JP2005263679A - Recurrence prevention agent for corpus uteri cancer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a recurrence prevention agent effective for corpus uteri cancer recognized recurrence or recurrence tendency, having much resistance to pharmacotherapy. <P>SOLUTION: The recurrence of corpus uteri cancer is vanished by 1-5 times/day and 2-4 g/dose administration of extracts of Lentinus edodes fungus body culture extracts to a corpus uteri cancer patient. Thereby, the recurrence prevention agent for corpus uteri cancer, containing extracts of Lentinus edodes fungus body is provided. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an agent for preventing recurrence of endometrial cancer containing a shiitake mycelium culture mainly composed of carbohydrate, protein and water-soluble lignin extracted from shiitake mycelium culture.

  Shiitake is a typical edible mushroom in Japan and China. In Japan, artificial cultivation has been conducted for about 300 years. Mushrooms that are eaten on a daily basis are called fruiting bodies, and are germ bodies that produce spores because the fungi leave their offspring, and the mycelium that is a vegetative body spends a long time in the ground and wood logs Form. To obtain this mycelium extract, inoculate Shiitake fungus on a solid medium based on bagasse (sugar cane squeeze) and defatted rice bran, and then extract and use the obtained mycelium Is done. Shiitake mycelium culture extract is also known for its anti-cancer action, immunoregulatory action, antiviral action and therapeutic effect against hepatitis. The cultured extract of shiitake mycelium is characterized by extremely few side effects despite having such various actions.

  In Patent Document 1, a mycelium of basidiomycetes and / or ascomycetes is cultured using a medium containing a plant fiber component, and substances obtained by extracting from the mycelium of this culture are carbohydrates, proteins, Mainly lignin. The mycelium extract thus obtained is said to have an antioxidant function. Further, in Patent Document 2, the extract component of shiitake mycelium has been found to have immunostimulatory activity far exceeding the fruiting body and antitumor activity and / or anticancer activity, and the extract is directly taken. Thus, antitumor agents and / or anticancer agents, particularly agents for enhancing LAK activity are disclosed.

  On the other hand, the proportion of endometrial cancer that reaches the peak of onset between the ages of 50 and 60 tends to increase year by year along with ovarian cancer. This is related to obesity, diabetes and the like resulting from diets such as high-fat and high-calorie diets, and is also considered to be deeply related to the increase in the number of unborn women and ovulation disorders as social conditions. Treatment methods for recurrence of endometrial cancer and prevention of recurrence include radiotherapy, chemotherapy, hormonal therapy, etc., but in particular, recurrence that can be used for a long time with few side effects. Prevention has not been established.

The anti-cancer effect of the above-mentioned shiitake mycelium culture extract is known, but it has recurred after the treatment, that is, after being completely treated by surgery and chemotherapy after treatment of endometrial cancer It has different properties from cancer and is more resistant to anticancer agents. This is a very poor prognosis with a 3-year recurrence rate of 20-30% for recurrence, while the 3-year recurrence rate for stage Ia to IIb after surgery for endometrial cancer is around 20%. It can also be seen that the anticancer drug used for the first administration is extremely ineffective. Thus, unlike the initial treatment, there has been a demand for the emergence of an effective drug for preventing recurrence for endometrial cancer that has relapsed and has a tendency to relapse that is extremely resistant to drug treatment.
JP 11-228441 A JP 2000-15986 A

  In view of the above facts, the present invention provides an effective drug for endometrial cancer in which recurrence and recurrence tendency are extremely resistant to drug treatment.

  As a result of intensive studies to solve the above problems, the present inventor has found that administration of a shiitake mycelium culture extract significantly suppresses postoperative recurrence of endometrial cancer. completed.

  A feature of the present invention is an agent for preventing recurrence of endometrial cancer characterized by containing a shiitake mycelium extract. When a cultured extract of shiitake mycelium was given to a patient with endometrial cancer who had a recurrence and a recurrence tendency that was extremely resistant to drug treatment, no recurrence of endometrial cancer was observed.

  Another feature of the present invention is a method for preventing recurrence of endometrial cancer patients, wherein the dose of shiitake mycelium extract is 2-4 g administered 1-5 times a day. The dose of shiitake mycelium extract was 2-4 g at a time, and it was administered 1-5 times a day, thereby suppressing the recurrence of endometrial cancer patients.

  Another feature of the present invention is a method for preventing recurrence of endometrial cancer, which is used in combination with an anticancer agent in a preventive agent for recurrence of endometrial cancer patients containing a shiitake mycelium extract. By using together with other anticancer agents, the effect of the shiitake mycelium culture extract can be further enhanced.

  The following examples illustrate some of the preferred forms of practicing the invention, but are not intended to limit the scope of the invention as recited in the claims.

  A method for obtaining a shiitake mycelium culture extract is carried out by inoculating spores or germinated mycelium in a medium mainly composed of plants. In the case of a solid medium, the water content is adjusted to 60 to 80%, sterilized by high-pressure steam according to a conventional method, then inoculated with mycelia or spores, for example, 3 in a culture room conditioned at a temperature of 18 to 25 ° C. Incubate for ~ 6 months. The medium in which the mycelium has spread is preferably transferred to a temperature treatment chamber and subjected to a temperature change treatment. In the temperature change treatment, for example, the mixture is first heated at 30 to 40 ° C. for 24 to 48 hours, and then transferred to a low temperature chamber and treated for 3 to 5 days. After that, when it is moved to a culture room, the generation of fruiting bodies starts. At this point, the culture is terminated and the culture is crushed with a crusher.

  On the other hand, in the case of liquid culture, plant raw materials are finely crushed and cultured by aeration culture or shaking culture, preferably at a temperature of 20 to 25 ° C. for about 2 weeks to 2 months. The culture is completed with the mycelium invading in the medium.

After completion of the culture, the mycelium is self-digested using an enzyme present in the mycelium and the culture is extracted. As a preferable method, in the case of an individual medium, the cultured culture is crushed, a small amount of water is added as necessary, and the mixture is treated at 40 to 90 ° C. for 3 to 6 hours to advance the mycelial enzyme reaction and self-digest. Let Subsequently, this crushed material is infiltrated with warm water or hot water of 50 ° C. or higher, and an active ingredient is extracted. Extraction can also be carried out under a high pressure such as 120 ° C. under a vapor pressure of 1.2 kg / cm ² , for example. If the preferable aspect of an extraction method is given, about 4L of water will be added with respect to 800 g of said crushed materials, and it will heat at 70 degreeC and will extract for 4 to 16 hours. As the extraction method, a method of circulating the extract for 12 to 16 hours, a method of stirring for 4 to 6 hours, or the like is preferably employed. The extract suspension thus obtained is preferably filtered or centrifuged, and the filtrate or supernatant is collected to obtain the mycelium metabolite and the active ingredient contained in the mycelium cells.

In the case of liquid culture, the whole culture is treated at 40 to 90 ° C. for 3 to 6 hours to self-digest mycelium to obtain a liquid suspension culture. Then, if necessary, a small amount of water is added, and the mixture is heated to 50 ° C. or higher, sometimes under high pressure conditions (for example, under a vapor pressure of 1.2 kg / cm ² ) to obtain an extract. The extract is filtered or centrifuged as necessary, and the filtrate or supernatant is collected to obtain the active ingredient.

  It can be formulated with a therapeutically effective amount of the above-described shiitake mycelium culture extract and one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the shiitake mycelium culture extracts of the present invention can be specifically formulated for administration in solids, including those adapted to: Oral administration forms may be, for example, liquid medicine (aqueous solution or non-aqueous solution or suspension), tablet, bolus, powder medicine, granule, or paste for application to the tongue.

  A therapeutically effective amount, as used herein, is the amount of an agent or composition effective to produce any desired therapeutic effect at a reasonable benefit / risk ratio applicable to any medical treatment. Means.

  As used herein, pharmaceutically acceptable is within the scope of good medical judgment, commensurate with a reasonable benefit / risk ratio, without problems or complications such as excessive toxicity, irritation, and allergic reactions. Used to refer to compounds, materials, compositions, and / or dosage forms suitable for use in contact with human and animal tissues.

  A pharmaceutically acceptable carrier, as used herein, is involved in carrying or transporting the shiitake mycelium of the present invention from one organ or part of the body to another organ or part of the body. Means a pharmaceutically acceptable material, composition or excipient, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the dosage form and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) Cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) glycerin, sorbitol, mannitol and polyethylene Polio like glycol (12) Esters such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (18) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in drug formulations. In some embodiments, the drug formulation is non-pyrogenic. That is, the patient's body temperature is not increased.

  “Pharmaceutically acceptable salt” in this regard refers to a relatively non-toxic inorganic or organic acid addition salt of a compound present in the cultured extract of shiitake mycelium of the present invention. These salts may be prepared by isolating the final formed salt of the compound present in the culture extract of the shiitake mycelium of the present invention. Typical salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lauric acid Salt, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionic acid Salt, and lauryl sulfonate.

  Pharmaceutically acceptable salts of the compounds in the culture extract of the shiitake mycelium of the present invention include conventional non-toxic salts or quaternary ammonium salts of the compounds, eg, from non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; and acetic acid, propionic acid, succinic acid, Glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid There are salts prepared from organic acids such as toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid and the like.

  Examples of pharmaceutically acceptable antioxidants include: (1) Water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium disulfite, sodium sulfite and the like; (2 ) Oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and (3) citric acid, ethylenediaminetetraacetic acid (EDTA) ), Metal chelating agents such as sorbitol, tartaric acid, phosphoric acid and the like.

  Dosage forms of the present invention include those suitable for oral administration. The dosage form may be conveniently presented in unit dosage form and may be prepared by any method well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100 percent, this amount is the active ingredient ranging from about 1% to about 99%, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

  The methods of preparing these dosage forms or compositions comprise the step of combining one or more agents of the present invention with a carrier and optionally with one or more accessory ingredients. In general, dosage forms are prepared by uniformly and intimately bringing into association one or more agents of the present invention with liquid carriers or finely divided solid carriers or both and, if necessary, shaping the product.

  Suitable dosage forms of the invention for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with seasoned active ingredients, usually sucrose and gum arabic or tragacanth), powders, granules, or As a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or pastilles (gelatin and glycerin, or inert groups such as sucrose and gum arabic) And / or a gargle and the like, each containing a predetermined amount of the compound of the present invention as an active ingredient. The agent of the present invention may be administered as a bolus, electuary or paste.

  In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is one or more pharmaceuticals such as sodium citrate or dicalcium phosphate (1) a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) for example Binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants such as glycerol; (4) agar, calcium carbonate, potato or tapioca starch, alginic acid Certain silicates and disintegrants such as sodium carbonate; (6) Absorption enhancers such as quaternary ammonium compounds; (7) Wetting agents such as cetyl alcohol and glycerol monostearate; (8) Absorbents such as kaolin and bentonite clay. (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, the drug composition may comprise a buffer. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules with excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be binders (eg, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg, sodium glycolate starch or crosslinked sodium carboxymethylcellulose), surfactants Alternatively, it can be prepared using a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

  Solid dosage forms such as tablets of the pharmaceutical composition of the present invention, such as dragees, capsules, pills and granules, are optionally scored or like coatings such as enteric coatings well known in the drug dispensing arts. May be prepared using a unique coating and shell. They use, for example, hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres in various ratios to provide the desired release profile, and slow or controlled release of the internal active ingredient. May be formulated to provide. They may be sterilized, for example, by filtration through a bacteria retaining filter, or by incorporating a sterilant in the form of a sterile solid composition that can be dissolved in a sterile injectable medium such as sterile water immediately before use. . These compositions may optionally contain opacifiers, in compositions that release one or more active ingredients only in certain parts of the gastrointestinal tract or preferentially there, optionally in a delayed manner. There may be. Examples of embedding compositions that can be used are polymeric substances and waxes. The active ingredient may be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms include, in addition to the active ingredient, inert diluents commonly used in the art, such as water and other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Like fatty acids esters of benzyl, propylene glycol, 1,3-butadiene glycol, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and sorbitan Solubilizers and emulsifiers, and mixtures thereof.

  In addition to inert diluents, oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents.

  Suspensions may be suspended in addition to the active compound, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. A turbidity agent may be included.

  Examples of suitable aqueous and non-aqueous carriers that can be used in the drug compositions of the present invention include water, ethanol, polyols (eg, glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, such as olive oil. Vegetable oils, as well as injectable organic esters such as ethyl oleate. The inherent fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size in the case of dispersants and by the use of surfactants.

  These compositions may contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbate and the like. It may be desirable to include isotonic agents such as sugars, sodium chloride in the composition. In addition, prolonged absorption of the injectable drug form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

The cultured extract of shiitake mycelium of the present invention may be given as a compound itself when administered to humans and animals as a drug, or together with a pharmaceutically acceptable carrier, for example, 0.1 to 99. It may be given as a drug composition containing 5% (more preferably 0.5-90%) of the active ingredient.
Example 1
For cultivation of shiitake mycelium, 80% bagasse and 20% defatted rice bran were mixed, prepared to have a water content of 70%, prepared a solid medium, sterilized according to a conventional method, and inoculated with the inoculum of shiitake mushroom . The medium is cultured for 4 months in a room adjusted to 22 ° C to 24 ° C. After the mycelium invades in the medium, it is transferred to a temperature treatment room and heated at 32 ° C to 34 ° C for 24 hours, and then 10 ° C. For 5 days. Thereafter, the culture medium was pulverized with a pulverizer in the culture chamber. The crushed medium was treated at 50 ° C. for 4 hours to promote self-digestion, then packed in a tank and extracted for 16 hours without circulating hot water at 60 ° C. The obtained suspension was prefiltered with a filter cake of diatomaceous earth, further filtered and sterilized with a membrane filter, concentrated, and freeze-dried to obtain a brown powder.

As a result of analyzing the components of the powder, carbohydrates: 35%, proteins: 12%, water-soluble lignin: 35%, and inorganic substances: 13%. In addition, each component analysis was performed by the phenol sulfuric acid method for saccharides, the semi-micro Kjeldahl method for proteins, the acetyl bromide method for water-soluble lignin, and the direct ashing method for minerals.
Example 2
The patients were 14 endometrial cancer patients who were diagnosed and treated by visiting our hospital. The average age of the patients was 60.2 ± 11.4 years (M ± SD), and postoperative progress Ia to IIb ( 2 cases with lymph node metastasis). All cases were radical hysterectomy cases, and 3 courses of CAP therapy (carboplatin, endoxan, adriamycin) were performed from the second week after the operation. At the same time, shiitake mycelium culture extract (LEM) was administered at 6 g / day (3 g × twice). After discharge from hospital, chemotherapy and hormone therapy were not performed, and LEM was administered alone. The course of treatment was checked every two to three months with ultrasound, CT-scan, vaginal stump smear, and tumor marker (CA-125, 199).

  As a result, the administration period of LEM is 27.5 ± 13.5 months, and no signs of recurrence have been observed in 12 cases during this administration period. In addition, there was one patient whose tumor marker CA-199 was elevated half a year after discharge, and when LEM intake was increased from 6 g / day (3 g × 2 times) to 9 g / day (3 g × 3 times), Tumor markers began to fall again. Similarly, there was one patient who showed an increase in the tumor marker CA-125 and an enlarged abdominal aortic lymph node 6 months after discharge, but the intake of LEM was changed from 6 g / day (3 g × 2 times) to 9 g / day. When the dose was increased to (3 g × 3 times), the tumor marker began to fall again, and then the lymph node size was also reduced. From the above results, it was revealed that LEM has an effect of suppressing recurrence in postoperative patients with endometrial cancer.

Claims (3)

An agent for preventing recurrence of endometrial cancer, comprising a shiitake mycelium culture extract. A method for preventing recurrence of endometrial cancer, comprising administering 2-4 g of shiitake mycelium culture extract 1-5 times a day. A method for preventing recurrence of endometrial cancer, comprising combining an anticancer agent with an agent for preventing recurrence of endometrial cancer containing a shiitake mycelium culture extract.