom Encyclopedia” (Katsuya Nakamura, Asakura Shoten, 1989), “Mushroom Cultivation Method” (Iwade Shinnosuke, Geo-sha, 5th edition 1985) or It is described in detail in "Primary Color Japanese Fungi Encyclopedia" (Imoseki et al., Childcare Company, 1983, 27).
[0022]
There is no particular limitation on the method for producing basidiomycetous mycelium extracts such as shiitake mycelium extract. For example, shiitake mycelium extract requires shiitake mycelium culture as described in JP-A-2-134325. It may be obtained by self-digestion, followed by hot water extraction and precipitation of the hot water extract into alcohol. If necessary, this precipitate may be further fractionated in a chromatographic column, such as ethylene glycol. The elution fraction may be collected and used.
[0023]
In the present invention, the effect of reducing the side effects of the anticancer drug is particularly preferable. The shiitake mycelium extract is preferably prepared using the method described in Japanese Patent Publication No. 60-23826. In addition, in the case of other basidiomycete mycelium extracts as described above other than shiitake mycelium extract, those prepared by the same method as shiitake mycelium extract are preferable.
[0024]
Hereinafter, an example of a method for preparing shiitake mycelium extract will be described in detail.
In order to prepare a shiitake mycelium extract, specifically, water, preferably pure water, is first mixed in a solid medium composed of bacus, and then inoculated with shiitake. In addition to rice bran, minerals such as phosphorus, iron, and germanium, peanut skin, brown rice, and the like may be added to the bacus medium as necessary.
[0025]
Next, the medium inoculated with shiitake mushrooms in this manner is placed in a culture chamber in which the temperature and humidity are controlled and the illuminance is also adjusted to grow the mycelium.
It is desirable that the mycelium spreads in the solid medium, and the filaments of the bacus base material are unbundled at a time immediately before and after the occurrence of the fruit body so that the amount of passage through the 12 mesh is 30% by weight or less. In addition, it is preferable to perform the bundling of the bacus base medium at the time immediately before and after the occurrence of the fruit body as described above, but it may be performed at a time after the fruit body has grown considerably.
[0026]
The solid medium thus unwound is mixed with water and one or more enzymes selected from cellulase, β-glucanase, protease or glucosidase, particularly cellulase, β-glucanase or protease. Add while keeping at 30-50 ° C. Cellulase is preferable as the enzyme to be added.
The addition amount of the enzyme is 0.5 to 5 g, preferably 1 to 3 g, per 1 kg of the solid medium. The water is preferably pure water that does not contain ions such as metal ions, and 1 kg of pure water, preferably 2 to 6 kg, is added to 1 kg of the unbound medium to obtain a mixture containing bacus.
[0027]
Next, shiitake mycelium extract is extracted from this bacas-containing mixture. To extract shiitake mycelium extract in this way, the medium-containing mixture is pulverized into a solid medium while being circulated using, for example, a gear pump with a transmission. In addition, it is desirable to add a crushing action so that about 70% by weight or more of the bacus fiber is equivalent to the passage of 12 mesh.
[0028]
Crushing and crushing of the bacass-containing mixture may be performed while maintaining the temperature of the mixture at 30 to 50 ° C., and may be performed while gradually increasing the temperature from the above temperature, but should be performed while increasing the temperature. Is preferred. When air at room temperature is injected into the bacass-containing mixture when the water temperature is 60 ° C. or higher, preferably 70 ° C. or higher, the air bubbles are rapidly heated and burst, impacting the bacus fibers and Extraction can be performed more efficiently.
[0029]
Next, the bacass-containing mixture thus treated is further heated to a temperature of up to 95 ° C., preferably about 75 to 90 ° C., and kept at this temperature for several tens of minutes. When the enzyme is inactivated and the mixture is sterilized, a shiitake mycelium extract is obtained.
In addition, you may filter the obtained shiitake mycelium extract using the filter cloth of 50-120 mesh, preferably about 60-100 mesh as needed.
[0030]
The shiitake mycelium extract thus obtained can be concentrated and used, or can be freeze-dried and used as a powder.
As mentioned above, although the example of the preferable preparation method of a shiitake mycelium extract was explained in detail, the above-mentioned other basidiomycete mycelium extracts used in the present invention can be replaced with the above-mentioned shiitake fungi, ganoderma, enoki mushroom, mesimacob, yamushi It can be prepared in the same manner as described above except that basidiomycetes such as maitake and eringi are used.
[0031]
The composition for reducing side effects of the anticancer agent of the present invention may contain any amount of basidiomycete mycelium extract such as the above-mentioned shiitake mycelium extract.
Examples of the anticancer agent to be used include cisplatin, adriamycin, mitomycin, 6-mercaptopurine, 5-fluorouracil and the like. Among these, cisplatin is preferable.
[0032]
Such a composition for reducing side effects of an anticancer drug may be orally administered in various dosage forms such as granules, liquids, tablets, and capsules, and can also be developed as an injection solution for use in anticancer drug administered patients. In addition, the anti-cancer agent side effect-reducing composition containing the above mycelial extract stock solution has its own cancer effect as well as the anti-cancer agent side effect improving effect, and can be directly administered to the anti-cancer agent-administered patient without dilution, For example, it can be administered after appropriately diluted with purified water, alcohol or the like.
[0033]
Such a side effect reducing composition of an anticancer agent is usually administered in an amount of 6 to 60 mg, preferably 20 to 60 mg per kg body weight in terms of solid content of the above basidiomycete mycelium extract. If the dose is less than 6 mg, a sufficient administration effect may not be expected.
As described above, when the composition for reducing side effects of an anticancer drug according to the present invention is administered to a patient or the like who has been administered an anticancer drug, death due to the side effects of the anticancer drug can be reduced and the survival rate can be significantly improved.
[0034]
Thus, it is considered that the side effect-reducing composition of the anticancer drug according to the present invention can improve the side effect of the anticancer drug and can significantly improve the survival rate of the patient for the following reasons.
That is, the side effect-reducing composition for anticancer agents comprising basidiomycetous mycelium extract such as shiitake mycelium extract is effective for extracting from basidiomycetous mycelium such as shiitake mycelium according to the study by the present inventors. Many of the ingredients and active ingredients extracted from solid media in which basidiomycetous mycelium such as shiitake mycelium are cultured, these ingredients (unidentified) act comprehensively, and side effects of anticancer drugs It is considered that the survival rate of patients receiving anticancer drugs, particularly cisplatin, may be increased.
[0035]
【The invention's effect】
According to the present invention, it is possible to improve the mortality due to side effects of cancer drugs, particularly cisplatin, and to significantly improve the survival rate. Certain side-effect reducing compositions for anti-cancer agents are provided.
[0036]
【Example】
EXAMPLES Hereinafter, although this invention is demonstrated further more concretely based on an Example, this invention is not restrict | limited at all by these Examples.
[0037]
[Preparation Example 1]
[Preparation of composition for reducing side effects of anticancer drugs comprising shiitake mycelium extract]
After pure water was appropriately contained in a solid medium consisting of 90 parts by weight of bacus and 10 parts by weight of rice bran, shiitake inoculum was inoculated and placed in a culture chamber in which the temperature and humidity were controlled to grow mycelium. After the mycelium spreads in the solid medium, the filaments of the bacus base material were unbundled so that the passage through 12 mesh was 24% by weight or less. To 1.0 kg of the unbundled medium, 3.5 liters of pure water and 2.0 g of purified cellulase were added while keeping the solid medium at 40 ° C. to obtain a mixture containing bacus.
[0038]
Next, while the medium-containing mixture is circulated by a gear pump with a transmission, pulverization and crushing action is added to the solid medium at the gear portion of the pump for about 200 minutes, so that about 80% by weight of the bacus fiber is equivalent to 12 meshes. did. Crushing and crushing of the bacas-containing mixture was performed while gradually raising the temperature of the mixture.
Thereafter, the bacass-containing mixture was further heated and left at 90 ° C. for 30 minutes.
[0039]
The enzyme was inactivated by heating to 90 ° C. and sterilized.
The obtained medium-containing mixture was filtered using a 60-mesh filter cloth to obtain a shiitake mycelium extract containing a micro suspended matter.
This shiitake mycelium extract was pulverized by freeze drying.
[0040]
[Preparation Examples 2-3]
In the above Preparation Example 1, instead of Shiitake mushroom, Enoki mushroom inoculum (Preparation Example 2) and Yamabushi mushroom inoculum (Preparation Example 3) were used in the same manner as in Preparation Example 1, Enoki mushroom mycelium extract powder, Yamabushi-mycelium extract powder was obtained.
[0041]
[Test Example 1]
Using the anticancer drug side effect-reducing composition comprising the shiitake mycelium extract (powder) obtained in Preparation Example 1, the effect of improving the patient mortality and nephritis, which are side effects of the anticancer drug on mice, was examined.
<Test method>
A group of healthy ddY male mice having a body weight of 36 to 40 g (16 mice) × 4 groups was prepared.
[0042]
These mice are fed as a feed with 1.0 g of shiitake mycelium extract (powder) added per 99.0 g of normal reared feed (A) group: 16 mice and shiitake mycelium per 97.0 g of normal reared feed (B) group giving 3.0 g of extract (powder): 16 animals, and giving only normal breeding feed (C) group: 16 animals, and giving feed similar to (C) group (D) group : Divided into 16 animals.
[0043]
These mice (A) to (D) were tested as follows.
(A) group That is, the mice in group (A) were given a diet powder containing shiitake mycelium extract (shii mushroom mycelium extract / normally fed feed powder = 1.0 g / 99.0 g) as a feed. However, the anticancer drug cisplatin was injected at a dose of 3 mg / kg body weight once a day for 7 days. Even after the end of the injection, the feed was continuously administered for 7 days.
[0044]
Next, the mice were fasted for 20 hours, blood was collected, and blood urea nitrogen level (Blood Urea Nitrogen, BUN) was measured. The survival rate of this mouse was also determined.
Group (B) In group (B), in the group (A) above, as a feed, shiitake mycelium extract-added feed powder having different shiitake mycelium extract content (shiitake mycelium extract / normally fed feed powder = 3.0 g / 97) In the same manner as in the above group (A), except for giving 0.0 g), after injection, rearing, and fasting, the survival rate of mice and blood urea nitrogen level (BUN) were measured in the same manner as described above. .
[0045]
(C) Group (C) In the above group (A), cisplatin injection was performed in the same manner as in the above group (A), except that only normal breeding feed containing no shiitake mycelium extract was given as feed in group (A). After breeding and fasting, the survival rate and blood urea nitrogen level (BUN) of the mice were measured in the same manner as described above.
[0046]
Group (D) Group (D) was reared in the same manner as group (A) except that in the above group (A), only normal breeding feed containing no shiitake mycelium extract was given and no cisplatin injection was given. After fasting, the mouse survival rate and blood urea nitrogen level (BUN) were measured.
[0047]
The results are shown in Table 1.
[0048]
[Table 1]

[0049]
According to Table 1 above, when the anticancer drug cisplatin was administered, in the group (C) given only normal feeding, the survival rate of mice was 43.75%, but shiitake mycelium extract was added. It can be seen that in the groups (A) and (B) fed with the feed, the survival rate of the mice is remarkably improved to around 90%. In addition, the BUN value derived from the renal damage by cisplatin administration did not change in any group to which any feed was given.
[0050]
The same effect as described above can be obtained when using Yamabushi mushroom mycelium extract and Enokitake mycelium extract instead of shiitake mycelium extract.

Claims (2)

As a shiitake mycelium extract, a solid medium containing mycelia obtained by inoculating shiitake fungus on a solid medium based on Bacus and then growing the mycelium is unbound, and this unbound solid medium And one or more enzymes selected from water and cellulase, β-glucanase or protease are added while keeping the solid medium at 30 to 50 ° C., and the solid medium is pulverized and mixed in the presence of the enzyme. crushed and extracted shiitake mycelium equi scan, then comprising a shiitake mycelium equi scan made by and sterilized to inactivate the enzyme by heating to temperatures of up to 95 ° C., of cisplatin carcinostatic A composition for reducing mortality due to side effects. Cisplatin, an anticancer drug, and
In combination with shiitake mycelium extract,
As the mycelium extract, a solid medium containing mycelium obtained by inoculating shiitake fungus on a solid medium based on Bacus and then growing the mycelium is unbound, and this unbound solid medium And one or more enzymes selected from water and cellulase, β-glucanase or protease are added while keeping the solid medium at 30 to 50 ° C., and the solid medium is pulverized and mixed in the presence of the enzyme. crushed and extracted shiitake mycelium equi scan, then comprising a shiitake mycelium equi scan comprising sterilized and to inactivate the enzyme by heating to temperatures of up to 95 ° C., deaths side effects of cisplatin Anticancer drugs with reduced rates.