A composition for treating or preventing renal cell carcinoma, comprising D-allose as an active ingredient, and a method for treating or preventing cancer using the same

Abstract

To provide compositions applicable by simple and hardly painful administration means for exerting effective anticancer effect.SOLUTION: The invention provides compositions for treating or preventing renal cell carcinoma comprising D-allose and / or derivative and / or mixture thereof as an effective ingredient through enteric administration (e.g., oral administration). The invention also provides a method for treating or preventing renal cell carcinoma in a subject comprising enteric administration (e.g., oral administration) of a composition comprising D-allose as an effective ingredient to treat or prevent renal cell carcinoma in a subject in need thereof.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] The present invention relates to a composition for treating or preventing renal cell carcinoma, which contains D-allose as an active ingredient and is administered enterally, and a method for treating or preventing renal cell carcinoma using the same. [Background technology]

[0002] Currently, cancer treatment requires surgery, chemotherapy, and / or radiation therapy to eradicate neoplastic cells within the patient. Each of these approaches has significant disadvantages for the patient. Regarding chemotherapy, various antitumor and anticancer drugs are known, but their side effects are generally problematic. Therefore, there is a strong need for novel compounds, compositions, and methods useful for treating cancer that have reduced or no side effects. Furthermore, there is a need for cancer treatment methods that provide cancer cell-specific therapy with greater specificity and less toxicity.

[0003] In addition, there is currently growing awareness and expectation regarding drugs and foods (functional foods) that are not only intended to treat but also prevent diseases. It is known that some "sugars" commonly found in foods are effective in treating and preventing diseases. For example, in the relationship between sugars and cancer, oligosaccharides have been reported to relieve constipation and reduce the risk of colon cancer by utilizing their intestinal regulating effects, and recently, polysaccharides such as agaricus have been reported to have cancer-suppressing effects. While there have been reports on the relationship between sugar chains and cancer metastasis, there have been few reports on the ability of "monosaccharides themselves" to inhibit cancer cell proliferation. For example, as described in Patent Document 1, a polysaccharide known to be effective in preventing cancer is known as a "colon cancer inhibitor containing as its active ingredient a water-soluble polysaccharide whose main component is arabinoxylan." Furthermore, there have been reports on the intestinal regulating effects of "oligosaccharides" to relieve constipation and reduce the risk of colon cancer, and recent reports on the cancer-suppressing effects of polysaccharides such as agaricus, as well as reports on the relationship between sugar chains and cancer metastasis.

[0004] In recent years, "rare sugars" have been attracting attention among monosaccharides, and their various physiological activities are being clarified. Rare sugars are defined as "monosaccharides and their derivatives that exist in small amounts in nature," and expectations are growing for their application and practical use in the medical field.

[0005] For example, Patent Document 2 reports an in vivo antioxidant containing D-allose, a rare sugar, as an active ingredient. This is a pharmaceutical composition for mammals, including humans, that contains an in vivo antioxidant containing D-allose as an active ingredient, and describes that it can be used to treat liver cancer or skin cancer.

[0006] Furthermore, Patent Document 3 reports that in vitro experiments showed that D-allulose suppressed the expression of the glucose transporter GLUT1 in cancer cell lines such as human liver cancer cells, human breast cancer cells, and human neuroblastoma cells. GLUT1 is a glucose transporter that is also expressed in normal cells, but its expression level is known to increase significantly in cancer cells. Therefore, if the expression of GLUT1 can be reduced in cancer cells, it is expected that the uptake of D-glucose by cancer cells will decrease, resulting in an anti-cancer effect.

[0007] However, although D-allulose, a rare sugar, has been reported to have an antitumor effect on human cancer cells in vitro, sufficient results have not been shown to show whether it can exert an anticancer effect in vivo, particularly to a degree that would be useful in clinical settings. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Patent No. 2787252 [Patent Document 2] Patent No. 5330976 [Patent Document 3] International Publication No. 2016 / 152293 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a composition that can be administered by a simple and painless means and that exerts an effective anti-cancer effect. [Means for solving the problem]

[0010] As a result of extensive research, the present inventors have found for the first time that D-allose can be efficiently taken up by renal cell carcinoma tissues engrafted in vivo and exert its anticancer effect even when administered enterally, for example, orally, and have completed the present invention. That is, the present invention encompasses the following inventions.

[0011] [1] A composition for treating or preventing renal cell carcinoma, comprising D-allose as an active ingredient and administered enterally. [2] The enteral administration is oral administration. item 1. The composition described in 1. [3] The D-allose is administered at 1 mg / kg body weight / day to 1000 mg / kg body weight / day. item 3. The composition according to claim 1 or 2. [4] The D-allose is D-allose and / or a derivative thereof and / or a mixture thereof. item 4. The composition according to any one of 1 to 3. [5] The D-allose derivative is one or more selected from the group consisting of sugar alcohols in which the carbonyl group of D-allose has become an alcohol group, uronic acids in which the alcohol group of D-allose has been oxidized, amino sugars in which the alcohol group of D-allose has been substituted with an amino group, and D-allose derivatives in which any hydroxy group of D-allose has been substituted with a hydrogen atom, a halogen atom, an amino group, a carboxyl group, a nitro group, a cyano group, a lower alkyl group, a lower alkoxy group, a lower acyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkyl-substituted amino group, an aralkyl group, an aryl group, or a heteroaryl group. item 4. The composition according to claim 4. [6] It is a medicine. item 6. The composition according to any one of 1 to 5. [7] It is a food product. item 6. The composition according to any one of 1 to 5. [8] The food is a health functional food or a dietary supplement. item 7. The composition described in 7. [9] The health functional food is a food for specified health uses or a food with nutrient functions. item 8. The composition described in 8.

[0012]

[10] Enteral administration of a composition for treating or preventing renal cell carcinoma, which contains D-allose as an active ingredient, to a subject in need thereof. 10. A method for treating or preventing renal cell carcinoma in a subject, comprising:

[11] The enteral administration is oral administration. item 10. The method according to claim 10.

[12] The D-allose is administered at 1 mg / kg body weight / day to 1000 mg / kg body weight / day. item 12. The method according to claim 10 or 11.

[13] The D-allose is D-allose and / or a derivative thereof and / or a mixture thereof. item 13. The method according to any one of 10 to 12.

[14] The D-allose derivative is one or more selected from the group consisting of sugar alcohols in which the carbonyl group of D-allose has become an alcohol group, uronic acids in which the alcohol group of D-allose has been oxidized, amino sugars in which the alcohol group of D-allose has been substituted with an amino group, and D-allose derivatives in which any hydroxy group of D-allose has been substituted with a hydrogen atom, a halogen atom, an amino group, a carboxyl group, a nitro group, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkyl-substituted amino group, an aralkyl group, an aryl group, or a heteroaryl group. item 13. The method according to claim 13.

[15] The composition is administered orally as a pharmaceutical. item15. The method according to any one of 10 to 14.

[16] The composition is orally administered as a food product. item 15. The method according to any one of 10 to 14.

[17] The food is a health functional food or a dietary supplement. item 16. The method according to claim 16.

[18] The health functional food is a food for specified health uses or a food with nutrient functions. item 17. The method according to claim 17. [Effects of the Invention]

[0013] As a result of intensive research, the present inventors have found for the first time that D-allose can be efficiently taken up by renal cell carcinoma cells in the body and exert its anticancer effect even through enteral administration, for example, oral administration. Unlike administration methods such as intraperitoneal administration or intravenous injection, which require administration under the supervision of a doctor and cause pain to patients, this invention is extremely excellent in terms of safety, simplicity, and reduction of pain. The present invention makes it possible to provide a new, simple, and painless treatment for renal cell carcinoma. [Brief explanation of the drawings]

[0014] [Figure 1] Figure 1 shows graphs showing the change in tumor D-allose concentration after D-allose administration in mouse models of renal cell carcinoma xenografts. (A) D-allose concentration in tumors after intraperitoneal administration of D-allose (400 mg / kg body weight) in a mouse model xenografted with a human renal cell carcinoma cell line (Caki-1). (B) D-allose concentration in tumors after intraperitoneal administration of D-allose (400 mg / kg body weight) in a mouse model xenografted with a human renal cell carcinoma cell line (ACHN). (C) D-allose concentration in tumors after oral administration of D-allose (400 mg / kg body weight) in a mouse model xenografted with a human renal cell carcinoma cell line (Caki-1). (D) D-allose concentration in tumors after oral administration of D-allose (400 mg / kg body weight) in a mouse model xenografted with a human renal cell carcinoma cell line (ACHN). [Figure 2]Figure 2 is a graph showing the changes in tumor volume and mouse body weight in a mouse model of renal cell carcinoma xenografts following oral administration of D-allose. (A) Change in tumor volume (%), (B) Change in mouse body weight (%). *P<0.05. [Figure 3] Figure 3 shows HE-stained images (magnification: 200x) of tumor tissues excised from renal cell carcinoma xenograft mouse models in the control group and the D-allose oral administration group. (A) Control group; (B) D-allose 400 mg / kg body weight / day oral administration group. [Figure 4] FIG. 4 shows the results of comparing the degree of nuclear division calculated from HE-stained images of tumor tissues excised from renal cell carcinoma xenograft mouse models of the control group and the D-allose oral administration group. [Figure 5] Figure 5 shows HE-stained images (magnification: 100x) of kidney tissues excised from renal cell carcinoma xenograft mouse models of the control group and the D-allose oral administration group. (A) Control group; (B) D-allose 400 mg / kg body weight / day oral administration group. [Figure 6] Figure 6 shows HE-stained images (magnification: 100x) of liver tissues excised from renal cell carcinoma xenograft mouse models of the control group and the D-allose oral administration group. (A) Control group; (B) D-allose 400 mg / kg body weight / day oral administration group. [Figure 7] Figure 7 is a graph showing the change in tumor volume in a mouse model of colon cancer xenografts following administration of D-allose. (A) Change in tumor volume (mm3) in a mouse model of colon cancer xenografts following intraperitoneal administration of D-allose. (B) Change in tumor volume (mm3) in a mouse model of colon cancer xenografts following oral administration of D-allose. *P<0.05. ***P<0.01. [Figure 8] Figure 8 shows the results of comparing the amount of intracellular reactive oxygen species (ROS) produced in human renal cell carcinoma cell lines (Caki-1, ACHN) with or without the addition of D-allose: (A) human renal cell carcinoma cell line Caki-1, (B) human renal cell carcinoma cell line ACHN. [Figure 9]9 shows the changes in TXNIP expression levels in human renal cell carcinoma cell lines (Caki-1, Caki-2) due to D-allose. (A) Human renal cell carcinoma cell line Caki-1, (B) human renal cell carcinoma cell line Caki-2. DETAILED DESCRIPTION OF THE INVENTION

[0015] Hereinafter, embodiments for carrying out the present invention will be described, but the technical scope of the present invention is not limited to the following embodiments. Note that the prior art documents cited in this specification are also incorporated herein by reference in their entirety.

[0016] In one embodiment, the present invention provides a composition for treating or preventing renal cell carcinoma, which comprises D-allose as an active ingredient and is administered enterally. The composition of the present invention may be provided as a pharmaceutical or a food. The food composition of the present invention may be, for example, a health food (e.g., a food for specified health uses or a food with nutrient function claims) or a dietary supplement.

[0017] In one embodiment, a method for treating or preventing renal cell carcinoma in a subject is provided, comprising enterally administering to a subject in need thereof a composition for treating or preventing renal cell carcinoma comprising D-allose as an active ingredient.

[0018] The D-allose that can be used in the present invention is found in far less abundance than D-glucose (glucose), which exists in large quantities in nature. Among monosaccharides, the basic units of sugars (there are a total of 34 types of monosaccharides (hexoses) with six carbon atoms, including 16 aldoses, 8 ketoses, and 10 sugar alcohols), D-glucose (glucose) is a "natural monosaccharide" that exists in large quantities in nature. In contrast, monosaccharides (aldoses, ketoses) and their derivatives (sugar alcohols) that exist only in trace amounts in nature are defined as "rare sugars." Currently, the rare sugars that can be mass-produced are D-psicose and D-allose. D-Allose is the D-isomer of D-allose, which is classified as an aldose, and is a hexose.

[0019] Methods for obtaining "D-allose" have been disclosed, including synthesis from D-psicose using L-rhamnose isomerase and treatment of a D-psicose-containing solution with D-xylose isomerase. However, the D-allose of the present invention is not limited to these methods and may be obtained by any method, including isomerization by chemical treatment. D-psicose, the raw material for D-allose, is generally obtained by treating fructose with an enzyme (epimerase). However, the method is not limited thereto. D-psicose may be obtained by a method using a microorganism that produces the enzyme, or may be extracted from or contained in natural products and used as is, or may be isomerized by chemical treatment. Methods for purifying D-psicose using enzymes are also known.

[0020] D-allose can also be used in the form of D-allose-containing syrup. D-allose-containing syrup can be obtained by appropriately mixing it with ordinary syrup (liquid sugar), but it is also readily available as a commercially available food product sold in general stores as "Rare Sugar Sweet" (sold by Rare Sweet Co., Ltd., sold by Matsutani Chemical Industry Co., Ltd.).

[0021] D-Allose-containing syrup can be obtained, for example, by treating monosaccharides (D-glucose or D-fructose) with alkali to induce the Lobry-de Bruyn-van Eckenstein rearrangement or the retroaldol reaction, followed by the aldol reaction (these reactions are called alkaline isomerization reactions). The resulting syrup containing various monosaccharides (including rare sugars) can be broadly referred to as "rare sugar-containing syrup." An example of such a syrup is one obtained by alkali isomerization of D-glucose and / or D-fructose to a D-glucose and / or D-fructose content of 55 to 99% by mass. The above-mentioned "rare sugar sweet" is a rare sugar-containing syrup obtained by the method disclosed in WO 2010 / 113785 using isomerized sugar as a raw material, and is produced so that the rare sugars are primarily D-psicose and D-allose. The rare sugars contained in the rare sugar-containing syrup obtained by this method are 0.5 to 17% by mass of D-psicose and 0.2 to 10% by mass of D-allose, based on the total sugar content. According to Takahashi et al. (Applied Glycoscience, Vol. 5, No. 1, pp. 44-49 (2015)), the syrup contains 5.4 g / 100 g of D-psicose, 5.3 g / 100 g of D-sorbose, 2.0 g / 100 g of D-tagatose, 1.4 g / 100 g of D-allose, and 4.3 g / 100 g of D-mannose.

[0022] Raw materials used in the production of the rare sugar-containing syrup include starch, sugar, isomerized sugar, fructose, glucose, etc. Isomerized sugar is broadly understood as a mixed sugar composed primarily of D-glucose and D-fructose in a specific composition ratio. It generally refers to a liquid sugar composed primarily of glucose and fructose, which is obtained by hydrolyzing starch with an enzyme such as amylase or with an acid and isomerizing a sugar solution primarily composed of glucose with glucose isomerase or alkali. According to the JAS standard, a sugar with a fructose content (the proportion of fructose in the sugar content) of less than 50% is called "glucose-fructose syrup," a sugar with a fructose content of 50% to 90% is called "fructose-glucose syrup," a sugar with a fructose content of 90% or more is called "high-fructose syrup," and a sugar-mixed sugar-fructose syrup containing glucose-fructose syrup but not more than the glucose-fructose syrup content is called "sugar-mixed fructose-glucose syrup." However, any of these isomerized sugars may be used as the raw material for the rare sugar-containing syrup of the present invention.

[0023] For example, rare sugar-containing syrup made from D-fructose contains 5.2% D-psicose, 1.8% D-allose, 15.0% glucose, and 69.3% D-fructose. Rare sugar-containing syrup made from isomerized sugar contains 3.7% D-psicose, 1.5% D-allose, 45.9% glucose, and 37.7% D-fructose. When D-glucose is used as the raw material, the syrup contains 5.7% D-psicose, 2.7% D-allose, 47.4% glucose, and 32.1% D-fructose. However, the sugar composition varies depending on the raw material and processing method. While D-allose can be separated and purified from these syrups for use, it is also possible to use the syrups as is.

[0024] In one embodiment, the D-allose that can be used in the present invention may be D-allose and / or its derivatives and / or mixtures thereof. Generally, a compound obtained by chemically converting the molecular structure of a starting compound is called a derivative of the starting compound. In this specification, the term "D-allose derivative" refers to a compound obtained by chemically converting the molecular structure of D-allose as a starting compound; and a compound obtained by chemically converting the molecular structure of a starting compound similar to D-allose (e.g., D-glucose) that has the same structure as a compound obtained by chemically converting the molecular structure of D-allose (referred to as a "structural analog of D-allose"). Common derivatives of hexoses, including D-allose, include, but are not limited to, sugar alcohols (when monosaccharides are reduced, the aldehyde and ketone groups become alcohol groups, resulting in polyhydric alcohols with the same number of carbon atoms), uronic acids (monosaccharides in which the alcohol group is oxidized; known natural examples include D-glucuronic acid, galacturonic acid, and mannuronic acid), and amino sugars (sugar molecules in which the OH group is replaced with an NH group, such as glucosamine, chondrosamine, and glycosides).The D-allose derivative may be a D-allose derivative selected from sugar alcohols in which the carbonyl group of D-allose has become an alcohol group, uronic acids in which the alcohol group of D-allose has been oxidized, and amino sugars in which the alcohol group of D-allose has been replaced with an amino group.

[0025] In other embodiments, the D-allose derivative may be a D-allose derivative in which any hydroxy group of D-allose (e.g., the hydroxy groups at the 2-, 3-, 4-, 5-, and / or 6-positions) is substituted with a hydrogen atom, a halogen atom, an amino group, a carboxyl group, a nitro group, a cyano group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkyl-substituted amino group, an aralkyl group, an aryl group, or a heteroaryl group.

[0026] The halogen atom refers to a fluorine, chlorine, bromine, or iodine atom. The alkyl moiety in the lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, and mono- or di-lower alkyl-substituted amino group refers to a linear, branched, or cyclic C1-C6 alkyl group, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclopropyl, cyclobutyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclopentyl, and cyclohexyl.

[0027] The lower alkanoyl group and the lower alkanoyl moiety of the lower alkanoyloxy group represent a straight-chain, branched, or cyclic C1-C7 alkanoyl group, and specific examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, cyclopropylcarbonyl, cyclobutylcarbonyl, 2-methylcyclopropylcarbonyl, and cyclohexylcarbonyl.

[0028] The aralkyl group refers to an aralkyl group having from 7 to 20 carbon atoms, and specific examples thereof include benzyl, phenethyl, α-methylbenzyl, benzhydryl, trityl, and naphthylmethyl.

[0029] The aryl group refers to a C6 to C14 aryl group, and specific examples include phenyl and naphthyl.

[0030] The heteroaryl group is a C3 to C8 heteroaryl group, which may be the same or different and is a monocyclic, polycyclic, or fused ring containing 1 to 4 N, O, and S atoms. Specific examples include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinonyl, 3-quinonyl, 4-quinonyl, 5-quinonyl, 6-quinonyl, 7-quinonyl, 8-quinonyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolidyl, 3-pyrrolidyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl.

[0031] In one embodiment, the D-allose derivative that can be used in the present invention may be, for example, a D-allose derivative such as 2-deoxy-D-allose, 5-deoxy-D-allose, 6-deoxy-D-allose, or 3-deoxy-D-allose (3-deoxy-D-glucose).

[0032] In this specification, "D-allose and / or its derivatives and / or mixtures thereof" may be abbreviated to simply "D-allose." Furthermore, "D-allose and / or its derivatives and / or mixtures thereof" that can be used in the present invention is interpreted to include pharmacologically acceptable salts and / or hydrates thereof.

[0033] As used herein, the term "food" refers to food in general, including general foods, including so-called health foods, as well as functional health foods, such as foods for specified health uses and foods with nutrient functions. Furthermore, dietary supplements (supplements, nutritional supplements), feed, food additives, etc. are also encompassed by the food of the present invention. The composition for treating or preventing renal cell carcinoma of the present invention contains D-allose as an active ingredient and is enterally administered. It may be used in the form of a sweetener, seasoning, food additive, food ingredient, food or drink, health food or drink, drug or quasi-drug, or feed that can be used to treat or prevent renal cell carcinoma. Regardless of the form used, enteral administration (e.g., oral administration) enables the treatment or prevention of renal cell carcinoma.

[0034] In one embodiment, the composition of the present invention is characterized by being administered enterally. As used herein, "enteral administration" refers to an administration mode in which the components of the composition of the present invention are absorbed from the intestinal tract, and may be, for example, oral administration or enteral administration (e.g., transnasal administration (administration via a catheter inserted from the nose to the stomach, duodenum, or jejunum); or transfistula administration (administration to the stomach, duodenum, or jejunum via a catheter inserted into a fistula created in the neck or abdomen)), and oral administration is preferred in the present invention. Since the composition of the present invention can be administered orally, a simple and painless treatment for renal cell carcinoma can be provided.

[0035] In one embodiment, D-allose may be administered at 1 mg / kg body weight / day to 1,000 mg / kg body weight / day, and this can be adjusted depending on age and symptoms. Generally, enterally administered substances, such as orally administered substances, are absorbed through the digestive tract before delivery, resulting in a significantly reduced delivery rate to the target tissue compared with direct injection (e.g., intraperitoneal injection, intravenous injection, etc.). However, the present inventors have discovered that D-allose contained in the composition of the present invention, even when administered at 1 mg / kg body weight / day to 1,000 mg / kg body weight / day, can be taken up by renal cell carcinoma and exert anticancer effects at a similar or approximately 20% reduced level compared with parenteral administration, such as intraperitoneal administration. On the other hand, oral administration of D-allose to colorectal cancer, another type of cancer, did not exert the anticancer effects observed when administered intraperitoneally. These findings suggest that enterally administered D-allose can be efficiently delivered to at least renal cell carcinoma and exert its anticancer effect. Therefore, it can be administered at a dose of 1 mg / kg body weight / day to 1000 mg / kg body weight / day, such as 10 mg / kg body weight / day to 800 mg / kg body weight / day, or 50 mg / kg body weight / day to 500 mg / kg body weight / day, which is ingestible by enteral administration.

[0036] When rare sugar D-allose and / or its derivatives and / or mixtures thereof are used as a food ingredient, an effective amount of rare sugar D-allose and / or its derivatives and / or mixtures thereof can be safely ingested in the course of daily eating habits. The reason for this is that rare sugar D-allose is an aldose, and as such is a highly safe compound that can be administered to humans.

[0037] In this specification, the term "drug" is used to include pharmaceutical products and quasi-drugs.

[0038] In the composition of the present invention, D-allose and / or its derivatives and / or mixtures thereof may be formulated with appropriate additives such as common excipients, stabilizers, preservatives, binders, disintegrants, etc., and provided in an appropriate dosage form such as tablets, powders, granules, capsules, solutions, syrups, elixirs, or oily or aqueous suspensions.

[0039] Solid preparations can be formulated by mixing pharmaceutically acceptable additives, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, or lubricants, with D-allose and / or its derivatives and / or mixtures thereof, as needed. They can be produced by adding excipients, disintegrants, binders, and lubricants to the D-allose and / or its derivatives and / or mixtures of the present invention, mixing the mixture, and compressing and shaping the mixture. Commonly used excipients include lactose, starch, and mannitol. Commonly used disintegrants include calcium carbonate and calcium carboxymethylcellulose. Commonly used binders include gum arabic, carboxymethylcellulose, and polyvinylpyrrolidone. Known lubricants include talc and magnesium stearate.

[0040] The tablets can be coated with known coatings for masking or to make them enteric-coated preparations. Examples of coating agents that can be used include ethyl cellulose and polyoxyethylene glycol.

[0041] In addition to the above-mentioned pharmaceuticals (pharmaceutical compositions), the compositions of the present invention can also be provided as foods (e.g., medical foods, foods for specified health uses, health supplements, health foods, functional foods, supplements, dietary supplements, or herbal teas). Even when enterally administered at a dose of 1 mg / kg body weight / day to 1000 mg / kg body weight / day (e.g., 50 mg to 50 g / day for a 50 kg adult), D-allose is efficiently taken up by renal cell carcinoma without significantly affecting other tissues, and therefore can be used not only to treat but also to prevent renal cell carcinoma.

[0042] The renal cell carcinoma to which the present invention is applicable may be not only primary renal cell carcinoma occurring in the kidney, but also metastatic renal cell carcinoma. The subject to which the present invention is applicable may also be a subject with unresectable cancer, such as metastatic advanced cancer or locally advanced cancer. The subject to which the present invention is applicable is also an animal, including humans (humans, mammals such as cows, pigs, dogs, and cats, birds such as chickens, etc.).

[0043] In one embodiment, the present invention may be used in combination with known anticancer agents, radiation therapy, and / or surgery (e.g., surgery). Anticancer agents that can be used in the present invention include, but are not limited to, molecularly targeted drugs, alkylating agents, antimetabolites, platinum preparations, hormones, topoisomerase inhibitors, microtubule-active anticancer agents, immunostimulants, anticancer antibiotics, and the like, and these may be used in combination. Molecularly targeted drugs may be, for example, low molecular weight compounds or antibodies, such as immune checkpoint inhibitors (e.g., PD-1 inhibitors, PD-L1 inhibitors, CTLA-1 inhibitors, KIR inhibitors, LAG3 inhibitors, CD137 inhibitors, CCR4 inhibitors, etc.), EGFR inhibitors (e.g., anti-EGFR antibodies), VEGFR inhibitors (e.g., anti-VEGFR antibodies), or GD2 inhibitors (e.g., GD2 antibodies). Examples of molecularly targeted drugs include ibritumomab tiuxetan, nivolumab, ipilimab, pembrolizumab, durvalumab, avelumab, atezolizumab, tremelimumab, rilumab, BMS986016, urelumab, imatinib, everolimus, erlotinib, gefitinib, sunitinib, cetuximab, sorafenib, dasatinib, tamibarotene, trastuzumab, trastuzumab emtansine, tretinoin, panitumumab, bevacizumab, bortezomib, lapatinib, rituximab, vemurafenib, and alectinib. Examples of alkylating agents include ifosfamide, carboquone, cyclophosphamide, dacarbazine, thiotepa, temozolomide, nimustine, busulfan, procarbazine, melphalan, and ranimustine. Examples of antimetabolites include enocitabine, capecitabine, carmofur, cladribine, gemcitabine, cytarabine, cytarabine ocfosfate, tegafur, tegafur-uracil, tegafur-gimeracil-oteracil potassium, doxifluridine, nelarabine, hydroxycarbamide, fluorouracil, fludarabine, pemetrexed, pentostatin, mercaptopurine, and methotrexate. Examples of platinum agents include oxaliplatin, carboplatin, cisplatin, and nedaplatin.Examples of hormone drugs include anastrozole, exemestane, estramustine, ethinylestradiol, chlormadinone, goserelin, tamoxifen, dexamethasone, toremifene, bicalutamide, flutamide, prednisolone, fosfestrol, mitotane, methyltestosterone, medroxyprogesterone, mepitiostane, leuprorelin, letrozole, etc. Examples of topoisomerase inhibitors include irinotecan, etoposide, nogitecan, etc. Examples of microtubule-active anticancer drugs include eribulin, docetaxel, nogitecan, paclitaxel, vinorelbine, vincristine, vindesine, vinblastine, etc. Examples of immunostimulants include interferon-α, interferon-β, interferon-γ, interleukin, ubenimex, lentinan, dried BCG, etc. Examples of anticancer antibiotics include actinomycin D, aclarubicin, amrubicin, idarubicin, epirubicin, zinostatin stimalamer, daunorubicin, doxorubicin, pirarubicin, bleomycin, peplomycin, mitomycin C, mitoxantrone, and liposomal doxorubicin.

[0044] Furthermore, radiation therapy used in combination with the cell composition for cancer therapy of the present invention may be any radiation therapy known to those skilled in the art. [Example]

[0045] The present invention will be described in more detail below with reference to examples, but these examples are not intended to limit the present invention in any way.

[0046] [Example] <Method for generating renal cell carcinoma xenograft mice> This experiment used two human renal cell carcinoma cell lines (Caki-1, ACHN). Each cell was cultured in RPMI-1640 medium (2000 mg D-glucose / L) supplemented with 10% fetal bovine serum, HEPES buffer, and penicillin-streptomycin at 37°C in a humidified atmosphere of 5% CO2. The renal cell carcinoma xenograft mouse model was cultured in MEM medium at a density of 1.0 × 10 5 A cell suspension of 0.1 mL was prepared and injected into the subcutaneous tissue of the thigh of female athymic nude mice (BALB / c nu / nu, 6 weeks old). One week later, the tumor volume increased to 200 mm 3 After confirming that this was the case, the sample was used in subsequent experiments.

[0047] <Changes in D-allose concentration in tumors after oral administration of D-allose to renal cell carcinoma xenograft mouse models>

[0048] The rare sugar D-allose was dissolved in saline at 400 mg / kg / 0.2 mL and administered intraperitoneally (Figure 1(A) and (B)) or orally (Figure 1(C) and (D)) to xenograft mouse models of two human renal cell carcinoma cell lines (Caki-1 and ACHN). Tumors were enucleated from the mice before D-allose administration and 1, 2, and 4 hours after administration. The tumors were sonicated in 1 mL of PBS, and the supernatant was centrifuged at 3,000 rpm for 5 minutes. Monosaccharides in the resulting supernatant were labeled with ABEE (4-aminobenzoic acid ethyl ester) and quantitatively analyzed for D-allose by HPLC (high-performance liquid chromatography) (Figure 1).

[0049] Similar to the results of intraperitoneal administration of D-allose (Figs. 1(A) and (B)), D-allose was detected in both Caki-1- and ACHN-derived tumors 1 hour after oral administration of D-allose to a renal cell carcinoma xenograft mouse model (Figs. 1(C) and (D)). In Caki-1, the highest value was reached at 1 hour after administration, and in ACHN, at 2 hours after administration, and the subsequent intratumoral concentration of D-allose decreased (Figs. 1(C) and (D)). Surprisingly, approximately 80% of the concentration of D-allose detected in tumors upon intraperitoneal administration was detected even after oral administration of D-allose. This suggests that D-allose can be efficiently delivered or taken up into renal cell carcinoma even when administered orally.

[0050] <Changes in tumor volume in a renal cell carcinoma xenograft mouse model by oral administration of D-allose>

[0051] The day when the tumor size of a renal cell carcinoma xenograft mouse model prepared using the human renal cell carcinoma cell line Caki-1 reached 200 mm 3 or more was designated as "day0", and a solution containing D-allose was orally administered starting from day1.

[0052] 0.2 mL of physiological saline or 0.2 mL of physiological saline containing 400 mg / kg of D-allose was injected via a Nelaton into the esophagus of each mouse divided into 2 groups (control group; D-allose group). The administration was performed once a day for a total of 32 days. The body weight of the mice and the major and minor diameters of the tumors were measured twice a week. The tumor volume was calculated as major diameter × minor diameter × minor diameter × 0.5. On the 32nd day after the start of oral administration, the tumors, along with the liver and kidneys, were excised from the mice and used for subsequent experiments.

[0053] In a xenograft mouse model created using Caki-1, the tumor volume in the D-allose-administered group was significantly smaller than that in the control group from day 8 onwards (Fig. 2(A)). Furthermore, the tumor volume in the D-allose-administered group on day 32 was significantly smaller than that before D-allose administration, suggesting that oral administration of D-allose not only inhibits tumor growth but also may shrink tumors (Mann-Whitney U test). There was no significant difference in body weight between the control and D-allose-administered groups during the observation period (Fig. 2(B)).

[0054] Tumors, kidneys, and livers were removed from the above-mentioned renal cell carcinoma xenograft mouse models (control group and D-allose-treated group, 32 days after the start of treatment). Each tissue was fixed in 4% paraformaldehyde-phosphate buffer, embedded in paraffin, and sliced ​​to a thickness of 4 μm. The thin sections were stained with hematoxylin and eosin (HE staining) and observed (Figures 3, 5, and 6).

[0055] Evaluation by a pathologist confirmed that tumors (Caki-1 cells) excised from the renal cell carcinoma xenograft mouse model in the D-allose oral administration group had reduced nuclear division (Figures 3 and 4).

[0056] Furthermore, no significant differences were observed in the HE stained images of kidney and liver tissues extracted from the control group and the D-allose oral administration group (Figures 5 and 6), suggesting that D-allose has no effect on kidney and liver tissues.

[0057] [Comparative Example] <Method for producing colon cancer xenograft mice> 2.0 × 10 human colon cancer cell line (DLD-1) was inoculated into the subcutaneous tissue of the thigh of male athymic nude mice (BALB / c Nude (nu / nu) mice). 6 A cell suspension containing 100 cells was injected, and the tumor volume was approximately 100-150 mm. 3 The day when this was reached was designated as "day 0," and administration of D-allose or D-glucose was initiated.

[0058] <Changes in tumor volume in a xenograft mouse model of colorectal cancer by intraperitoneal administration of D-allose> In xenograft mice with colorectal cancer in which the tumor volume had reached approximately 100 mm 3 D-allose or D-glucose at 400 mg / kg was intraperitoneally administered. Physiological saline was used as a solvent, adjusted to 0.2 ml, and administered once a day for a total of 30 days. The tumor volume was measured every 6 days. As a result, the tumor volume in the D-allose administration group was significantly smaller than that in the D-glucose group after 18 days from the start of administration (Mann-Whitney U test) (Figure 7(A)).

[0059] <Changes in tumor volume in a xenograft mouse model of colorectal cancer by oral administration of D-allose> In xenograft mice with colorectal cancer in which the tumor volume had reached approximately 100 - 150 mm 3 D-allose or D-glucose at 100 mg / kg was orally administered. Distilled water was used as a solvent, prepared to 0.2 ml, and administered once a day for a total of 30 days. The tumor volume was measured every 6 days. As a result, no significant difference was observed in the tumor volume between the D-allose administration group and the D-glucose administration group (Mann-Whitney U test) (Figure 7(B)).

[0060] <Effect of D-allose on intracellular reactive oxygen species (ROS) production in human renal cell carcinoma cell lines (Caki-1, ACHN)> For a 100 mm dish, 5.0×10 human renal cell carcinoma cell lines (Caki-1 or ACHN) 5Cells were seeded, co-cultured with DMSO or D-allose (50 mM) for 1 hour after 24-hour culture, then 10 μM 2,7-Dichlorofluorescin diacetate (DCF-DA; D6883, Sigma-Aldrich, USA) was added, and the cells were left standing at 37 °C for 30 minutes. Cells were collected by trypsinization, centrifuged at 3500×g for 5 minutes and collected, then the cells were resuspended in ice-cold PBS, and DCF-DA fluorescence was detected using CytoFLEX S (Beckman Coulter, CA, USA). All experiments were performed 3 times, and the data were analyzed using CytExpert software and shown as mean ± SE (Figure 8).

[0061] As a result, in two human renal cell carcinoma cell lines, it was revealed that 1-hour co-culture with 50 mM D-allose significantly increased intracellular ROS.

[0062] <Effect of D-allose on TXNIP expression in human renal cell carcinoma cell lines (Caki-1, Caki-2)> For a 100 mm dish, 5.0×10 human renal cell carcinoma cell lines (Caki-1 or Caki-2) 5Cells were seeded and cultured for 24 hours, then co-cultured with D-allose (10, 25, or 50 mM). Cells were harvested 48 hours after treatment, and protein was extracted and measured using a Bio-Rad Protein Assay Kit (Bio-Rad Laboratories, Inc., USA). Protein samples (40 μg) were electrophoresed on 10% Mini-PROTAN TGX Precast Gels (Bio-Rad) and transferred to PVDF Western blotting membranes using a Trans-Blot Turbo transfer system (Bio-Rad). After 1 hour of blocking (Superblock T20, Thermo, Rockford, IL, USA), the primary antibody was anti-TXNIP (D5F3E, CST, USA, 1:1000) using an iBind Flex Western System (Thermo). β-actin (ab8227, abcam, CamBridge, UK, 1:1000) was used as a loading control.

[0063] As a result, it was revealed that D-allose increased the expression of TXNIP in two human renal cell carcinoma cell lines in a dose-dependent manner (Figure 9).

Claims

1. A composition for administration to a subject for the treatment of renal cell carcinoma, the composition comprising the active ingredient D-allose for the treatment of said renal cell carcinoma and an anticancer agent different from said D-allose, and is to be administered orally.

2. A composition for treating renal cell carcinoma, comprising D-allose as an active ingredient, characterized in that the composition is orally administered to a subject who has been or will be administered an anticancer agent other than the D-allose.

3. 3. The composition according to claim 1, wherein the D-allose is administered at a dose of 1 mg / kg body weight / day to 1000 mg / kg body weight / day.

4. The composition according to any one of claims 1 to 3, wherein the anticancer drug is at least one selected from the group consisting of molecular targeted drugs, alkylating agents, antimetabolites, platinum preparations, hormone agents, topoisomerase inhibitors, microtubule-acting anticancer drugs, immunostimulants, and anticancer antibiotics.

5. The composition according to any one of claims 1 to 4, which is a pharmaceutical product.

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