Epithelial cancer treatment

Abstract

The present application aims to provide an epithelial cancer therapeutic drug with less side effects. To achieve the above object, the epithelial cancer therapeutic drug of the present application is characterized by containing at least one selected from the group consisting of an oxoacid, an oxoacid ion, and an oxoacid salt for treating or preventing an epithelial cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to an epithelial cancer therapeutic agent. BACKGROUND

[0002] As an epithelial cancer therapeutic agent, a so-called anticancer agent is widely used (Non-Patent Literature 1, etc.). In addition, as a therapeutic agent for bladder cancer, a so-called BCG is also used.

[0003] PRIOR ART DOCUMENTS

[0004] NON-PATENT LITERATURE

[0005] Non-Patent Literature 1: Shinkan, Urinary Organ Nursing, Koga Hirofumi, Yamaguchi Shigetomo, 19, 7, 731-736, 2014 SUMMARY

[0006] PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] However, in general, anticancer agents and BCG have strong side effects, and patients suffer greatly due to the side effects.

[0008] Therefore, an object of the present application is to provide an epithelial cancer therapeutic agent with small side effects.

[0009] MEANS FOR SOLVING THE PROBLEMS

[0010] In order to achieve the above object, the epithelial cancer therapeutic agent of the present application is characterized by containing at least one selected from the group consisting of an oxoacid, an oxoacid ion, and an oxoacid salt, for treating or preventing an epithelial cancer. Note that in the present application, "treatment" also includes "prevention" unless otherwise specified. In the present application, "prevention" includes, for example, recurrence prevention, and includes, for example, recurrence prevention of an epithelial cancer.

[0011] EFFECT OF THE INVENTION

[0012] According to the present application, an epithelial cancer therapeutic agent with small side effects can be provided. BRIEF DESCRIPTION OF DRAWINGS

[0013] Figure 1 is a graph showing the results of the proliferation analysis of UM-UC-3 cells and 5637 cells using MA-T.

[0014] Figure 2 is a photograph showing the results immediately after the start of the photographing (0 hours of culture) after the addition of MA-T or without the addition of MA-T in the time-lapse photographing of bladder cancer cells.

[0015] Figure 3 is a photograph showing the results 48 hours after the start of the photographing (48 hours of culture) after the addition of MA-T or without the addition of MA-T in the time-lapse photographing of bladder cancer cells.

[0016] Figure 4 Figure is a graph showing the analysis of apoptosis of 5637 cells with or without MA-T addition.

[0017] Figure 5 Figure is a photograph showing the reduction of bladder tumor by intravesical administration of MA-T in mice by in vivo imaging.

[0018] Figure 6 Figure is a graph showing the change in body weight of mice with intravesical administration of MA-T.

[0019] Figure 7 Figure is a photograph showing the results of pathological tissue analysis of the bladder of Figure 6

[0020] Figure 8 Figure and photograph showing the increase in luminescence, the inhibition of the increase in bladder weight, and the results of tumor tissue pathological analysis under the anti-tumor effect of MA-T produced by transplanting luciferase-expressing bladder cancer cells into mice.

[0021] Figure 9 Figure is a graph showing the inhibition of the increase in tumor tissue volume and the increase in tumor weight caused by MA-T treatment of bladder cancer postoperative specimen transplants in mice over time.

[0022] Figure 10 Figure is a photograph showing the results of tumor tissue pathological analysis of Figure 9

[0023] Figure 11 Figure is a graph showing the time of contact of 500 ppm NaClO2 aqueous solution with UM-UC-3 cells (left) and the concentration dependence of NaClO2 aqueous solution on cell proliferation of each bladder cancer cell (right).

[0024] Figure 12 Figure is a photograph showing UM-UC-3 cells incubated with PBS or NaClO2 for 120 minutes and removed immediately (0 hours) or after 24 hours of culture (24 hours) of the cells.

[0025] Figure 13 Figure is a graph showing the induction of apoptosis of UM-UC-3 cells contacted with 500 ppm NaClO2 aqueous solution.

[0026] Figure 14 Figure is a graph showing the results of cell cycle analysis of UM-UC-3 cells after 24 hours (overnight) of culture after contact with 500 ppm NaClO2 aqueous solution.

[0027] Figure 15 ​​is a graph showing evaluation of the anti-tumor effect of NaClO2 epithelial cancer treatment drug. In Figure 15 In the graph on the lower left, the horizontal axis indicates days from 12 days after tumor transplantation, and the vertical axis indicates tumor volume (mm 3 ). Figure 15 The photograph on the upper right shows a photograph of a bladder excised at 27 days after transplantation, and the graph on the lower right shows the weight (mg) of the excised tumor.

[0028] Figure 16 is a graph and fluorescence microscope images showing time-dependent changes in radical production caused by contact of NaClO2, benzalkonium chloride, and MA-T with bladder cancer cells.

[0029] Figure 17 is a graph showing the survival rate after 48 hours of culture after contact of tongue cancer cells "HSC-3" and oral cancer cells "HO-1-u-1" with 500 ppm NaClO2 aqueous solution for 2 hours.

[0030] Figure 18 is a graph showing the survival rate after 48 hours of culture after contact of uterine cancer cells "HeLa" and uterine cancer cells "HeLaS3" with 500 ppm NaClO2 aqueous solution for 2 hours.

[0031] Figure 19 is a graph showing the survival rate after 48 hours of culture after contact of large intestine cancer cells "HT29" and large intestine cancer cells "HT116" with 500 ppm NaClO2 aqueous solution for 2 hours.

[0032] Figure 20 is a graph showing the effect of the use of NaClO2 aqueous solution alone and the use of benzalkonium chloride (radical production catalyst) in combination on the proliferation inhibition of uterine cancer cells "HeLa".

[0033] Figure 21 is a graph showing the effect of the use of NaClO2 aqueous solution alone and the use of benzalkonium chloride (radical production catalyst) in combination on the proliferation inhibition of uterine cancer cells "HeLaS3".

[0034] Figure 22 is a graph showing the effect of NaClO2 aqueous solution on the proliferation inhibition of pancreatic cancer cells "PK05" and "PK10". DETAILED DESCRIPTION

[0035] Hereinafter, the present application will be described more specifically by citing examples. However, the present application is not limited to the following description.

[0036] Note that in the present application, in the case where isomers such as tautomers or stereoisomers (e.g., geometric isomers, conformational isomers, and optical isomers) exist in a compound (e.g., ammonium and the like described later), unless otherwise specified, any isomer can be used in the present application. In addition, in the present application, in the case where a substance (e.g., an oxygen-containing acid, an oxygen-containing acid ion, a radical generation catalyst, and the like described later) can form a salt, unless otherwise specified, the above-mentioned salt can also be used in the present application. The above-mentioned salt can be an acid addition salt or a base addition salt. Furthermore, the acid that forms the above-mentioned acid addition salt can be an inorganic acid or an organic acid, and the base that forms the above-mentioned base addition salt can be an inorganic base or an organic base. As the above-mentioned inorganic acid, there is no particular limitation, and examples thereof include sulfuric acid, phosphoric acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hypofluorous acid, hypochlorous acid, hypobromous acid, hypoiodous acid, fluorous acid, chloric acid, bromic acid, iodic acid, hyperfluorous acid, hyperchloric acid, hyperbromic acid, and hyperiodic acid. The above-mentioned organic acid is also not particularly limited, and examples thereof include p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. As the above-mentioned inorganic base, there is no particular limitation, and examples thereof include ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, carbonates, and bicarbonates, and more specifically, examples thereof include sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, and calcium carbonate. The above-mentioned organic base is also not particularly limited, and examples thereof include ethanolamine, triethylamine, and tris(hydroxymethyl)aminomethane. The method for producing these salts is also not particularly limited, and for example, the above-mentioned compounds and the like can be produced by appropriately adding the above-mentioned acid or base thereto using a publicly known method.

[0037] In addition, in the present application, a chain substituent (e.g., an alkyl group, an unsaturated aliphatic hydrocarbon group, and the like) can be linear or branched, and the number of carbon atoms is not particularly limited, and for example, it can be 1 to 40, 1 to 32, 1 to 24, 1 to 18, 1 to 12, 1 to 6, or 1 to 2 (2 or more in the case of an unsaturated hydrocarbon group). In addition, in the present application, the number of ring members (the number of atoms constituting the ring) of a cyclic group (e.g., an aryl group, a heteroaryl group, and the like) is not particularly limited, and for example, it can be 5 to 32, 5 to 24, 6 to 18, 6 to 12, or 6 to 10. In addition, in the case where isomers exist in a substituent and the like, unless otherwise specified, any isomer can be used, and for example, in the case where only "naphthyl" is mentioned, it can be 1-naphthyl or 2-naphthyl.

[0038] [1. Epithelial carcinoma therapeutic agent]

[0039] As described above, the epithelial cancer therapeutic drug of the present application is characterized by containing at least one selected from the group consisting of an oxoacid, an oxoacid ion, and an oxoacid salt. In addition, as described later, the epithelial cancer therapeutic drug of the present application can contain any component other than the oxoacid, the oxoacid ion, and the oxoacid salt, or can not contain any component.

[0040] [1-1. Oxoacid, Oxoacid Ion, and Oxoacid Salt]

[0041] In the epithelial cancer therapeutic drug of the present application, for example, the oxoacid described above can be at least one selected from the group consisting of boric acid, carbonic acid, orthocarbonic acid, carboxylic acid, silicic acid, nitrous acid, nitric acid, phosphorous acid, phosphoric acid, arsenic acid, sulfurous acid, sulfuric acid, sulfonic acid, sulfinic acid, chromic acid, dichromic acid, permanganic acid, and halogen oxoacid.

[0042] The oxoacid can be, for example, a halogen oxoacid. The halogen oxoacid can be, for example, at least one selected from the group consisting of a chlorine oxoacid, a bromine oxoacid, and an iodine oxoacid. The halogen oxoacid can be, for example, a chlorine oxoacid.

[0043] The halogen oxoacid can be, for example, at least one selected from the group consisting of hypochlorous acid, chlorous acid, chloric acid, perchloric acid, hypobromous acid, bromous acid, bromic acid, perbromic acid, hypoiodous acid, iodous acid, iodic acid, and periodic acid. The halogen oxoacid can be, for example, at least one selected from the group consisting of hypohalous acid, halous acid, halic acid, and perhalic acid. The halogen oxoacid can be, for example, halous acid. The halogen oxoacid can be, for example, chlorous acid.

[0044] In the epithelial cancer therapeutic drug of the present application, when the oxoacid is in the form of an oxoacid salt, the oxoacid salt is not particularly limited, and can be either an inorganic salt or an organic salt. The inorganic salt and the organic salt are also not particularly limited, and specific examples thereof are, for example, as described above.

[0045] The content of the at least one substance selected from the group consisting of oxyacid, oxyacid ion, and oxyacid salt in the epithelioma treatment drug of the present application is not particularly limited. For example, when the epithelioma treatment drug of the present application does not contain the radical generating catalyst described later, the content of the oxyacid ion can be 0.1 μg or more, 1 μg or more, 2 μg or more, 3 μg or more, 5 μg or more, 10 μg or more, 100 μg or more, 200 μg or more, 500 μg or more, 1000 μg or more, 1500 μg or more, 2500 μg or more, or 5000 μg or more, and can also be 10000 μg or less, 5000 μg or less, 2500 μg or less, 2000 μg or less, 1500 μg or less, 1000 μg or less, 500 μg, 100 μg or less, or 10 μg or less, per 1 g of the epithelioma treatment drug. When the epithelioma treatment drug of the present application contains the radical generating catalyst described later, the content of the oxyacid ion can be, for example, 0.1 μg or more, 1 μg or more, 2 μg or more, 3 μg or more, 5 μg or more, 10 μg or more, 100 μg or more, 200 μg or more, 500 μg or more, 1000 μg or more, 1500 μg or more, 2500 μg or more, or 5000 μg or more, and can also be 10000 μg or less, 5000 μg or less, 2500 μg or less, 2000 μg or less, 1500 μg or less, 1000 μg or less, 500 μg, 100 μg or less, or 10 μg or less, per 1 g of the epithelioma treatment drug.

[0046] [1-2. Radical generating catalyst]

[0047] As described above, the epithelioma treatment drug of the present application can also contain a radical generating catalyst, which is a substance that catalyzes generation of radicals from the at least one substance selected from the group consisting of the oxyacid, oxyacid ion, and oxyacid salt contained in the epithelioma treatment drug of the present application. Hereinafter, the radical generating catalyst described above is sometimes referred to as "radical generating catalyst of the present application".

[0048] The radical generating catalyst of the present application can be, for example, an organic compound or an inorganic substance. The organic substance can be, for example, at least one selected from the group consisting of ammonium, amino acid, protein, peptide, phospholipid, and salts thereof. The inorganic substance can contain one or both of metal ions and non-metal ions. The metal ions can include one or both of typical metal ions and transition metal ions. The inorganic substance can be, for example, at least one selected from the group consisting of alkaline earth metal ions, rare earth ions, Mg 2+ , Sc 3+ , Li + , Fe 2+ , Fe 3+ , Al 3+at least one selected from the group consisting of alkali metal ions, alkaline earth metal ions, rare earth ions, and ions of elements belonging to Groups 13 to 17 of the periodic table. As the alkali metal ions, for example, ions of lithium, sodium, potassium, rubidium, cesium, or francium can be mentioned, and more specifically, for example, ions of Li 2+ , Sr 2+ , Ba 2+ , and Ra 2+ may be mentioned. In addition, "rare earth" is a general term for 17 elements of scandium 21 Sc, yttrium 39 Y, and 15 elements from lanthanum 57 La to lutetium 71 Lu (lanthanoids). As the rare earth ions, for example, trivalent cations of each of the above 17 elements can be mentioned.

[0049] In addition, the above radical generation catalyst can be, for example, at least one selected from the group consisting of CaCl2, MgCl2, FeCl2, FeCl3, AlCl3, AlMeCl2, AlMe2Cl, BF3, BPh3, BMe3, TiCl4, SiF4, and SiCl4. Here, "Ph" represents a phenyl group, and "Me" represents a methyl group.

[0050] The above radical generation catalyst can be, for example, a Lewis acid having a value of 0.4 eV or more. In addition, the radical generation catalyst can be, for example, a Bronsted acid having an acid dissociation constant pK a of 5 or more. The upper limit value of the above pK a is not particularly limited, and is, for example, 50 or less.

[0051] Note that in the radical generation catalyst of the present application, the above radical generation catalyst can be appropriately selected in consideration of the strength of reactivity, the strength of acidity, safety, and the like, as necessary.

[0052] In the present application, the reason why the above ammonium, amino acid, peptide, and phospholipid, and the like function as a radical generation catalyst is not clear, but it is presumed that this is because the above ammonium, amino acid, peptide, and phospholipid, and the like have a function as a Lewis acid. Note that in the present application, "Lewis acid" refers to, for example, a substance that functions as a Lewis acid with respect to the above radical generation source.

[0053] The Lewis acidity of the radical generation catalyst of the present application is, for example, 0.4 eV or more, 0.5 eV or more, or 0.6 eV or more. The upper limit value of the Lewis acidity is not particularly limited, and is, for example, 20 eV or less. In the present application, as a criterion for determining whether the Lewis acidity is the above value or less, for example, it is sufficient that the measured value based on either of the following "Method for measuring Lewis acidity (1)" or "Method for measuring Lewis acidity (2)" is the above value or less.

[0054] The Lewis acidity can be determined, for example, by the method described in Ohkubo, K.; Fukuzumi, S. Chem. Eur. J., 2000, 6, 4532, J. AM. CHEM. SOC. 2002, 124, 10270-10271, or J. Org. Chem. 2003, 68, 4720-4726, and specifically, by the "Method for determining Lewis acidity (1)" described below.

[0055] (Method for determining Lewis acidity (1))

[0056] Acetonitrile (MeCN) containing cobalt tetraphenylporphyrin in the following chemical formula (1a), saturated O2, and a determination object of Lewis acidity (for example, a cation such as a metal, represented by M n+ in the following chemical formula (1a) was subjected to determination of a change in ultraviolet-visible absorption spectrum at room temperature. An index of Lewis acidity, ΔE value (eV) can be calculated from the obtained reaction rate constant (k cat ). The larger the value of k cat , the stronger the Lewis acidity. In addition, the Lewis acidity of an organic compound can also be estimated from the energy level of the lowest unoccupied orbital (LUMO) calculated by quantum chemical calculation. The larger the value on the positive side, the stronger the Lewis acidity.

[0057] [Formula 1a]

[0058]

[0059] Note that, the following shows an example of the reaction rate constant of CoTPP with oxygen in the presence of a Lewis acid, which becomes an index of Lewis acidity determined (calculated) by the above-described determination method. In the following table, the numerical value indicated by "k cat , M -2 s -1 " is the CoTPP and oxygen in the presence of a Lewis acid. The numerical value indicated by "LUMO, eV" is the energy level of LUMO. In addition, "benzetonium chloride" indicates benzethonium chloride, "benzalkonium chloride" indicates benzalkonium chloride, "tetramethylammonium hexafluorophosphate" indicates tetramethylammonium hexafluorophosphate, "tetrabutylammonium hexafluorophosphate" indicates tetrabutylammonium hexafluorophosphate, and "ammonium hexafluorophosphate" indicates ammonium hexafluorophosphate.

[0060] [Table tpp]

[0061]

[0062] In addition, in the present application, the measurement of the Lewis acidity can be performed as follows: in the measurement method (1) of the Lewis acidity, ubiquinol 1 (Q1) is used instead of oxygen molecule (O2), and the anion radical of ubiquinol 1 is generated by reduction of ubiquinol 1. Hereinafter, such a measurement method of the Lewis acidity is sometimes referred to as "measurement method (2) of the Lewis acidity". In the measurement method (2) of the Lewis acidity, the measurement can be performed in the same manner as the measurement method (1) of the Lewis acidity except that ubiquinol 1 (Q1) is used instead of oxygen molecule (O2). In addition, in the measurement method (2) of the Lewis acidity, the ΔE value (eV) as an index of the Lewis acidity can be calculated from the obtained reaction rate constant (kcat) in the same manner as the measurement method (1) of the Lewis acidity. The measurement method (2) of the Lewis acidity is described, for example, in Ohkubo, K.; Fukuzumi, S. Chem. Eur. J., 2000, 6, 4532, and can be performed in accordance with or in accordance with the method described in the document. cat ) can be calculated from the obtained reaction rate constant (k

[0063] The above-described measurement method (2) of the Lewis acidity can be performed by measuring the reaction rate constant (k cat ) with respect to the following chemical reaction formula (1b).

[0064] [Formula 1b]

[0065] CoTPP: cobalt (II) tetraphenylporphyrin

[0066] Q1: ubiquinol 1

[0067]

[0068] In the above-described chemical formula (1b), M n+ represents the above-described radical generation catalyst,

[0069] CoTPP represents cobalt (II) tetraphenylporphyrin,

[0070] Q1 represents ubiquinol 1,

[0071] [(TPP)Co] + represents cobalt (III) tetraphenylporphyrin cation,

[0072] (Q1)·- represents an anion radical of ubiquinol 1.

[0073] The Lewis acidity of the radical generation catalyst of the present application is measured, for example, by the reaction rate constant (kcat) with respect to the above-described chemical reaction formula (1b), that is, "measurement method (2) of the Lewis acidity".cat ) of the measured value (K obs ) is 1.0 x 10 -5 S -1 The above, 2.0 x 10 -5 S -1 The above, 3.0 x 10 -5 S -1 The above, 4.0 x 10 -5 S -1 The above, 5.0 x 10 -5 S -1 The above, 6.0 x 10 -5 S -1 The above, 7.0 x 10 -5 S -1 The above, 8.0 x 10 -5 S -1 The above, 9.0 x 10 -5 S -1 The above, 1.0 x 10 -4 S -1 The above, 2.0 x 10 -4 S -1 The above, 3.0 x 10 -4 S -1 The above, 4.0 x 10 -4 S -1 The above, 5.0 x 10 -4 S -1 The above, 6.0 x 10 -4 S -1 The above, 7.0 x 10 -4 S -1 The above, 8.0 x 10 -4 S -1 The above, 9.0 x 10 -4 S -1 The above, 1.0 x 10 -3 S -1 The above, 2.0 x 10 -3 S -1 The above, 3.0 x 10 -3 S -1 The above, 4.0 x 10 -3 S -1 The above, 5.0 x 10 -3 S -1 The above, 6.0 x 10 -3 S -1 The above, 7.0 x 10 -3 S -1 The above, 8.0 x 10 -3 S -1 The above, 9.0 x 10 -3 S-1 Above, 1.0 x 10 - 2 S -1 Above, 2.0 x 10 -2 S -1 Above, 3.0 x 10 -2 S -1 Above, 4.0 x 10 -2 S -1 Above, 5.0 x 10 -2 S -1 Above, 6.0 x 10 -2 S -1 Above, 7.0 x 10 -2 S -1 Above, 8.0 x 10 -2 S -1 Above, or 9.0 x 10 -2 S -1 Above, also can be 1.0 x 10 - 1 S -1 Below, 9.0 x 10 -2 S -1 Below, 8.0 x 10 -2 S -1 Below, 7.0 x 10 -2 S -1 Below, 6.0 x 10 -2 S -1 Below, 5.0 x 10 -2 S -1 Below, 4.0 x 10 -2 S -1 Below, 3.0 x 10 -2 S -1 Below, 2.0 x 10 -2 S -1 Below, 1.0 x 10 -2 S -1 Below, 9.0 x 10 -3 S -1 Below, 8.0 x 10 -3 S -1 Below, 7.0 x 10 -3 S -1 Below, 6.0 x 10 -3 S -1 Below, 5.0 x 10 -3 S -1 Below, 4.0 x 10 -3 S -1 Below, 3.0 x 10 -3 S -1 Below, 2.0 x 10 -3 S-1 Below, 1.0 x 10 -3 S -1 Below, 9.0 x 10 -4 S -1 Below, 8.0 x 10 -4 S -1 Below, 7.0 x 10 -4 S -1 Below, 6.0 x 10 -4 S -1 Below, 5.0 x 10 -4 S -1 Below, 4.0 x 10 -4 S -1 Below, 3.0 x 10 -4 S -1 Below, 2.0 x 10 -4 S -1 Below, 1.0 x 10 -4 S -1 Below, 9.0 x 10 -5 S -1 Below, 8.0 x 10 - 5 S -1 Below, or 7.0 x 10 -5 S -1 Below.

[0074] In the radical generation catalyst of the present application, the above-mentioned ammonium can be a quaternary ammonium, or a tertiary, secondary, primary or unsubstituted ammonium. In addition, the above-mentioned ammonium is not particularly limited, and can be, for example, a nucleic acid base or the like, or an amino acid, a peptide or the like described later.

[0075] In addition, the radical generation catalyst of the present application can be a cationic surfactant, and can also be a quaternary ammonium cationic surfactant. As the quaternary ammonium cationic surfactant, for example, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetrimonium chloride, decamethonium chloride, edrophonium, didecyldimethylammonium chloride, tetramethylammonium chloride, tetrabutylammonium chloride, benzyltriethylammonium chloride, oxitropium, carbachol, glycopyrronium, safflower, choline allyl sulfide, tetraethylammonium bromide, cetyltrimethylammonium bromide, succinylcholine, sphingomyelin, GMl ganglioside, denatonium, trigonelline, neostigmine, paraquat, pyridostigmine, phellodendrine, pralidoxime methyl iodide, betaine, betanoside, uracil, betalain, lecithin, adenine, guanine, cytosine, thymine, uracil, and choline (benzoylcholine chloride and choline chloride lauryl ester hydrate, choline phosphate, acetylcholine, choline, dipalmitoylphosphatidylcholine, and edrophonium hydrochloride, etc.) can be exemplified. However, the quaternary ammonium in the method for producing radicals of the present application is not limited to a surfactant.

[0076] In the radical generation catalyst of the present application, the ammonium can be an ammonium salt represented by the following formula (XI).

[0077] [Chemical Formula XI]

[0078]

[0079] In the above formula (XI),

[0080] R 11 , R 21 , R 31 , and R 41 are each a hydrogen atom or an aromatic ring, or an alkyl group, and the alkyl group can include an ether bond, a carbonyl group, an ester bond, or an amide bond, or an aromatic ring, R 11 , R 21 , R 31 , and R 41 may each be the same or different, or

[0081] R 11 , R 21 , R 31 , and R 41 two or more of which can be integrated to form a cyclic structure together with the N + to which they are bonded, and the cyclic structure can be saturated or unsaturated, can be an aromatic ring or a non-aromatic ring, and can have one or more substituents, and X - is an anion.

[0082] X - for example, anions other than dithionate ions.

[0083] R 11 , R 21 , R 31 , and R 41 In the above, the aromatic ring is not particularly limited, and for example, can or can not contain a hetero atom, and can or can not have a substituent. As the above aromatic ring containing a hetero atom (heteroaromatic ring), for example, a nitrogen-containing aromatic ring, a sulfur-containing aromatic ring, an oxygen-containing aromatic ring, and the like can be exemplified. As the above aromatic ring not containing a hetero atom, for example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, and the like can be exemplified. As the heteroaromatic ring, for example, a pyridine ring, a thiophene ring, a pyrene ring, and the like can be exemplified. The nitrogen-containing aromatic ring can or can not have a positive charge. As the nitrogen-containing aromatic ring not having a positive charge, for example, a pyrroline ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a quinoline ring, an isoquinoline ring, an acridine ring, a 3,4-benzoquinoline ring, a 5,6-benzoquinoline ring, a 6,7-benzoquinoline ring, a 7,8-benzoquinoline ring, a 3,4-benzoisoquinoline ring, a 5,6-benzoisoquinoline ring, a 6,7-benzoisoquinoline ring, a 7,8-benzoisoquinoline ring, and the like can be exemplified. As the nitrogen-containing aromatic ring having a positive charge, for example, a pyrrolium ring, a pyridinium ring, a pyridazinium ring, a pyrimidinium ring, a pyrazinium ring, a quinolinium ring, an isoquinolinium ring, an acridinium ring, a 3,4-benzoquinolinium ring, a 5,6-benzoquinolinium ring, a 6,7-benzoquinolinium ring, a 7,8-benzoquinolinium ring, a 3,4-benzoisoquinolinium ring, a 5,6-benzoisoquinolinium ring, a 6,7-benzoisoquinolinium ring, a 7,8-benzoisoquinolinium ring, and the like can be exemplified. As the oxygen-containing aromatic ring or the sulfur-containing aromatic ring, for example, an aromatic ring obtained by replacing at least one of carbon atoms or nitrogen atoms of the above aromatic ring not containing a hetero atom or the above nitrogen-containing aromatic ring with at least one of oxygen atoms and sulfur atoms can be exemplified.

[0084] R 11 , R 21 , R 31 , and R 41 In the above, when the above alkyl group or the above aromatic ring has a substituent, the above substituent is not particularly limited, and is arbitrary, and for example, a sulfo group, a nitro group, a diazo group, and the like can be exemplified.

[0085] The above ammonium salt represented by Chemical Formula (XI) can be, for example, an ammonium salt represented by Chemical Formula (XII).

[0086] [Chemical Formula XII]

[0087]

[0088] In the above Chemical Formula (XII),

[0089] R 111 is an alkyl group having 5 to 40 carbon atoms, can contain an ether bond, a ketone carbonyl group, an ester bond, or an amide bond, a substituent, or an aromatic ring,

[0090] R 21 and X - are the same as those in the above formula (XI).

[0091] In R 111 , the above aromatic ring is not particularly limited, for example, can contain a hetero atom, or can not contain a hetero atom, can have a substituent, or can not have a substituent. In R 111 , specific examples of the above aromatic ring are not particularly limited, for example, are the same as those of R 11 , R 21 , R 31 , and R 41 in the above formula (XI).

[0092] In R 111 , when the above alkyl group or the above aromatic ring has a substituent, the above substituent is not particularly limited, is arbitrary, for example, is the same as those of R 11 , R 21 , R 31 , and R 41 in the above formula (XI).

[0093] In the above formula (XII),

[0094] R 21 for example, can be a methyl group or a benzyl group, 1 or more hydrogen atoms of the benzene ring of the above benzyl group can be replaced with an arbitrary substituent, or can not be replaced with an arbitrary substituent, the above arbitrary substituent for example, can be an alkyl group, an unsaturated aliphatic hydrocarbon group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group (-OH), a mercapto group (-SH), or an alkylthio group (-SR, R is an alkyl group).

[0095] The ammonium salt represented by the above formula (XII) for example, can be an ammonium salt represented by the following formula (XIII).

[0096] [Chemical Formula XIII]

[0097]

[0098] In the above formula (XIII), R 111 and X - are the same as those in the above formula (XII).

[0099] The ammonium can be, for example, at least one selected from the group consisting of benzethonium chloride, benzalkonium chloride, cetrimonium chloride, tetramethylammonium chloride, ammonium chloride, methylammonium chloride, tetrabutylammonium chloride, cetylpyridinium chloride, cetrimonium bromide, dequalinium chloride, ephedrine, didecyldimethylammonium chloride, benzyltriethylammonium chloride, oxitropium bromide, carbachol, glycopyrronium, safflower, sinapine, tetraethylammonium bromide, cetyltrimethylammonium bromide, succinylcholine, sphingomyelin, GMl ganglioside, denatonium, trigonelline, neostigmine, paraquat, pyridostigmine, phellodendrine, pralidoxime iodide, betaine, betanoside, uracil, betalain, lecithin, adenine, guanine, cytosine, thymine, uracil, and choline. The ammonium can be, for example, benzethonium chloride.

[0100] The ammonium salt represented by the above formula (XI) can be, for example, an ammonium salt represented by the following formula (XIV).

[0101] [Chemical Formula XIV]

[0102]

[0103] In the above formula (XIV),

[0104] R 100 The above ring structure can be saturated or unsaturated, can be an aromatic ring or a non-aromatic ring, can have one or more substituents or can have none, R 11 and X - are the same as described above.

[0105] The ammonium salt represented by the above formula (XI) can be, for example, an ammonium salt represented by the following formula (XV).

[0106] [Chemical Formula XV]

[0107]

[0108] In the above formula (XV),

[0109] Each Z is CH or N, and can be the same or different, and in the case of CH, H can be replaced with a substituent,

[0110] R 11 and X - are the same as described above with respect to formula (XI).

[0111] The ammonium salt represented by the above formula (XI) can be, for example, an ammonium salt represented by the following formula (XVI).

[0112] [Chemical Formula XVI]

[0113]

[0114] In the above formula (XVI),

[0115] R 101 , R 102 , R 103 , and R 104 are each a hydrogen atom or a substituent, R 101 , R 102 , R 103 , and R 104 may be the same or different, or

[0116] R 101 , R 102 , R 103 , and R 104 two or more of which can be integrated, and together with the bonded N + form a cyclic structure, and the above cyclic structure can be saturated or unsaturated, and can be an aromatic ring or can not have one or more substituents,

[0117] Z is CH or N, and in the case of CH, H can be replaced with a substituent,

[0118] R 11 and X - are the same as in the above formula (XI).

[0119] The ammonium salt represented by the above formula (XI) can be, for example, an ammonium salt represented by the following formula (XVII).

[0120] [XVII]

[0121]

[0122] In the above formula (XVII),

[0123] R 111 to R 118 are each a hydrogen atom or a substituent, R 111 to R 118 may be the same or different, or

[0124] R 111 to R 118 two or more of which can be integrated to form a cyclic structure, and the above cyclic structure can be an aromatic ring or a non-aromatic ring, and can have or can not have one or more substituents, and Z is CH or N, and in the case of CH, H can be replaced with a substituent,

[0125] R 11 and X - are the same as in the above formula (XI).

[0126] The ammonium salt represented by the above formula (XI) can be, for example, at least one selected from the group consisting of benzethonium chloride, benzalkonium chloride, cetyltrimethylammonium chloride, tetramethylammonium chloride, ammonium chloride, methylammonium chloride, and tetrabutylammonium chloride. In addition, the ammonium salt represented by the above formula (XII) is particularly preferably benzethonium chloride.

[0127] In addition, benzethonium chloride (Bzn + Cl - ) can be represented, for example, by the following formula. In addition, benzalkonium chloride can be represented, for example, by R 111 in the above formula (XIII) is an alkyl group having 8 to 18 carbon atoms, X - is a chloride ion.

[0128] [Chemical Formula Bzn]

[0129]

[0130] Note that, in the above formulae (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII), X is an arbitrary anion, and is not particularly limited. In addition, X" is not limited to a monovalent anion, and can be an anion having an arbitrary valence number such as a divalent or trivalent anion. In the case where the anion has a charge of a valence number of two or three, the number of molecules of the ammonium (monovalent) in the above formulae (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII) is the number of molecules of the anion x the valence number of the anion (for example, in the case where the anion is divalent, the number of molecules of the ammonium (monovalent) is twice the number of molecules of the anion). As X - , for example, halogen ions (fluoride ions, chloride ions, bromide ions, and iodide ions), acetate ions, nitrate ions, sulfate ions, and the like can be exemplified.

[0131] The radical generation catalyst of the present application is not limited to, for example, the above formulae (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII), and can be an ammonium having an arbitrary structure containing an aromatic ring. As the above aromatic ring, there is no particular limitation, and aromatic rings exemplified in R 11 , R 21 , R 31 , and R 41 in the above formula (XI) can be exemplified.

[0132] The radical generation catalyst of the present application may, for example, be a sulfonic acid amine or an ammonium thereof. The sulfonic acid amine described above is, for example, an amine having a sulfonic group (sulfonic acid group) in the molecule. As the aforementioned sulfonic acid amine, for example, taurine, aminosulfonic acid, 3-amino-4-hydroxy-1-naphthalenesulfonic acid, aminosulfonic acid, p-toluidine-2-sulfonic acid, o-anisidine-5-sulfonic acid, Direct Blue 14, 3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxypropanesulfonic acid, 3-[(3-cholestamidopropyl)dimethylammonio]-1-propanesulfonic acid salt, aminomethanesulfonic acid, 3-sulfopropylamine, 2-aminobenzenesulfonic acid, R(+)-3-aminotetrahydrofurfuryl benzene, 4-amino-5-hydroxy-1,7-naphthalene disulfonic acid, N-(2-acetamido)-2-aminoethanesulfonic acid, 4'-amino-3'-methoxyazobenzene-3-sulfonic acid sodium, lapatinib di-p-toluenesulfonic acid, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, 8-amino-1,3,6-naphthalene trisulfonic acid disodium hydrate, 1-aminonaphthalene-2-sulfonic acid, (2S,3S)-3-amino-2-methyl-4-oxo-1-azetidinesulfonic acid, 3-(1-naphthylamino)propanesulfonic acid sodium, 3-methyl-4-aminobenzenesulfonic acid, 3-cyclohexylamino-2-hydroxypropanesulfonic acid sodium, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid sodium, 4-amino-1-naphthalenesulfonic acid, aminosulfonic acid sodium, tricaine, p-aminobenzenesulfonic acid sodium, 1,4-benzenediamine-2-sulfonic acid, p-anisidine-2-sulfonic acid, 6-amino-1-naphthalenesulfonic acid, 3,4-diaminobenzenesulfonic acid, 3-amino-4-chlorobenzenesulfonic acid, 3-[(4-amino-3-methylphenyl)azo]benzenesulfonic acid, 3-amino-4-hydroxy-5-nitrobenzenesulfonic acid, 5-amino-6-hydroxy-3-nitrobenzenesulfonic acid, 4-acetamido-2-aminobenzenesulfonic acid hydrate, 2-aminophenol-4-sulfonic acid, 1-amino-2-methoxy-5-methyl-4-benzenesulfonic acid, dansyl acid, aminosulfonic acid [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-7H-pyrrolo[2,3-D]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl ester; 5-sulfo-4'-diethylamino-2,2'-dihydroxyazobenzene, 2-aminonaphthalene-6,8-disulfonic acid, 2-[N,N-bis(2-hydroxyethyl)amino]-1-ethanesulfonic acid sodium, 3-acetyl-2-(methylaminosulfonyl)thiophene, 4-amino-2-chlorotoluene-5-sulfonic acid sodium, 5-(3-amino-5-oxo-2-pyrazolin-1-yl)-2-phenoxybenzenesulfonic acid, potassium aminosulfonate, p-aminobenzeneazosulfonic acid, 3-[(3-cholestamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid salt, 3-amino-2,7-naphthalenedisulfonic acid sodium, 3-[N,N-bis(hydroxyethyl)amino]-2-hydroxypropanesulfonic acid sodium salt, cobalt(II) bis(amidosulfate), 3-(4-amino-3-methoxyphenylazo)benzenesulfonic acid, nickel(II) aminosulfonate tetrahydrate, 2,4-diaminobenzenesulfonic acid sodium salt, 5-amino-2-chlorotoluene-4-sulfonic acid, 2,5-dichloro-p-aminobenzenesulfonic acid, 4-methylbenzenesulfonic acid, APTS (aminopyrene trisulfonic acid), 4'-aminoazobenzene-3-sulfonic acid, Pontacyl Brilliant Red 2B, p-anisidine-3-sulfonic acid, 4,4'-bis(4-naphthylazo)-2,2'-dichlorobenzenesulfonic acid, 3-naphthylamine-8-hydroxy-4,6-disulfonic acid, 4-amino-1,5-naphthalene disulfonic acid sodium salt, 4-aminoazobenzene-4'-sulfonic acid sodium salt, 5-amino-2-methylbenzenesulfonic acid, 7-amino-1,3-naphthalene disulfonic acid disodium salt, Alizarine Carmoisine SE, 7-amino-2-naphthalenesulfonic acid sodium salt, 6-amino-5-bromopyridine-3-sulfonic acid, 2-aminoethanethiol p-toluenesulfonic acid salt, 2-amino-1-naphthalenesulfonic acid sodium salt, 6-amino-1,3-naphthalene disulfonic acid disodium salt hydrate, N,N,N',N'-tetraethylsulfonamide, 5-amino-2-ethoxybenzenesulfonic acid, 3,5-diamino-2,4,6-trimethylbenzenesulfonic acid, 7-amino-1-naphthalenesulfonic acid, aminosulfonic acid guanidine, 2-amino-5-nitrobenzenesulfonic acid, diamidogen nickel(II) sulfate, 4-amino-4'-nitrostilbene-2,2'-disulfonic acid disodium salt, aniline-2,5-disulfonic acid monosodium salt, 5-amino-1-naphthol-3-sulfonic acid hydrate, 2,5-dichlorothiophenesulfonic acid sodium salt, 6-aminohexanoic acid hexyl ester p-toluenesulfonic acid salt, rac-(R*)-2-(4-chlorophenyl)-3-amino-1-propanesulfonic acid, 2-(N,N-dipropyl)aminobenzene ether-4-sulfonic acid, 2-amino-4-chlorophenol-6-sulfonic acid, 6-amino-1,3-naphthalene disulfonic acid, 5,10,15,20-tetra[4-(trimethylammonio)phenyl]-21H,-23H- porphine toluenesulfonic acid salt, 5-amino-2-[(4-aminophenyl)amino]benzenesulfonic acid, 4-amino-3-chlorobenzenesulfonic acid, 2-aminobenzenesulfonic acid phenyl ester, 4-acetylamino-4'-isothiocyanostilbene-2,2'-disulfonic acid disodium salt, (S)-3-amino-oxetanone p-toluenesulfonic acid salt, 5-acetylamino-4-hydroxy-2,7-naphthalene disulfonic acid disodium salt, 2-phenylamino-5-aminobenzenesulfonic acid, 4-octadecylamino-4-oxo-2-[(sodium oxy) sulfonyl]butyric acid sodium salt, 3,5-diamino-4-methylbenzenesulfonic acid, and the like.

[0133] The radical generation catalyst of the present application may, for example, be a nicotinic amine or an ammonium thereof. The nicotinic amine is, for example, an amine having a cyclic structure in the molecule and the cyclic structure contains a nicotinic skeleton. As the nicotinic amine, there can be mentioned, for example, nicotinamide, alkaloid, and the like.

[0134] The radical generation catalyst of the present application can be, for example, a nitrous amine or a nitrous ammonium. The nitrous amine or the nitrous ammonium described above means, for example, a compound obtained by reacting an amine with nitrous acid or a nitrous acid derivative. As the nitrous amine or the nitrous ammonium described above, there can be mentioned, for example, a diazo compound, a diazo salt, an N-nitroso compound, a C-nitroso compound, and the like.

[0135] Further, in the radical generation catalyst of the present application, the ammonium described above can include a plurality of ammonium structures (N + ) in one molecule. Furthermore, the ammonium described above can be associated with a plurality of molecules to form a dimer or a trimer or the like, for example, through π electron interaction.

[0136] In the radical generation catalyst of the present application, the amino acid described above is not particularly limited. The amino acid described above can include, for example, at least one amino group or imino group and at least one carboxyl group in one molecule. The amino acid described above can be, for example, an α-amino acid, a β-amino acid, a γ-amino acid, or an amino acid other than these. The amino acid described above can be, for example, an amino acid constituting a protein, and specifically, for example, at least one selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, and 4-hydroxyproline.

[0137] In the radical generation catalyst of the present application, the peptide described above is not particularly limited. The peptide described above can be, for example, a peptide in which two or more of the amino acid molecules described above are bonded by a peptide bond. The peptide described above can be, for example, at least one selected from the group consisting of oxidized glutathione (GSSG) and reduced glutathione (GSH).

[0138] In the radical generation catalyst of the present application, the phospholipid described above is not particularly limited. The phospholipid described above can be, for example, a lipid including a phosphorus atom in a molecule, and can be, for example, a lipid including a phosphoester bond (P-O-C) in a molecule. The phospholipid described above can have, for example, at least one of an amino group, an imino group, an ammonium group, and an imine group in a molecule, or can not have any of these. The phospholipid can be, for example, at least one selected from the group consisting of phosphatidylserine, phosphatidylcholine, phosphatidic acid, phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin.

[0139] As described above, the radical generation catalyst of the present application is a catalyst that catalyzes generation of radicals from at least one substance selected from the group consisting of the above-mentioned oxyacids, oxyacid ions, and oxyacid salts contained in the epithelial cancer treatment drug of the present application. Therefore, the radical generation catalyst of the present application can catalyze generation of radicals from a radical generation source, for example, in vitro, but preferably in vivo. The in vivo can be, for example, in a human body, or in a body of an animal other than a human.

[0140] The radical generation catalyst of the present application can catalyze generation of radicals from a radical generation source, for example, in a digestive organ. The digestive organ can be, for example, at least one selected from the group consisting of an oral cavity portion, a pharynx portion, an esophagus, a stomach, a duodenum, a small intestine, and a large intestine. The digestive organ can be, for example, a large intestine. The small intestine can be, for example, at least one selected from the group consisting of a duodenum, a jejunum, and an ileum. The large intestine can be, for example, at least one selected from the group consisting of a cecum, a colon, and a rectum. The radical generation catalyst of the present application can be used, for example, for sterilization in the digestive organ, induction of change in intestinal bacterial flora, treatment or inhibition of symptoms of ulcerative colitis, and the like.

[0141] The content of the above-mentioned radical generation catalyst in the epithelial cancer treatment drug of the present application is not particularly limited. For example, the content of the above-mentioned radical generation catalyst can be 0.1 μg or more, 1 μg or more, 2 μg or more, 3 μg or more, 5 μg or more, 10 μg or more, 100 μg or more, 200 μg, 500 μg or more, 1500 μg or more, 2500 μg or more, or 5000 μg or more, or can be 10000 μg or less, 5000 μg or less, 2500 μg or less, 2000 μg or less, 1000 μg or less, 500 μg, 100 μg or less, or 10 μg or less, per 1 g of the epithelial cancer treatment drug.

[0142] [1-3. Other Optional Components]

[0143] As described above, the epithelial cancer treatment drug of the present application is characterized by containing at least one selected from the group consisting of oxyacids, oxyacid ions, and oxyacid salts. The epithelial cancer treatment drug of the present application can contain any component other than the oxyacids, oxyacid ions, and oxyacid salts, or can not contain any component other than the oxyacids, oxyacid ions, and oxyacid salts. As the above-mentioned any component, for example, the above-mentioned radical generation catalyst can be listed. In addition, the epithelial cancer treatment drug of the present application can contain any component other than the above-mentioned radical generation catalyst, or can not contain any component other than the above-mentioned radical generation catalyst. The above-mentioned any component other than the radical generation catalyst is not particularly limited. As to specific examples thereof, the description is made in the following "2. Form, manufacturing method, use method, and the like of the epithelial cancer treatment drug".

[0144] [2. Form, method of production, method of use, etc. of an epithelial cancer therapeutic]

[0145] The form of the epithelial cancer therapeutic of the present application is not particularly limited, and can be, for example, a solid, a powder, a semi-solid, a liquid, or the like. In the case of a solid, for example, it can be a tablet, a capsule, or the like.

[0146] The method of production of the epithelial cancer therapeutic of the present application is also not particularly limited, and can be produced, for example, by a method that is the same as or based on the method of production of a general medicament. Specifically, for example, only the entire components of the epithelial cancer therapeutic of the present application can be mixed. Alternatively, for example, after mixing the above-described entire components, it can be compressed to produce a tablet, or it can be encapsulated.

[0147] As described above, the epithelial cancer therapeutic of the present application can contain any component other than the above-described radical-generating catalyst, or can not contain any component. The above-described any component is not particularly limited, and can be, for example, the same as or based on a general medicament. As the above-described any component, for example, in the case where the epithelial cancer therapeutic of the present application is a liquid, water, a pH buffer, physiological saline, or the like can be exemplified.

[0148] The epithelial cancer therapeutic of the present application can also contain, for example, one or more pharmaceutically acceptable additives as the above-described any component. That is, for example, the sulfated polysaccharide or the sulfated oligosaccharide can be formulated together with one or more pharmaceutically acceptable additives before administration. The above-described additives are not particularly limited, and can be, for example, an inert substance such as a carrier, a diluent, a flavoring agent, a sweetening agent, a lubricant, a dissolving agent, a suspending agent, a binding agent, a tablet disintegrating agent, and a capsule material, or the like. In addition to these, for example, any additive that is generally used in the medical field can be appropriately used.

[0149] The above-described additives can be used, for example, with the following exemplified substances when the epithelial cancer therapeutic of the present application is orally administered. As the carrier, for example, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, or the like can be used. Examples of the disintegrating agent include cornstarch, starch, methyl cellulose, agar, bentonite, xanthan gum, and alginic acid. As the binding agent, for example, gelatin, natural sugars, beta-lactose, corn sweetener, natural and synthetic rubber, acacia rubber, tragacanth gum, sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax, or the like can be used. As the lubricant, for example, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, table salt, talc, or the like can be used.

[0150] The epithelial cancer treatment drug of the present invention can be mixed with at least one selected from the group consisting of oxyacids, oxyacid ions, and oxyacid salts, as well as the aforementioned free radical generating catalyst and other arbitrary components as needed, and can also be encapsulated in a carrier. The carrier can be, for example, in the form of capsules, sachets, paper, or other containers. The carrier can also function as a diluent, and can be solid, semi-solid, or a liquid that acts as a carrier. Furthermore, the form of the medicine of the present invention is not particularly limited, and can be, for example, tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft / hard gelatin capsules, suppositories, sterile injection solutions, and packaged sterile powders, etc.

[0151] The administration method of the epithelial cancer treatment drug of the present invention is not particularly limited, and it can be administered orally or non-orally depending on its purpose. When administered orally, the form is not particularly limited, and common forms commonly used by those skilled in the art, such as enteric-coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solvents, suspensions, syrups, solid or liquid aerosols, and emulsions, can be selected. Furthermore, when administered non-orally, the form is not particularly limited, and intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, injection, and infusion, can be selected, as well as forms commonly used by those skilled in the art.

[0152] Furthermore, the dosage and dosing interval of the epithelial cancer treatment drug of the present invention are not particularly limited and can be appropriately selected according to its purpose. These can be selected by those skilled in the art by considering various factors including the patient's age, weight, sex, medical condition, disease, route of administration, the patient's metabolic and excretory function level, the dosage form used, and the specific oxyacid, oxyacid ion, or oxyacid salt administered. In the case of local administration, the concentration of the epithelial cancer treatment drug of the present invention per administration can be, for example, 100 ppm (0.1% by mass) or more, 200 ppm or more, 300 ppm or more, 500 ppm or more, 1000 ppm or more, 2500 ppm or more, or 5000 ppm or more, for example, 5000 ppm (3% by mass) or less, 2500 ppm or less, 1000 ppm or less, 500 ppm or less, 300 ppm or less, or 200 ppm or less. For each dosing interval of the epithelial cancer treatment drug of the present invention, in the case of local administration, the interval until the next dosing can be, for example, more than 1 day, more than 2 days, more than 3 days, more than 4 days, more than 5 days, more than 6 days, or more than 7 days, or for example, less than 7 days, less than 6 days, less than 5 days, less than 4 days, less than 3 days, or less than 2 days. For example, for bladder cancer, in order to prevent recurrence, the epithelial cancer treatment drug of the present invention can be administered immediately after transurethral resection and in 4 to 8 weekly doses (dose of 10 to 40 ml, for example, 30 ml).

[0153] The oxyacid, oxyacid ion, or oxyacid salt as the effective ingredient of the epithelial cancer therapeutic drug of the present application has lower toxicity than general epithelial cancer therapeutic drugs. In addition, the toxicity of the oxyacid, oxyacid ion, or oxyacid salt as the effective ingredient of the epithelial cancer therapeutic drug of the present application is well known, and thus it is possible to select a safe amount of administration and an administration interval, etc. for a patient. Therefore, according to the present application, it is possible to provide an epithelial cancer therapeutic drug having very small side effects, for example, compared to a generally used anticancer agent or BCG preparation. In addition, according to the epithelial cancer therapeutic drug of the present application, a strong recurrence inhibitory action (recurrence prevention effect) can be obtained, for example. That is, according to the epithelial cancer therapeutic drug of the present application, the recurrence rate of epithelial cancer can be made extremely low, for example.

[0154] In addition, the epithelial cancer therapeutic drug of the present application can also be used as an apoptosis promoter for epithelial cancer cells, for example. By promoting apoptosis of epithelial cancer cells, it is possible to more effectively inhibit the proliferation of the above-mentioned epithelial cancer cells, for example.

[0155] In addition, according to the present application, it is possible to provide a production method of the epithelial cancer therapeutic drug of the present application using at least one selected from the group consisting of the above-mentioned oxyacid, oxyacid ion, and oxyacid salt. The production method of the epithelial cancer therapeutic drug of the present application is specifically as described above. In the production method of the epithelial cancer therapeutic drug of the present application, the above-mentioned radical generating catalyst can or can not be used, and any component other than the above-mentioned radical generating catalyst can or can not be used, as described above. In addition, according to the present application, it is possible to provide a treatment method for epithelial cancer of the above-mentioned patient, which includes a step of administering the epithelial cancer therapeutic drug of the present application to the patient. In the above-mentioned administration procedure, the administration method, the amount of administration, the administration interval, etc. are not particularly limited, and are as described above, for example.

[0156] The administration target of the epithelial cancer therapeutic drug of the present application or the patient as the treatment target of the present application is a human or a non-human animal other than a human, for example. The above-mentioned non-human animal can be exemplified by a mouse, a rat, a rabbit, a monkey, a dog, a cow, etc.

[0157] [Examples]

[0158] Hereinafter, examples of the present application will be described. However, the present application is not limited to the following examples.

[0159] [Example 1: Bladder cancer therapeutic drug using MA-T]

[0160] The bladder cancer treatment drug (epithelial cancer treatment drug of the present application) was manufactured as described below, and the effect thereof was further confirmed. Note that, hereinafter, an aqueous solution (agent) containing NaCIO2and benzalkonium chloride is sometimes referred to as "MA-T". In MA-T, the concentrations of NaCIO2and benzalkonium chloride are not particularly limited, and, for example, the same mass of NaCIO2and benzalkonium chloride can be used. Hereinafter, for example, an aqueous solution (agent) containing 100 ppm of NaCIO2and 100 ppm of benzalkonium chloride is sometimes referred to as "100 ppm MA-T". MA-T functions as an epithelial cancer treatment drug of the present application because it contains NaCIO2. In addition, hereinafter, the epithelial cancer treatment drug of the present application manufactured using MA-T is sometimes referred to as "MA-T epithelial cancer treatment drug of the present application".

[0161] [(1) Cell culture]

[0162] The bladder cancer cell line UM-UC-3 was obtained from ATCC (American Type Culture Collection), and BOY-12E was obtained from Tohoku University, Japan. UM-UC-2, 5637, and EJ-1 were obtained from Nara Medical University, Japan.

[0163] The UM-UC-3, UM-UC-2, and EJ-1 cells were cultured in D-MEM (Low glucose, trade name of FUJIFILM Wako Pure Chemical Corporation) to which fetal bovine serum (FBS, Biosera) was added to 10% by volume, the 5637 cells were cultured in RPMI-1640 (trade name of FUJIFILM Wako Pure Chemical Corporation), and the BOY-12E cells were cultured in E-MEM (trade name of FUJIFILM Wako Pure Chemical Corporation) to which fetal bovine serum (FBS, Biosera) was added to 10% by volume, respectively, at 37°C in a 5% CO2environment. At the time of subculture, 0.025% trypsin / EDTA was added to the cells, and the cells were incubated at 37°C in a 5% CO2environment, whereby the cells were peeled off, and further centrifuged at 1500 rpm for 3 minutes, and the cells were recovered.

[0164] [(2) Reagent preparation]

[0165] 10000 ppm of NaCIO2 (sodium chlorite) aqueous solution and 10000 ppm of benzalkonium chloride aqueous solution were diluted with 10 x phosphate buffered saline (PBS) and distilled water (DW) to final 1 x PBS as shown in the following table to prepare 1 x PBS aqueous solutions of NaCIO2 and benzalkonium chloride. These aqueous solutions correspond to the epithelial cancer treatment drug of the present application containing MA-T, i.e., "the MA-T epithelial cancer treatment drug of the present application". In addition, in PBS, "10 x" indicates 10-fold concentration, and "1 x" indicates 1-fold concentration. The amounts of each solution required when the total amount of the prepared aqueous solutions is set to 400 μL are shown in Table 1 below.

[0166] [Table 1]

[0167]

[0168] Figure 1 A graph showing the results of concentration and reaction time-dependent analysis of the effect of the mixed aqueous solution of NaCIO2 and benzalkonium chloride on the cell proliferation of UM-UC-3 cells and 5637 cells is shown in FIG. 2. The horizontal axis is time (hr), and the vertical axis is the number of cells expressed by the normalized exponential. The results of analysis based on the microelectronic cell chip technology (xCelligence) are expressed as normalized cell index by normalizing the value immediately after addition. As shown in the figure, even at a low concentration of 25 ppm each of the mixed aqueous solution of NaCIO2 and benzalkonium chloride, inhibition of bladder cancer cell proliferation can be observed, and it can be confirmed that if the concentration of the mixed aqueous solution of NaCIO2 and benzalkonium chloride becomes high, bladder cancer cell proliferation is further inhibited, and at 100 ppm, the proliferation of any cells is completely inhibited

[0169] [(3) Time-lapse photography]

[0170] UM-UC-3 cells were seeded at 1 x 10 4cells / 1000ml / dish into 3 cm dishes, and the next day, after removing the culture medium, 1000 μL / well of a 100 ppm MA-T aqueous solution was added, and incubation was performed for 120 minutes. After removing the MA-T aqueous solution, the usual culture medium was added to all of the wells, and using a BZ-X710 (trade name) of KEYENCE Co., Ltd. that was provided with a microscope incubation system (HITACHI Co., Ltd.), the field was photographed every 10 minutes for 48 hours using a 20-fold lens. The resulting images were subjected to dynamic image processing using software built into the system. In addition, as a control, a sample that was treated in the same manner except that PBS was used instead of the MA-T aqueous solution was subjected to the same photographing and dynamic image processing.

[0171] In Figure 2 and Figure 3 are photographs showing the results of the time-lapse photography. Figure 2 is a photograph taken immediately after the start of the photography (0 hours of culture), Figure 3 is a photograph taken 48 hours after the start of the photography (48 hours of culture). Figure 2 and 3 In "Control" in each of and , the PBS addition group (control) is indicated, and "MA-T" indicates the 100 ppm MA-T (i.e., the MA-T epithelial cancer treatment drug of the present application was added) sample. As shown in the figures, in the PBS addition group (Control), the proliferation of the UM-UC-3 cells was confirmed after 48 hours, and in contrast, the proliferation was inhibited in the UM-UC-3 cells to which the MA-T epithelial cancer treatment drug of the present application was added. That is, it was confirmed that the MA-T epithelial cancer treatment drug of the present application has an effect of inhibiting the proliferation of bladder cancer cells.

[0172] [(4) Apoptosis analysis]

[0173] Each of the cells was inoculated in a 6-well plate. UM-UC-3 cells were inoculated at 5 x 10 4 cells / well, and 5637 cells were inoculated at 8 x 10 4Cell / cone seeding. The next day, the culture medium was removed, and 100 ppm MA-T aqueous solution was added. Then, after incubation at 37°C in a 5% CO2 environment (12 hours for UM-UC-3 cells and 6 hours for 5637 cells), the cells including the supernatant were recovered, centrifuged at 3000 rpm for 5 minutes, and cell pellets were obtained. After the cell pellets were washed twice with 1 x PBS, 294 μL of 1 x binding buffer of the Annexin V-FITC Apoptosis Detection Kit (trade name of Bio Vision Inc.), 3 μL of propidium iodide, and 3 μL of Annexin were added to suspend the pellets. The suspension was passed through a 37 μm nylon mesh (NBC mesh tech Co.) and transferred to a round bottom flask tube (Falcon Co.). Then, each stained cell population was analyzed by FACS Calibur (trade name of Becton Dickinson Co.). To adjust the voltage of FACS, each single staining sample of propidium iodide and Annexin V was prepared. Note that, as a control, a sample treated in the same manner except that PBS was used was used, and apoptosis analysis was performed in the same manner.

[0174] Figure 4 Apoptosis analysis of 5637 cells is shown in the graph. In the graph, "Control" indicates a PBS sample (control), and "MA-T" indicates a 100 ppm MA-T sample (i.e., a sample to which the epithelial cancer treatment drug of the present application was added). As shown in the graph, in the PBS sample (control), the apoptosis rate of 5637 cells was 8.5%, and, in contrast, in the MA-T in which the epithelial cancer treatment drug of the present application was added, the apoptosis rate of 5637 cells was 30.2%. That is, it was confirmed that the epithelial cancer treatment drug of the present application has an effect of promoting apoptosis of epithelial cancer cells.

[0175] [(5) Anti-tumor effect of MA-T using a luciferase-expressing bladder cancer cell syngeneic transplantation model]

[0176] Evaluation was performed using a luciferase-expressing bladder cancer cell mouse syngeneic transplantation model, which is a uniquely developed technique. Specifically, luciferase-expressing human bladder cancer cells UM-UC-3 were prepared, and, on the tenth day after transplantation into mice, a luciferase substrate was administered, and in vivo imaging of luciferase activity was performed (before administration). Then, 50 μl of MA-T was administered intravesically, and, 2 days later, imaging was performed again. As a result, as described below, a significant decrease in luciferase activity was observed by MA-T administration.

[0177] [(5-1) Construction of a bladder cancer cell syngeneic transplantation model]

[0178] After linearizing the pGL4.51 [luc2 / CMV / Neo] vector (Promega) with Pstl (NEB), the pGL4.51 linearized vector was purified using the Wizard SV Gel and PCR Clean-Up System. The pGL4.51 linearized vector was transfected into UM-UC-3 cells by the forward method using Lipofectamine 3000, and selection was performed using 3000 μg / mL G-418 (trade name of Wako Pure Chemical Industries, Ltd.), whereby luciferase-expressing human bladder cancer cells UM-UC-3 Fluc were produced. Using this cell, a bladder cancer cell orthotopic transplantation model was constructed according to the following procedure.

[0179] (1) After 6- to 7-week-old female BALB / c Slc-nu / nu were kept in a supine position under isoflurane anesthesia, a 24G3 / 4 needle-removed venous indwelling F&F (trade name of Terumo Corporation) was used to discharge urine into the bladder through a catheter from the urethral orifice.

[0180] (2) 100 μL of 0.2% trypsin (Life technologies) / 0.05% EDTA (DOJINDO) was injected into the bladder. With the catheter inserted, the urethral orifice was stopped with a disposable clamp (Nakamura Seisakusho, AM-130g), and the catheter was slowly pulled out.

[0181] (3) After 5 minutes from the trypsin / EDTA injection, the supine position was changed to a prone position, and the abdomen was ground to discharge the trypsin / EDTA.

[0182] (4) 100 μL of PBS was injected into the bladder, and the in-and-out of PBS was repeated 2 to 3 times to wash the bladder.

[0183] (5) UM-UC-3 Fluc cells (5.0 x 10 6 cells / mouse) were suspended in 50 μL of serum-free DMEM medium and injected into the bladder. Then, the urethral orifice was fixed with a clean cloth in a manner that the cells did not leak out, and the catheter was removed.

[0184] (6) The mouse was placed in an anesthesia box (Shinano Seisakusho) and left for 2 hours.

[0185] (7) After 2 hours from the cell injection, the clamp was removed, and after confirming the state of the mouse, the mouse was returned to the original cage.

[0186] In vivo imaging of the UM-UC-3 Fluc cell orthotopically transplanted mouse was performed according to the following procedure.

[0187] (1) As a substrate for luciferase, 4 mg of VivoGlo In Vivo Imaging Substrates (trade name of Promega) was dissolved in 200 μL of PBS. 200 μL of the prepared solution was intraperitoneally administered. After the administration, the mouse was left in the cage for 3 minutes and then placed under anesthesia for 3 minutes. Then, using an imaging device NightOWL (trade name of BERTHOLD TECHNOLOGIES), imaging was performed with binning 1 x 1 for 60 seconds of exposure time.

[0188] (2) The luminescence of luciferase on the tenth day and the twenty-fourth day after the transplantation was measured, and the ratio thereof was expressed as a luminescence ratio in fold.

[0189] Further, as described above, MA-T administration was performed after in vivo imaging. Specifically, after the luciferase activity was measured 10 days after the UM-UC-3 Fluc transplantation, 100 ppm of MA-T was introduced into the bladder in 50 μl. After the administration, the mouse was left to move in the cage for 3 minutes and then placed under anesthesia for 3 minutes. Two days later, in vivo imaging was performed again using the imaging device NightOWL (trade name of BERTHOLD TECHNOLOGIES), with binning 1 x 1 for 60 seconds of exposure time.

[0190] Figure 5 The results of in vivo imaging before the MA-T administration and 2 days after the administration are shown in the photographs. In the figure, "MA-T107" indicates a mouse to which MA-T was administered, and "Control" indicates a mouse for which in vivo imaging was similarly performed except that 50 μl of PBS was administered into the bladder instead of MA-T. As shown in the figure, in the mouse to which MA-T was not administered, a decrease in luminescence, that is, a reduction in the tumor was hardly observed, but in the mouse to which MA-T was administered, the reduction in the tumor was remarkable.

[0191] [(5-2) Changes in the body weight of a mouse to which MA-T was administered into the bladder and analysis of pathological tissues of the bladder]

[0192] A mouse for which a bladder syngeneic transplantation model was similarly constructed as in the above "(5-1) Construction of a bladder syngeneic transplantation model" was administered with 100 ppm of MA-T or PBS as a control into the bladder in 50 μl twice a week for 2 weeks. After the administration, the changes in the body weight of the above mouse were measured until 10 days later. In Figure 6 The results are shown in the graph. The horizontal axis is days, and the vertical axis is the body weight of the mouse (change in body weight ratio) with the body weight of the mouse at the start of the measurement (0 days) set to 1. "MA-T107" is a mouse to which MA-T was administered, and "PBS" is a mouse to which PBS as a control was administered. As shown in the figure, no significant decrease in the body weight was confirmed by the MA-T administration.

[0193] Further, on the tenth day after the end of administration, the bladders of the mice were removed, and the pathological tissues were analyzed. Figure 7 The results thereof are shown in the microphotographs. Figure 7 The upper row shows the overall image of the bladder, and the lower row shows the enlarged image. As shown in the figure, no abnormalities in the pathological histology were observed in the PBS administration group and the MA-T administration group.

[0194] [(6) Tumor tissue pathological analysis]

[0195] The bladders of the UM-UC-3 Fluc-transplanted mice of the twenty-fourth day described in the above "(5) Anti-tumor effect of MA-T using a syngeneic transplantation model of bladder cancer cells expressing luciferase" were removed, fixed with 10% neutral buffered formalin, paraffin blocks of the tumor tissues were prepared, and hematoxylin-eosin (HE) staining was performed.

[0196] Figure 8 The ratios of the luciferase luminescence values of the bladder tumors measured on the tenth day and the twenty-fourth day after transplantation and the weights of the bladders measured after dissection on the twenty-fourth day are shown in the graph. In the graph, "Control" indicates the PBS sample (control), and "MA-T" indicates the administration group of the 100 ppm MA-T (i.e., the epithelial cancer treatment drug of the present application) sample. In addition, Figure 8 The photograph on the right is a photograph taken after HE staining. As Figure 8 shown, in the MA-T of the present application, it was confirmed that the proliferation of bladder cancer cells was inhibited, and the bladder tumor was histologically damaged, as compared with the PBS sample (control).

[0197] [(7) Evaluation of MA-T anti-tumor effect using patient-derived xenograft (PDX) mice of bladder cancer]

[0198] A mouse model in which a tumor from a clinical specimen of bladder cancer was passage-transplanted was used. Three months ago, tumors were removed from SHO hairless SCID mice (male, 4 weeks old at the time of tumor transplantation) in which passage 8 tumors were transplanted. The removed tumors were cut into pieces of about 5 mm square, and each tumor tissue piece was immersed in a 100 ppm MA-T aqueous solution and a 1x PBS solution as a control for 120 minutes. Then, the tumors were transplanted subcutaneously into SHO hairless SCID mice (male, 4 weeks old) (PBS immersion group: n = 10, MA-T immersion group: n = 10), and the tumor diameters (long diameter and short diameter) were measured every 3 days from the day of transplantation. The tumor volume was calculated by the following mathematical formula (A). The tumors were removed on the thirty-second day after transplantation, and the weights of the respective tumors were measured. Statistical processing was performed by student t-test.

[0199] Tumor volume = (long diameter x short diameter2) / 2 (A)

[0200] [(7-1) Tumor tissue pathological analysis]

[0201] The tumor tissue excised from the PDX mouse of the above-mentioned "(7) Evaluation of the antitumor effect of MA-T aqueous solution using patient-derived xenograft (PDX) mouse of bladder cancer" was fixed with 10% neutral buffered formalin, paraffin blocks of the tumor tissue were prepared, and HE staining was performed.

[0202] Figure 9 The left graph shows the relationship between the days after tumor transplantation and the tumor volume. The horizontal axis is the days after transplantation (days), and the vertical axis is the tumor volume (mm 3 ). In addition, Figure 9 The right graph shows the weight (mg) of the tumor excised at the thirty-second day after transplantation, in which Figure 9 "Control" indicates the PBS sample (control), and "MA-T" indicates the 100 ppm MA-T (i.e., the MA-T epithelial cancer therapeutic drug of the present application was added) sample. As Figure 9 shown, it was confirmed that the proliferation of the bladder cancer tumor was inhibited in the group treated with the MA-T epithelial cancer therapeutic drug of the present application compared to the PBS sample (control).

[0203] Further, as Figure 10 shown, the results of HE staining of the tumor excised at the thirty-second day, in the MA-T aqueous solution-treated group, the tumor necrosis image was confirmed histologically.

[0204] [Example 2: Bladder cancer therapeutic drug containing sodium chlorite (NaClO2)]

[0205] As described below, a bladder cancer therapeutic drug containing NaClO2 (the epithelial cancer therapeutic drug of the present application) was manufactured, and its effect was further confirmed. Note that hereinafter, the epithelial cancer therapeutic drug of the present application containing NaClO2 will be referred to as "the NaClO2 epithelial cancer therapeutic drug of the present application" or simply "the NaClO2 epithelial cancer therapeutic drug".

[0206] [(1) Cell culture]

[0207] The bladder cancer cell line UM-UC-3, the colon cancer cell lines HT-29 and HCT116 were obtained from ATCC (American Type Culture Collection) and used as they were, and BOY-12E was obtained from Tohoku University in Japan and used as it was. UM-UC-2, 5637, and EJ-1 were obtained from Nara Medical University in Japan and used as they were.

[0208] UM-UC-3 cells, UM-UC-2 cells, EJ-1 cells, 5637 cells, and BOY-12E cells were used as they were, having been cultured by the method described in "(1) Cell culture" in Example 1 above. HeLa cells, HeLaS3 cells, HSC-3 cells were cultured using E-MEM (Fuji Photo Film and Dainippon Pharmaceutical Co., Ltd.), and HO-1-u-1 cells were cultured using DMEM / F12 medium (1:1 mix) (Fuji Photo Film and Dainippon Pharmaceutical Co., Ltd.). HT-29 cells and HCT116 cells were cultured in McCoy's 5a medium (Dainippon Pharmaceutical Co., Ltd.) to which fetal bovine serum (FBS, Biosera) had been added so as to be 10% by volume, respectively, at 37°C in a 5% CO2 environment. At the time of subculture, 0.025% trypsin / EDTA (ethylenediaminetetraacetic acid) was added to the cells, which were incubated at 37°C in a 5% CO2 environment, whereby the cells were peeled off and further centrifuged at 1500 rpm for 3 minutes, and the cells were recovered.

[0209] [(2) Reagent preparation]

[0210] A 10000 ppm NaClO2 (sodium chlorite) aqueous solution (Lot. No. 170612C) was diluted with 10 x phosphate buffered saline (PBS) and distilled water (DW) as shown in the table below so as to be 1 x PBS in the final concentration, to prepare a 1 x PBS aqueous solution of NaClO2. These aqueous solutions correspond to the epithelial cancer treatment drug of the present application, i.e., "the NaClO2 epithelial cancer treatment drug of the present application" containing NaClO2. In addition, in PBS, "10 x" indicates a 10-fold concentration, and "1 x" indicates a 1-fold concentration. The amounts of each solution required when the total amount of the prepared NaClO2 aqueous solution is 400 μL are shown in Table 1 below.

[0211] [Table 2]

[0212]

[0213] [(3) WST-8 analysis]

[0214] The WST-8 analysis was performed as follows.

[0215] [Study of reaction time and concentration of NaCIO2 aqueous solution]

[0216] Each cell was inoculated in a 96-well plate. At this time, each of UM-UC-3, UM-UC-2, EJ-1, and BOY-12E cells was inoculated at 1200 cells / well, and 5637 cells were inoculated at 1500 cells / well. The next day, the medium was removed from all wells, and 500 ppm (reaction time study) and each concentration of NaCIO2 aqueous solution was added to 100 μL / well in triplicate wells. After incubating the plate at 37°C in a 5% CO2 environment for 30, 60, 90, 120 minutes (considering the tolerable time of urination caused by intravesical instillation in a clinical test, the longest time was set to 120 minutes) and 120 minutes (concentration study), the solution in each well was removed. Then, 90 μL of the usual medium was added to each of all wells, and further cultured for 48 hours. Then, 10 μL of Cell Counting Kit-8 (trade name of DOJINDO) was added to each well, incubated at 37°C in a 5% CO2 environment for 2 hours, and the absorbance at 450 nm and the control at 630 nm was measured using an iMark microplate reader (trade name of BIORAD).

[0217] Figure 11 The graph of FIG. 8 shows the cell proliferation ratio when 500 ppm NaCIO2 aqueous solution was contacted with UM-UC-3 cells for each time (left graph) and the concentration dependence of NaCIO2 aqueous solution on cell proliferation of each bladder cancer cell (right graph). The horizontal axis is time (min) in the left graph and concentration (ppm) in the right graph. The vertical axis is the cell proliferation ratio expressed as a normalized index. As shown in the figure, by incubating 500 ppm NaCIO2 aqueous solution with UM-UC-3 cells, cell proliferation was inhibited in a time-dependent manner, and by incubating for 120 minutes, more than 60% of the proliferation was observed to be inhibited. In addition, when NaCIO2 aqueous solution was cultured for 120 minutes with respect to various bladder cancer cells, concentration-dependent proliferation inhibition was observed, and at 500 ppm or more, it was confirmed that the proliferation of bladder cancer was almost completely inhibited.

[0218] Figure 12The photographs show the cells incubated with PBS or NaClO2 for 120 minutes and then removed immediately (0 hours) or cultured for 24 hours (24 hours). In the NaClO2 group (upper right photograph), morphological changes in the cells have been observed after incubation with NaClO2 for 120 minutes (0 hours after removal of NaClO2), compared with the control group (upper left photograph). Further, after incubation with NaClO2 for 120 minutes, 24 hours after removal thereof, cell retraction (lower central photograph) and formation of vesicles considered to be apoptotic vesicles through enlargement of a part thereof (lower right photograph) have been confirmed. "Control" indicates a PBS addition group sample (control) without addition of NaClO2, and NaClO2 indicates a sample to which 500 ppm of NaClO2 (i.e., the NaClO2 epithelioma therapeutic agent of the present application) has been added.

[0219] [(4) Apoptosis analysis]

[0220] In a 6-well plate, 5 x 10 4 UM-UC-3 cells were seeded at 5 x 10 After removal of the NaClO2 aqueous solution, 1 x binding buffer 294 μL, propidium iodide 3 μL, and annexin V 3 μL of the annexin V-FITC apoptosis detection kit (trade name of Bio Vision Inc.) were added to the cells, and the cells were suspended. The suspension was passed through a 37 μm nylon mesh (NBC mesh tech) and transferred to a round bottom flask tube (Falcon). Then, the population of each stained cell was analyzed by FACSCalibur (trade name of Becton Dickinson). To adjust the voltage of FACS, single staining samples of propidium iodide and annexin V were prepared. Note that, as a control (Control), a sample treated in the same manner except that NaClO2 aqueous solution was replaced with PBS not containing NaClO2 was used, and apoptosis analysis was performed in the same manner.

[0221] Figure 13Apoptosis analysis of UM-UC-3 cells. In this figure, "Control" indicates a PBS sample to which NaClO2 was not added (control), and "NaClO2" indicates a sample to which 500 ppm of NaClO2 (i.e., the NaClO2 epithelioma treatment drug of the present application was added) was added. As shown in the figure, the apoptosis rate of UM-UC-3 cells in the PBS sample to which NaClO2 was not added (control) was 14.6%, whereas the apoptosis rate of UM-UC-3 cells in 500 ppm of NaClO2 to which the epithelioma treatment drug of the present application was added was 43.8%. That is, it was confirmed that the NaClO2 epithelioma treatment drug of the present application had a significant effect of inducing apoptosis of bladder cancer cells.

[0222] [(5) Cell cycle analysis]

[0223] For UM-UC-3 cells, the operation until the cell pellet was obtained was performed in the same manner as in the above "(4) Apoptosis analysis". In the obtained cell pellet, 1 drop of 70% ethanol aqueous solution 700 μL was added, and it was stored overnight at -20°C. After centrifugation at 3000 rpm for 5 minutes at 4°C, the supernatant was removed, and it was washed twice with 1 x PBS. Further, 10 mg / mL of RNase (trade name of FUJIFILM and Otsuka Pharmaceutical Co., Ltd.) 10 μL, 1 x PBS 50 μL were added, and it was incubated at room temperature for 30 minutes. Then, it was suspended in FACS buffer (3% FCS in 1 x PBS) 500 μL to which 0.5 mg / mL of PI (Propidium iodide, SIGMA Aldrich Co.) solution 50 μL was added. After passing the suspension through a 37 μm nylon mesh, it was measured using FACSCalibur (trade name of Becton Dickinson Co.). Note that, as a control (Control), a sample that was treated in the same manner except that PBS not containing NaClO2 was used instead of the NaClO2 aqueous solution was used, and cell cycle analysis was performed in the same manner.

[0224] Figure 14This figure shows the cell cycle analysis results of UM-UC-3 cells cultured for 24 hours (overnight) after the removal of the NaClO2 aqueous solution. In this figure, "Control" represents the PBS sample without NaClO2 (control), and "NaClO2" represents the sample with 500 ppm NaClO2 (i.e., the NaClO2 epithelial cancer therapeutic agent of the present invention). As shown in the figure, in the group with the NaClO2 epithelial cancer therapeutic agent of the present invention, compared with the PBS group (control), the subG1 phase fraction of apoptotic cells was significantly increased. That is, it is confirmed that the NaClO2 epithelial cancer therapeutic agent of the present invention induces apoptosis and death of bladder cancer cells.

[0225] [(6) Evaluation of the antitumor effect of NaClO2 on bladder cancer treatment in patient-derived xenograft (PDX) mice]

[0226] The mouse tumor model, which was derived from a clinical bladder cancer specimen, was operated in the same manner as in Example 1 above [(7) Evaluation of the antitumor effect of MA-T in patient-derived xenograft (PDX) mice], except that 500 ppm NaClO2 aqueous solution was used instead of 100 ppm MA-T aqueous solution. The SHO hairless SCID mice (male, 4 weeks old) used were n=8 in both the PBS-immersed group and the NaClO2-immersed group. Tumor diameters (long and short axes) were measured every 3 days starting from day 12 of transplantation. Additionally, the weight of the removed tumor was measured after photographing it on day 27.

[0227] exist Figure 15 In the chart at the bottom left, the horizontal axis represents the number of days from 12 days after tumor transplantation, and the vertical axis represents the tumor volume (mm). 3 ).in addition, Figure 15 The top photo shows the tumor removed during an autopsy on the 27th day after transplantation, and the bottom right photo shows the weight (mg) of the removed tumor. Figure 15 In this context, "Control" refers to the PBS sample (control), and "NaClO2" indicates the tumor transplantation result after immersion in 500 ppm NaClO2 (i.e., the NaClO2 epithelial carcinoma treatment drug of the present invention). Figure 15 As shown, in the group immersed in the NaClO2 anti-epithelial carcinoma drug of the present invention, significant inhibition of bladder cancer tumor proliferation was confirmed compared with the PBS group (control). Furthermore, based on the analysis of photographs of the removed tumors and tumor weight, it was also confirmed that the increase of bladder tumors was inhibited.

[0228] [(7) Verification of free radical generation]

[0229] The radical generation of an aqueous NaCIO2 solution, an aqueous benzethonium chloride solution (a radical generation catalyst), and MA-T was verified. UM-UC-3 cells were seeded at 5000 cells / well in a 96-well plate. The next day, the medium was removed, and 50 μL / well of CellROX (a trade name of Thermo Fisher Corporation) diluted with Hank's Balanced Salt Solution (HBSS) was added as a quantitative reagent for the detection of reactive oxygen species in living cells at a concentration of 20 μM, and incubated at 37°C for 1 hour. Then, 50 μL / well of an aqueous NaCIO2 solution (A), an aqueous benzethonium chloride solution (B), and MA-T diluted with HBSS were added, and the fluorescence intensity was measured over time using a fluorescent plate reader GloMAX (a trade name of Promega Corporation). In addition, the fluorescence of reactive oxygen species in UM-UC-3 cells to which an aqueous NaCIO2 solution was added at a final concentration of 500 ppm was detected using a BioZero fluorescent microscope (a trade name of KEYENCE) with an excitation filter (Red 627 nm) and an emission filter (660-720 nm).

[0230] In the left graph of FIG. 8, Figure 16 In the left graph of FIG. 8, the vertical axis indicates the sample to which the fluorescence intensity was added on the horizontal axis. In NaCIO2 (A) and benzethonium chloride (B) alone, which have no radical generation ability, NaCIO2 (A) was confirmed to generate time-dependent reactive oxygen species by contact with cells. In addition, it was found that 100 ppm NaCIO2 (A100) detected reactive oxygen species equal to or more than MA-T (a mixture of 100 ppm NaCIO2 and 100 ppm benzethonium chloride), and 500 ppm NaCIO2 alone was confirmed to significantly generate reactive oxygen species on bladder cancer cells. It is considered that this indicates that the reactive oxygen species other than MA-T are generated by contact of NaCIO2 with bladder cancer cells. In addition, Figure 16 In the right photograph, the images of the cells obtained using the BioZero fluorescent microscope are shown. The upper panel is an image of a control to which no NaCIO2 and benzethonium chloride were added, and the lower panel is an image to which an aqueous NaCIO2 solution was added at a final concentration of 500 ppm. As shown in the figure, 500 ppm NaCIO2 alone was confirmed to show fluorescence indicating significant generation of reactive oxygen species in bladder cancer cells.

[0231] [(8) Effects of NaCIO2 on tongue cancer cells, oral cancer cells, uterine cancer cells, cervical cancer cells, and large intestine cancer cells]

[0232] As described below, the effect of the NaCIO2 epithelial cancer therapeutic drug of the present application as a therapeutic drug for epithelial cancer cells other than bladder cancer cells was confirmed.

[0233] In addition to the incubation time being set to 60 minutes (1 hour) instead of 120 minutes, taking into account the allowable time for the subject cancer patient, and the bladder cancer cells being changed to tongue cancer cells "HSC-3", oral cancer cells "HO-1-u-1", uterine cancer cells "HeLa", uterine cancer cells "HeLaS3", large intestine cancer cells "HT29", or large intestine cancer cells "HT116", the cancer cell proliferation analysis was performed in the same manner as in the above "(3) WST-8 analysis" by culturing each cancer cell for 48 hours. Figure 17 、 Figure 18 and Figure 19 The graphs of FIGS. 1 Figure 17 、 Figure 18 and Figure 19 In the graphs of FIGS. 1

[0234] As shown in FIGS. 1 Figure 17 、 Figure 18 and Figure 19 It was confirmed that the NaClO2epithelial cancer cell treatment drug of the present application also showed an inhibitory effect on the proliferation of cancer cells for tongue cancer cells, oral cancer cells, uterine cancer cells, cervical cancer cells, and large intestine cancer cells.

[0235] [(9) Confirmation of the effect of the radical generation catalyst]

[0236] In addition to adding benzethonium chloride (radical generation catalyst) to the NaClO2aqueous solution, the cancer cell proliferation analysis was performed in the same manner as in the above "(8) Effect of NaClO2on tongue cancer, oral cancer, uterine cancer cells, cervical cancer cells, and large intestine cancer cells" by culturing each of the uterine cancer cells "HeLa" and the uterine cancer cells "HeLaS3" for 48 hours. The same measurement was performed with the concentration of benzethonium chloride in the NaClO2aqueous solution being changed to 5 ppm, 10 ppm, 15 ppm, and 20 ppm.

[0237] The results are shown in the graphs of FIGS. 1 Figure 20 and Figure 21 In the graphs of FIGS. 1 Figure 20 and Figure 21 In the graphs of FIGS. 1 Figure 20 and Figure 21 In the graphs of FIGS. 1 Figure 20 and Figure 21In the above, "Control" indicates the result when benzethonium chloride was not added, i.e., the result of the above "(9) Effects of NaCIO2 on tongue cancer, oral cancer, uterine cancer cells, cervical cancer cells, and large intestine cancer cells". As shown in Figure 20 and Figure 18 As shown in the above, even if only NaCIO2 is used, the inhibitory effect on cancer cell proliferation is observed, but by adding benzethonium chloride (a radical generation catalyst), the additive effect of the inhibitory effect on cancer cell proliferation can be confirmed.

[0238] [Example 3: Pancreatic cancer treatment drug containing sodium chlorite (NaCIO2)]

[0239] As described below, a pancreatic cancer treatment drug (epithelial cancer treatment drug of the present application) containing NaCIO2 was manufactured, and the effect thereof was further confirmed. Note that the pancreatic cancer treatment drug of the present application corresponds to the epithelial cancer treatment drug of the present application containing NaCIO2, i.e., "NaCIO2 epithelial cancer treatment drug of the present application" or simply "NaCIO2 epithelial cancer treatment drug".

[0240] As described below, the effects of an aqueous NaCIO2 solution (NaCIO2 epithelial cancer treatment drug of the present application) on pancreatic cancer primary culture cells were analyzed.

[0241] [(1) Cell culture]

[0242] Primary culture cells PK05 and PK10 established in the Department of Pharmaceutical Sciences, Osaka University were used from pancreatic cancer clinical samples. These cells were cultured in a medium in which FBS (Biosera) was added to RPMI-1640 (trade name of Fuji Photo Film and Light Pure Chemical Corporation) to be 10% by volume, at 37°C in a 5% CO2 environment. At the time of passage, 0.025% trypsin / EDTA (ethylenediaminetetraacetic acid) was added to the cells, and the cells were incubated at 37°C in a 5% CO2 environment, whereby the cells were peeled off, and further centrifuged at 1500 rpm for 3 minutes, and the cells were recovered.

[0243] [(2) Reagent preparation]

[0244] In the same manner as "(2) Reagent Preparation" of Example 2 "Bladder cancer treatment agent containing sodium chlorite (NaClO2)", 10000 ppm of an aqueous solution of NaClO2 (sodium chlorite) (Lot. No. 170612C), 10x phosphate buffered saline (PBS), and distilled water (DW) were mixed to become 1x PBS, and NaClO2 was made to be a prescribed concentration. In this way, 1x PBS aqueous solutions containing NaClO2 at concentrations of 0 ppm, 2 ppm, 4 ppm, 8 ppm, 16 ppm, 31 ppm, 63 ppm, 125 ppm, 250 ppm, or 500 ppm were prepared, respectively. These aqueous solutions were the same as the aqueous solutions prepared in "(2) Reagent Preparation" of Example 2 "Bladder cancer treatment agent containing sodium chlorite (NaClO2)" except for the concentration of NaClO2. These aqueous solutions correspond to the epithelial cancer treatment agent of the present application containing NaClO2, that is, "NaClO2 epithelial cancer treatment agent of the present application". In addition, in PBS, "10x" indicates a 10-fold concentration, and "1x" indicates a 1-fold concentration.

[0245] [(3) Cell viability evaluation]

[0246] Each of the cells of PK05 or PK10 cultured in "(1) Cell culture" was seeded at 5000 cells / well in a 96-well plate. The next day, the medium was removed from all wells, and each concentration of the aqueous solution of NaClO2 prepared in "(2) Reagent Preparation" was added to 3 (three acrylate) wells at 100 μL / well. The plate was cultured at 37°C in a 5% CO2 environment for 48 hours. Then, 10 μL of Cell Counting Kit-8 (trade name of DOJINDO) was added per well, and the plate was incubated at 37°C in a 5% CO2 environment for 2 hours. The absorbance at a wavelength of 450 nm and the reference wavelength of 630 nm was measured using an iMark microplate reader (trade name of BIORAD). The results are shown in the graph of FIG. 6. In FIG. 6, "A agent" indicates NaClO2. In FIG. 6, the horizontal axis is the concentration (ppm) of the aqueous solution of NaClO2, and the vertical axis is the survival rate (%) of the cancer cells. Note that in the vertical axis, the survival rate (%) of the cancer cells is taken as 100% for the cells in the well to which an aqueous solution of 1x PBS (Control) to which NaClO2 was not added (i.e., not containing sodium chlorite) was added. As is clear from FIG. 6, the survival rate (%) of the cancer cells decreased as the concentration of NaClO2 increased. In other words, the higher the concentration of NaClO2, the lower the survival rate of the cancer cells. In addition, the survival rate (%) of the cancer cells was lower in the case of PK10 than in the case of PK05. This is because the cancer cells of PK10 are more resistant to the cytotoxicity of NaClO2 than the cancer cells of PK05. Figure 22 Figure 22 Figure 22 Figure 22 ​​​As shown, for any of the pancreatic cancer cells in PK05 and PK10, a NaCIO2 concentration-dependent proliferation inhibitory effect was confirmed. That is, each concentration of the NaCIO2 aqueous solution prepared in "(2) Reagent Preparation" was confirmed to function as a pancreatic cancer treatment drug (i.e., an epithelial cancer treatment drug). In addition, in incubation with a NaCIO2 aqueous solution of 31 ppm or more, it was confirmed that the proliferation of the pancreatic cancer cells was almost completely inhibited.

[0247] <Notes>

[0248] Part or all of the embodiments and examples of the present application can be described as the following notes. However, the present application is not limited to the following notes.

[0249] (Note 1)

[0250] An epithelial cancer treatment drug characterized by containing at least one selected from the group consisting of an oxoacid, an oxoacid ion, and an oxoacid salt, for treating or preventing an epithelial cancer.

[0251] (Note 2)

[0252] The epithelial cancer treatment drug according to Note 1, wherein the epithelial cancer is a cancer of at least one tissue selected from the group consisting of the urinary system, the reproductive system, the digestive system, the circulatory system, and the respiratory system.

[0253] (Note 3)

[0254] The epithelial cancer treatment drug according to Note 1 or 2, wherein the epithelial cancer is a cancer of at least one tissue selected from the group consisting of bladder cancer, uterine cancer, cervical cancer, ovarian cancer, fallopian tube cancer, testicular cancer, prostate cancer, large intestinal cancer, small intestinal cancer, duodenal cancer, gastric cancer, esophageal cancer, laryngeal cancer, oral cancer, tongue cancer, pharyngeal cancer, liver cancer, pancreatic cancer, gallbladder cancer, spleen cancer, peritoneal cancer, lung cancer, and eye cancer.

[0255] (Note 4)

[0256] The epithelial cancer treatment drug according to any one of Notes 1 to 3, wherein the oxoacid is a halogen oxoacid.

[0257] (Note 5)

[0258] The epithelial cancer treatment drug according to Note 4, wherein the halogen oxoacid is at least one selected from the group consisting of a chlorine oxoacid, a bromine oxoacid, and an iodine oxoacid.

[0259] (Note 6)

[0260] The epithelial cancer treatment drug according to Note 4 or 5, wherein the halogen oxoacid is at least one selected from the group consisting of a hypohalous acid, a halous acid, a halic acid, and a perhalic acid.

[0261] (Paragraph 7)

[0262] The epithelial cancer therapeutic agent according to Paragraph 4 or 5, wherein the halogen oxyacid is at least one selected from the group consisting of hypochlorous acid, chlorous acid, chloric acid, perchloric acid, hypobromous acid, bromous acid, bromic acid, perbromic acid, hypoiodous acid, iodous acid, iodic acid, and periodic acid.

[0263] (Paragraph 8)

[0264] The epithelial cancer therapeutic agent according to any one of Paragraphs 1 to 7, further comprising a radical generation catalyst that catalyzes generation of radicals from at least one selected from the group consisting of the oxyacid, oxyacid ion, and oxyacid salt contained in the epithelial cancer therapeutic agent.

[0265] (Paragraph 9)

[0266] The epithelial cancer therapeutic agent according to Paragraph 8, wherein the radical generation catalyst comprises at least one selected from the group consisting of ammonium, amino acid, protein, peptide, phospholipid, and salts thereof.

[0267] (Paragraph 10)

[0268] The epithelial cancer therapeutic agent according to Paragraph 9, wherein the ammonium is an ammonium salt represented by the following formula (XI),

[0269] [XI]

[0270]

[0271] In the above formula (XI),

[0272] R 11 , R 21 , R 31 , and R 41 are each a hydrogen atom or an aromatic ring, or an alkyl group, and the above alkyl group can contain an ether bond, a carbonyl group, an ester bond, or an amide bond, or an aromatic ring, R 11 , R 21 , R 31 , and R 41 may be the same or different, or

[0273] R 11 , R 21 , R 31 , and R 41 two or more of which can be integrated to form a cyclic structure together with the N + to which they are bonded, and the above cyclic structure can be saturated or unsaturated, and can be an aromatic ring or a non-aromatic ring, and can have one or more substituents,

[0274] X - is an anion.

[0275] (Note 11)

[0276] The epithelial cancer treatment drug according to Note 10, wherein the ammonium salt represented by Chemical Formula (XI) is an ammonium salt represented by the following Chemical Formula (XII),

[0277] [Chemical Formula XII]

[0278]

[0279] in the above Chemical Formula (XII),

[0280] R 111 is an alkyl group having 5 to 40 carbon atoms, and can contain an ether bond, a ketone carbonyl group, an ester bond, or an amide bond, a substituent, or an aromatic ring,

[0281] R 21 and X - are the same as described above.

[0282] (Note 12)

[0283] The epithelial cancer treatment drug according to any one of Notes 9 to 11, wherein the ammonium is at least one selected from the group consisting of benzethonium chloride, benzalkonium chloride, cetyltrimethylammonium chloride, tetramethylammonium chloride, ammonium chloride, methylammonium chloride, tetrabutylammonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, dequalinium chloride, ephedrine, didecyldimethylammonium chloride, benzyltriethylammonium chloride, oxitropium, carbachol, glycopyrronium, safflower, choline esilate, tetraethylammonium bromide, cetyltrimethylammonium bromide, succinylcholine, sphingomyelin, GM1 ganglioside, denatonium, trigonelline, neostigmine, paraquat, pyridostigmine, phellodendrine, pralidoxime iodide, betaine, betanoside, uracil, betalain, lecithin, adenine, guanine, cytosine, thymine, uracil, and choline.

[0284] (Note 13)

[0285] The epithelial cancer treatment drug according to Note 10, wherein the ammonium salt represented by Chemical Formula (XI) is an ammonium salt represented by the following Chemical Formula (XIV),

[0286] [Chemical Formula XIV]

[0287]

[0288] in the above Chemical Formula (XIV),

[0289] R 100may form a ring structure, the above-mentioned ring structure can be saturated or unsaturated, can be an aromatic ring or a non-aromatic ring, can have one or more substituents or can not have a substituent, R 11 and X - is the same as the above chemical formula (XI).

[0290] (Paragraph 14)

[0291] The epithelial cancer therapeutic agent according to any one of paragraphs 8 to 13, wherein the Lewis acidity of the radical generation catalyst is 0.4 eV or more.

[0292] (Paragraph 15)

[0293] The epithelial cancer therapeutic agent according to any one of paragraphs 1 to 14, which is an apoptosis promoter for epithelial cancer cells.

[0294] (Paragraph 16)

[0295] A pharmaceutical composition characterized by containing at least one selected from the group consisting of an oxoacid, an oxoacid ion, and an oxoacid salt, for treating or preventing an epithelial cancer.

[0296] (Paragraph 17)

[0297] The pharmaceutical composition according to paragraph 16, wherein the epithelial cancer is a cancer of at least one tissue selected from the group consisting of a urinary system, a reproductive system, a digestive system, a circulatory system, and a respiratory system.

[0298] (Paragraph 18)

[0299] The pharmaceutical composition according to paragraph 16 or 17, wherein the epithelial cancer is a cancer of at least one tissue selected from the group consisting of a bladder cancer, a uterine cancer, a cervical cancer, an ovarian cancer, a fallopian tube cancer, a testicular cancer, a prostate cancer, a large intestinal cancer, a small intestinal cancer, a duodenal cancer, a gastric cancer, an esophageal cancer, a laryngeal cancer, an oral cancer, a tongue cancer, a pharyngeal cancer, a liver cancer, a pancreatic cancer, a gallbladder cancer, a spleen cancer, a peritoneal cancer, a lung cancer, and an eye cancer.

[0300] (Paragraph 19)

[0301] The pharmaceutical composition according to any one of paragraphs 16 to 18, wherein the oxoacid is a halogen oxoacid.

[0302] (Paragraph 20)

[0303] The pharmaceutical composition according to paragraph 19, wherein the halogen oxoacid is at least one selected from the group consisting of a chlorine oxoacid, a bromine oxoacid, and an iodine oxoacid.

[0304] (Paragraph 21)

[0305] The pharmaceutical composition according to the above-mentioned 19 or 20, wherein the halogen oxyacid is at least one selected from the group consisting of hypohalous acid, halous acid, halic acid and perhalic acid.

[0306] (Paragraph 22)

[0307] The pharmaceutical composition according to the above-mentioned 19 or 20, wherein the halogen oxyacid is at least one selected from the group consisting of hypochlorous acid, chlorous acid, chloric acid, perchloric acid, hypobromous acid, bromous acid, bromic acid, perbromic acid, hypoiodous acid, iodous acid, iodic acid and periodic acid.

[0308] (Paragraph 23)

[0309] The pharmaceutical composition according to any one of the above-mentioned 26 to 22, wherein a radical generation catalyst is further contained, and the radical generation catalyst is a substance which catalyzes generation of a radical from at least one substance selected from the group consisting of the oxyacid, the oxyacid ion and the oxyacid salt contained in the pharmaceutical composition.

[0310] (Paragraph 24)

[0311] The pharmaceutical composition according to the above-mentioned 23, wherein the radical generation catalyst contains at least one selected from the group consisting of ammonium, amino acid, protein, peptide, phospholipid and salts thereof.

[0312] (Paragraph 25)

[0313] The pharmaceutical composition according to the above-mentioned 24, wherein the ammonium is an ammonium salt represented by the following formula (XI),

[0314] [Chemical Formula XI]

[0315]

[0316] in the above-mentioned formula (XI),

[0317] R 11 , R 21 , R 31 and R 41 are each a hydrogen atom or an aromatic ring, or an alkyl group, and the above-mentioned alkyl group can contain an ether bond, a carbonyl group, an ester bond, or an amide bond, or an aromatic ring, R 11 , R 21 , R 31 and R 41 may be the same or different,

[0318] or two or more of R 11 , R 21 , R 31 and R 41 may be integrated, and the N +together form a cyclic structure, the cyclic structure can be saturated or unsaturated, and can be an aromatic ring or a non-aromatic ring, and can have one or more substituents,

[0319] X - is an anion.

[0320] (Paragraph 26)

[0321] The pharmaceutical composition described in Paragraph 25, wherein the ammonium salt represented by Chemical Formula (XI) is an ammonium salt represented by the following Chemical Formula (XII),

[0322] [Chemical Formula XII]

[0323]

[0324] in the above Chemical Formula (XII),

[0325] R 111 is an alkyl group having 5 to 40 carbon atoms, and can include an ether bond, a ketone (carbonyl) group, an ester bond, or an amide bond, a substituent, or an aromatic ring,

[0326] R 21 and X - are the same as those in the above Chemical Formula (XI).

[0327] (Paragraph 27)

[0328] The pharmaceutical composition according to any one of Paragraphs 24 to 26, wherein the ammonium is at least one selected from the group consisting of benzethonium chloride, benzalkonium chloride, cetyltrimethylammonium chloride, tetramethylammonium chloride, ammonium chloride, methylammonium chloride, tetrabutylammonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, dequalinium chloride, edrophonium chloride, didecyldimethylammonium chloride, benzyltriethylammonium chloride, oxitropium bromide, carbachol, glycopyrronium bromide, safflower, choline allylsulfate, tetraethylammonium bromide, cetyltrimethylammonium bromide, succinylcholine, sphingomyelin, GM1 ganglioside, denatonium benzoate, trigonelline, neostigmine, paraquat, pyridostigmine, phellodendrine, pralidoxime methyl iodide, betaine, betanin, uracil, lecithin, adenine, guanine, cytosine, thymine, uracil, and choline.

[0329] (Paragraph 28)

[0330] The pharmaceutical composition described in Paragraph 25, wherein the ammonium salt represented by Chemical Formula (XI) is an ammonium salt represented by the following Chemical Formula (XIV),

[0331] [Chemical Formula XIV]

[0332]

[0333] in the above formula (XIV),

[0334] R 100 may form a cyclic structure, the above cyclic structure can be saturated or unsaturated, can be an aromatic ring or a non-aromatic ring, can have one or more substituents or can not have one, R 11 and X - is the same as the above formula (XI).

[0335] (Paragraph 29)

[0336] The pharmaceutical composition according to any one of paragraphs 23 to 28, wherein the Lewis acidity of the radical generation catalyst is 0.4 eV or more.

[0337] (Paragraph 30)

[0338] The pharmaceutical composition according to any one of paragraphs 16 to 29, which is an apoptosis promoter for epithelial cancer cells.

[0339] (Paragraph 31)

[0340] Use of at least one selected from the group consisting of an oxyacid, an oxyacid ion, and an oxyacid salt for the production of the epithelial cancer therapeutic agent according to any one of paragraphs 1 to 15.

[0341] (Paragraph 32)

[0342] Use of at least one selected from the group consisting of an oxyacid, an oxyacid ion, and an oxyacid salt for the production of the pharmaceutical composition according to any one of paragraphs 16 to 30.

[0343] (Paragraph 33)

[0344] Use of at least one selected from the group consisting of an oxyacid, an oxyacid ion, and an oxyacid salt as the epithelial cancer therapeutic agent according to any one of paragraphs 1 to 15 or the pharmaceutical composition according to any one of paragraphs 16 to 30.

[0345] (Paragraph 34)

[0346] A method for treating or preventing epithelial cancer in the patient, comprising a step of administering the epithelial cancer therapeutic agent according to any one of paragraphs 1 to 15 or the pharmaceutical composition according to any one of paragraphs 16 to 30 to the patient.

[0347] (Paragraph 35)

[0348] A method for treating or preventing epithelial cancer in the patient, comprising a step of administering at least one selected from the group consisting of an oxyacid, an oxyacid ion, and an oxyacid salt to the patient in order to treat or prevent epithelial cancer in the patient.

[0349] (Paragraph 36)

[0350] Use of the epithelial cancer therapeutic drug according to any one of Paragraphs 1 to 15 or the pharmaceutical composition according to any one of Paragraphs 16 to 30, which comprises a procedure of administering the epithelial cancer therapeutic drug according to any one of Paragraphs 1 to 15 or the pharmaceutical composition according to any one of Paragraphs 16 to 30 to a patient for treating or preventing epithelial cancer in the patient.

[0351] (Paragraph 37)

[0352] Use of at least one substance selected from the group consisting of an oxyacid, an oxyacid ion, and an oxyacid salt, which comprises a procedure of administering at least one substance selected from the group consisting of an oxyacid, an oxyacid ion, and an oxyacid salt to a patient for treating or preventing epithelial cancer in the patient.

[0353] The present application has been described above with reference to the embodiments and examples, but the present application is not limited to the above-described embodiments and examples. Various modifications that can be understood by those skilled in the art can be made to the configuration and details of the present application within the scope of the present application.

[0354] [Industrial Applicability]

[0355] As described above, according to the present application, an epithelial cancer therapeutic drug having a small side effect can be provided. The epithelial cancer therapeutic drug of the present application is useful as a therapeutic drug for various epithelial cancers such as bladder cancer, tongue cancer, oral cancer, uterine cancer, cervical cancer, large intestine cancer, and the like. For example, as shown in the examples, the epithelial cancer therapeutic drug of the present application is useful as a therapeutic drug for epithelial cancer in which apoptosis induction by production of reactive oxygen species is induced.

[0356] This application claims priority to Japanese Application No. 2020-089253, filed May 21, 2020, and incorporates it by reference in its entirety.

Claims

1. Use of a composition in the manufacture of a medicament for treating an epithelial cancer, said composition comprising at least one selected from the group consisting of a hypohalous acid and a hypohalous acid salt, said composition being free of a radical generating catalyst.

2. Use of a composition according to claim 1, wherein, The epithelial cancer is a cancer of at least one tissue selected from the group consisting of urinary system, reproductive system, digestive system, circulatory system, and respiratory system.

3. Use of a composition according to claim 1 or 2, wherein, The epithelial cancer is a cancer of at least one tissue selected from the group consisting of bladder cancer, uterine cancer, cervical cancer, ovarian cancer, fallopian tube cancer, testicular cancer, prostate cancer, large intestine cancer, duodenum cancer, stomach cancer, esophagus cancer, larynx cancer, tongue cancer, pharynx cancer, liver cancer, pancreas cancer, gall bladder cancer, spleen cancer, peritoneum cancer, lung cancer, and eye cancer.

4. Use of a composition according to claim 1 or 2, wherein, The epithelial cancer is a cancer of at least one tissue selected from the group consisting of small intestine cancer and oral cavity cancer.

5. Use of a composition according to claim 1 or 2, wherein, The composition comprises at least one selected from the group consisting of chlorous acid and a chlorous acid salt.

6. Use of a composition according to claim 5, wherein, The composition comprises a chlorous acid salt.

7. Use of a composition according to claim 6, wherein, The chlorous acid salt is sodium chlorite.

8. Use of a composition according to claim 1 or 2, wherein, The composition is an apoptosis promoter of epithelial cancer cells.

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