Radiosensitivity enhancer

Abstract

The present application discloses, as one embodiment of the invention, a radiosensitivity enhancer for cancer radiotherapy. The radiosensitivity enhancer contains, as an active ingredient, at least one compound selected from a compound (Ia) represented by formula (Ia), a compound (Ib) represented by formula (Ib), a compound (Ic) represented by formula (Ic), and salts thereof. (In each formula, the meaning of each symbol is as described in the description.)

Description

Radiosensitivity enhancer

[0001] As one of its embodiments, the present invention discloses a radiosensitivity enhancer in cancer radiotherapy, and is useful, for example, in the field of medicine.

[0002] Radiation therapy is widely used as one of the treatment strategies for various cancers in the medical field, along with surgical therapy and drug therapy. Taking prostate cancer as an example, it is one of the standard treatment methods for localized prostate cancer. However, more than 15% of intermediate-risk patients (Non-Patent Documents 1 and 2), and approximately half of high-risk or higher-risk patients experience recurrence after radical irradiation (Non-Patent Documents 3 and 4). In the radiotherapy of prostate cancer, in recent years, internal radiotherapy with RI has attracted attention, and the effectiveness of radium chloride 223 (Ra223) for castration-resistant prostate cancer (CRPC) with bone metastasis and 177Lu-PSMA for metastatic CRPC (mCRPC) has been reported. However, clinically, the problem remains that a sufficient prognosis improvement effect has not yet been obtained, and in order to further improve the treatment effect of radiotherapy, research and development of an agent that enhances the radiosensitivity of cancer cells has been awaited. As described above, taking prostate cancer as an example, enhancing radiosensitivity is also an urgent issue in the radiotherapy of various other cancers.

[0003] Zumsteg ZS, et al. Int. J. Radiat. Oncol. Biol. Phys. 2013 Bolla M, et al. J Clin Oncol. 2021 Aizawa R, et al. Int J Clin Oncol. 2021 Narang AK, et al. Int. J. Radiat. Oncol. Biol. Phys. 2016

[0004] In order to meet the above requirements in the medical field, one of the embodiments of the present invention aims to provide a new radiosensitivity enhancer in cancer radiotherapy.

[0005] In order to solve the above problems, the inventors of the present invention used an evaluation system using prostate cancer cells as specific cancer cells as described in detail in the Examples section below, evaluated the radiation sensitivity enhancing effect of a large number of compounds in radiation therapy, and found that a group of compounds having the specific structure described below enhance radiation sensitivity. Based on this finding, further studies were conducted to complete the present invention.Hereinafter, the present invention will be described with reference to specific embodiments thereof. However, the present invention is not limited thereto.

[0006] [1] A radiation sensitivity enhancer for cancer radiation therapy, comprising at least one compound selected from the compound (Ia) represented by the following formula (Ia), the compound (Ib) represented by the formula (Ib), and the compound (Ic) represented by the formula (Ic), and salts thereof, as an active ingredient.

[0007] Formula (Ia)

[0008]

[0009] (In the formula, R

[0015] , , , ９ , ８ , ,

[0014] represents a hydroxy group or an acyloxy group, and R ２ represents a hydroxy group or an acyloxy group, and R ３ represents a hydrogen atom, a hydroxy group, or an acyloxy group, and R ４ represents a halogen atom, and R ５ represents an amino group or an acylamino group.) <​​​​​​​​​​​​​​​​​​​​​​​​​１－６ (Indicates a hydrocarbon group.) [2] Compound (Ia) is, in formula (Ia), R １ However, it is a hydroxyl group, R ２ However, it is a hydroxyl group, R ３ However, it is a hydrogen atom, R ４ However, it is a halogen atom, and R ５ However, it is an amino group, a compound; compound (Ib) is, in formula (Ib), R ６ However, C １－６ It is an alkylthio group, and R ７ However, C １－６ It is a compound that has an alkoxycarbonyl-amino group; compound (Ic) is in formula (Ic), R ８ However, it is a hydroxyl group, and R ９ However, C ２－６ A radiosensitivity enhancer according to [1] above, which is an alkynyl group compound. [3] A radiosensitivity enhancer according to [1] or [2] above, which contains at least one compound selected from cladribine, albendazole, and norethindrone, and salts thereof, as an active ingredient. [4] A radiosensitivity enhancer according to any one of [1] to [3] above, which contains cladribine or a salt thereof as an active ingredient. [5] A radiosensitivity enhancer according to any one of [1] to [3] above, which contains albendazole or a salt thereof as an active ingredient. [6] A radiosensitivity enhancer according to any one of [1] to [3] above, which contains norethindrone or a salt thereof as an active ingredient.

[0016] [7] A radiosensitizer according to any one of [1] to [6] above, which is administered to subjects requiring enhanced sensitivity of cancer to radiation in radiotherapy. [8] A radiosensitizer according to any one of [1] to [7] above, wherein the enhancement of radiosensitivity is due to enhanced DNA damage in cancer cells. [9] A radiosensitizer according to any one of [1] to [8] above, wherein the enhancement of radiosensitivity is for the purpose of curing cancer, enhancing the therapeutic effect of palliative irradiation for metastatic cancer, or enhancing the therapeutic effect of internal radiotherapy for metastatic cancer.

[10] A radiosensitizer according to any one of [1] to [9] above, in which radiotherapy for cancer is performed in combination with other cancer therapies.

[11] A radiosensitizer according to any one of [1] to

[10] above, in which the cancer is prostate cancer or colorectal cancer.

[0017]

[12] A method for enhancing radiosensitivity in radiotherapy for cancer, comprising administering an effective amount of at least one compound selected from the compound represented by formula (Ia), the compound represented by formula (Ib), and the compound represented by formula (Ic), as defined in [1] above, and salts thereof, to a subject requiring such administration.

[13] At least one compound selected from the compound represented by formula (Ia), the compound represented by formula (Ib), and the compound represented by formula (Ic), as defined in [1] above, and salts thereof, for use in enhancing radiosensitivity in radiotherapy for cancer.

[14] Use of at least one compound selected from the compound represented by formula (Ia), the compound represented by formula (Ib), and the compound represented by formula (Ic), as defined in [1] above, and salts thereof, for the manufacture of a pharmaceutical for enhancing radiosensitivity in radiotherapy for cancer. *) For the meaning of each inventive feature in the embodiments described in

[12] to

[14] above ("enhancing radiosensitivity", "compound (Ia) represented by formula (Ia)", "compound (Ib) represented by formula (Ib)", "compound (Ic) represented by formula (Ic)", "forms of use of compounds (Ia) to (Ic) or their salts", etc.) and their specific embodiments (preferred embodiments), refer to the corresponding inventive features described in [2] to

[11] above as preferred embodiments for Embodiment [1].

[0018] One embodiment of the present invention is a radiosensitivity enhancer for cancer radiotherapy.

[0019] Figure 1 shows the evaluation results for cladribine, albendazole, and norethindrone in the evaluation (2nd screening) using LNCaP-MLuc cells performed in Example 1 below. Figure 2 shows the results of cladribine-mediated clonal formation assays performed in DU145 cells, PC3 cells, and 22Rv1 cells in Example 2 below. Figure A shows the results for DU145 cells, Figure B shows the results for PC3 cells, and Figure C shows the results for 22Rv1 cells. Figure 3 shows the evaluation results for γ-H2AX lesion formation by cladribine in DU145 cells performed in Example 3 below. Figure A shows the image acquisition results of the lesion visualized with a fluorescence microscope, and Figure B shows the percentage of cells containing the fluorescent lesion. Figure 4 shows the evaluation results for γ-H2AX lesion formation by cladribine in PC3 cells performed in Example 4 below. In the figures, Figure A shows the imaging results of images of lesions visualized with a fluorescence microscope, and Figure B shows the percentage of cells containing fluorescent lesions. Figure 5 shows the evaluation results of γ-H2AX lesion formation by cladribine in 22Rv1 cells performed in Example 5 below. In the figures, Figure A shows the imaging results of images of lesions visualized with a fluorescence microscope, and Figure B shows the percentage of cells containing fluorescent lesions. Figure 6 shows the results of the cell cycle distribution study performed in Example 6 below. In the figures, Figure A shows the assay results in DU145 cells, and Figure B shows the assay results in PC3 cells. Figure 7 shows a line graph summarizing the data shown in Figure 6 by cell cycle. Figure 8 shows the results of in vivo verification of the radiosensitizing effect of cladribine using DU145 cells, performed in Example 7 below. In the figures, the horizontal axis of Figure A shows the number of days since the start of treatment, and the vertical axis shows the ratio of tumor volume to the volume at the start of treatment. Figure B shows the Kaplan-Meier curve. Figure 9 shows the results of in vivo verification of the radiosensitizing effect of cladribine performed in Example 8 below using 22Rv1. In the figure, the horizontal axis of Figure A shows the number of days since the start of treatment, and the vertical axis shows the ratio of tumor volume to the volume at the start of treatment. Figure B shows the Kaplan-Meier curve. Figure C shows the results of weight monitoring. Figure 10 shows the results of the γH2AX assay performed when cladribine was administered in Example 8 below.Figures A and B show the test results when DU145 cells were used, and Figures C and D show the results when 22Rv1 cells were used. Figure 11 shows the results of the study on the tumor growth inhibitory effect of cladribine alone, conducted in Example 9 below. Figure 12 shows the results of the study on the effect of cladribine on the response of cancer cells to replication stress, conducted in Example 10 below. In the figures, Figures A and B show the test results in DU145 cells, and Figures C and D show the test results in PC3 cells.

[0020] The present invention will be described below with reference to representative embodiments. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. As stated above, the present invention is not limited to the following embodiments.

[0021] One embodiment of the present invention is a radiosensitizer for radiotherapy of cancer, comprising as an active ingredient at least one compound selected from the following compounds: compound (Ia) represented by formula (Ia), compound (Ib) represented by formula (Ib), and compound (Ic) represented by formula (Ic), and salts thereof.

[0022] Equation (Ia)

[0023]

[0024] (In the formula, R １ R represents a hydroxyl group or an acyloxy group. ２ R represents a hydroxyl group or an acyloxy group. ３ R represents a hydrogen atom, a hydroxyl group, or an acyloxy group. ４ R indicates a halogen atom, and ５ (This indicates an amino group or acylamino group.)

[0025] Formula (Ib)

[0026]

[0027] (In the formula, R ６ C １－６ It shows an alkylthio group, and R ７(This indicates an acylamino group.)

[0028] Formula (Ic)

[0029]

[0030] (In the formula, R ８ R represents a hydrogen atom, a hydroxyl group, or an acyloxy group, and ９ C １－６ (Helps represent a hydrocarbon group.) (Embodiment A). Hereafter, this will also be referred to as "this enhancer." The enhancer of Embodiment A will be described in detail below. The above compounds (Ia), (Ib), and (Ic) will also be collectively referred to as "compound (I)."

[0031] (Enhancement of Radiosensitivity) "Enhancement of radiosensitivity" refers to the improvement in the sensitivity of cancer cells targeted for radiotherapy to radiation, compared to before administration, by administering compound (I) or a salt thereof. In this enhancer, the enhancement of radiosensitivity is thought to be achieved by enhancing DNA damage in cancer cells. In this enhancer, the enhancement of radiosensitivity can be used in one aspect to cure cancer, to enhance the therapeutic effect of palliative irradiation for metastatic cancer, or to enhance the therapeutic effect of internal radiotherapy for metastatic cancer. In one aspect, this enhancer can also be used for cancers that are resistant to radiotherapy. In one aspect, this enhancer is administered to patients who require enhanced sensitivity of their cancer to radiation in radiotherapy.

[0032] (Cancers to which this enhancer can be applied) The cancers to which this enhancer can be applied are not particularly limited as long as they are cancers that are candidates for radiotherapy. Such cancers include at least one selected from the group consisting of breast cancer, gastric cancer (sometimes called gastric adenocarcinoma), colorectal cancer (sometimes called colorectal cancer, including colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer), gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial carcinoma, prostate cancer, bladder cancer, gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penile cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, glioblastoma pleomorphoni, sarcoma, osteosarcoma, and melanoma. In particular, at least one cancer selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, colorectal cancer, and pancreatic cancer is included. Prostate cancer or colorectal cancer are especially included.

[0033] (Compound (I) or its salt) The following describes Compound (I) or its salt, which is the active ingredient of this enhancer.

[0034] (1) Compound (I) Each group in compound (I) and its preferred embodiment will be described. Examples of "halogen atoms" include fluorine, chlorine, bromine, and iodine. １－６ Examples of "hydrocarbon groups" include C １－６ Alkyl alkyl group, C ２－６ Alkenyl group, C ２－６ Examples include alkynyl groups, etc. １－６ Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. ２－６Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl. ２－６ Examples of alkynyl (group) include ethinyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. １－６ Examples of "alkoxy (group)" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. １－６ Examples of alkylthio (groups) include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. １－６ Examples of "alkoxy-carbonyl (group)" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. Examples of "acyl groups" that constitute the "acyl" portion in "acyloxy group" and "acylamino group" include formyl group, carboxyl group, and C １－６ Alkyl-carbonyl group, C ２－６ Alkenyl-carbonyl group (e.g., crotonoyl), sulfino group, C １－６ Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C １－６ Alkyl sulfonyl group, C ６－１４ Aryl sulfonyl group, phosphono group, mono- or di-C １－６Examples include alkylphosphono groups (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0035] (2) Compound (Ia) Compound (Ia) is as defined above, but in a preferred embodiment, in formula (Ia), R １ However, it is a hydroxyl group, R ２ However, it is a hydroxyl group, R ３ However, it is a hydrogen atom, R ４ However, it is a halogen atom, and R ５ However, compounds that are amino groups are examples. A more preferred embodiment of compound (Ia) is cladribine, which is represented by the following structural formula.

[0036]

[0037] Cladribine is a known compound approved in Japan as an anti-cancer agent (product name: Leustatin Injection), and its synthesis method has also been reported. However, the effect of cladribine in enhancing the sensitivity of cancer cells to radiation in radiotherapy was not known. Other compounds (Ia) can also be synthesized and obtained by those skilled in the art.

[0038] (3) Compound (Ib) Compound (Ib) is as defined above, but in a preferred embodiment, in formula (Ib), R ６ However, C １－６ It is an alkylthio group, and R ７ However, C １－６ Examples of compounds include those with an alkoxycarbonyl-amino group. A more preferred embodiment of compound (Ib) is albendazole, represented by the following structural formula.

[0039]

[0040] Albendazole is a benzimidazole-based anthelmintic synthesized by GlaxoSmithKline in the UK, possessing broad-spectrum antiparasitic activity. It is a known compound approved in Japan as an anthelmintic (product name: Escazol tablets). However, the effect of albendazole in enhancing the radiation sensitivity of cancer cells in radiotherapy was previously unknown. Other compounds (Ib) can also be synthesized and obtained by those skilled in the art.

[0041] (4) Compound (Ic) Compound (Ic) is defined as above, but in a preferred embodiment, in formula (Ic), R ８ However, it is a hydroxyl group, and R ９ However, C ２－６ Examples of compounds include those with an alkynyl group. A more preferred embodiment of compound (Ic) is norethindrone, represented by the following structural formula. Note that its name in the Japanese Pharmacopoeia is norethisterone.

[0042]

[0043] Norethindrone is a known compound approved in Japan as an oral progestin (product name: Norulten Tablets), and its synthesis method has also been reported. However, the effect of norethindrone in enhancing the sensitivity of cancer cells to radiation in cancer radiotherapy was not known. Other compounds (Ic) can also be synthesized and obtained by those skilled in the art.

[0044] The compounds (Ia) to (Ic) described above were discovered for the first time through a two-stage screening process from a diverse group of compounds detailed in Example 1 below. The finding that these compounds enhance the radiation sensitivity of the target cancer was completely unpredictable, even to those skilled in the art.

[0045] (Salts of Compound (I), etc.) In this enhancer, compound (I) can be used in either its free form or its salt form (preferably a pharmaceutically acceptable salt thereof). Those skilled in the art can appropriately select from both forms to implement this embodiment, taking into account the characteristics of each compound (I) used. Conversion from compound (I) to its salt form and conversion from a salt of compound (I) to its free form can be appropriately performed by those skilled in the art. Examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate; salts with organic acids such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate; and salts with amino acids such as glutamate and aspartate. If compound (I) or its salt is a solvate (e.g., hydrate), the solvate of the target compound can be isolated from the reaction mixture by various methods, such as distillation and crystallization, after reacting the starting compound in a suitable solvent. Solvates can be produced by desolvating the solvate through methods such as heating or drying. Both solvates and solvates are included within the scope of compound (I) or its salts. If compound (I) has optical isomers, both these individual optical isomers and mixtures thereof are included within the scope of compound (I), and these isomers can be optically resolved or individually produced according to known means as desired. If compound (I) exists as a diastereomer, each can be isolated as desired using separation and purification methods commonly used in the pharmaceutical field. If compound (I) is a racemic mixture, it can be separated into the S and R isomers using conventional optical resolution methods. If compound (I) has stereoisomers, both the isomers individually and mixtures thereof are included within the scope of compound (I).

[0046] (Forms of Use of Compound (I) or its Salt) (Dosage Form, Target, Dosage, etc.) In this enhancer, Compound (I) or its salt (hereinafter collectively referred to as "the Compound") can be used for enhancing radiosensitivity in radiotherapy for cancer, either in its own form or in a pharmaceutical form containing the Compound as an active ingredient together with a pharmaceutically acceptable carrier. More specifically, the Compound can be used as an enhancer in either a pharmaceutical form consisting of the Compound itself as a single active ingredient, or in a pharmaceutical form containing the Compound as a single active ingredient together with a pharmaceutically acceptable carrier (substantially without pharmacological activity) (the latter will also be referred to hereinafter as "pharmaceutical composition"). In this specification, the above two forms may be collectively referred to as "pharmaceutical."

[0047] Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), syrups, liquids, emulsions, suspensions, controlled-release formulations (e.g., immediate-release formulations, sustained-release formulations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal adhesive films), injections (e.g., subcutaneous injections, intravenous injections (e.g., bolus injections), intramuscular injections, intraperitoneal injections), drip infusions, transdermal formulations, ointments, lotions, patches, suppositories (e.g., anal suppositories, vaginal suppositories), pellets, and the like.

[0048] As "carriers acceptable as pharmaceuticals," various carriers commonly used in the field of pharmaceutical formulation technology can be used.

[0049] Specific examples of "pharmaceutical carriers" include, for example, in solid dosage forms, excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silica, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.) and disintegrants (e.g., starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, L-hydroxypropylcellulose, etc.).

[0050] In liquid formulations, solvents (e.g., water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizers (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffers (e.g., buffers such as phosphates and citrates), and analgesics (e.g., benzyl alcohol, etc.) can be used.

[0051] If necessary, further formulation additives such as preservatives (e.g., parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, α-tocopherol, etc.), colorants, and sweeteners may be added.

[0052] The pharmaceutical composition of this enhancer varies depending on the dosage form, administration method, carrier, etc., but it can be manufactured by adding this compound in a ratio of typically 0.01 to 99% (w / w), preferably 0.1 to 85% (w / w), to the total amount of the formulation. The pharmaceutical composition can be manufactured by methods conventional in the field of pharmaceutical technology, depending on its form. The pharmaceutical composition may also be molded into a sustained-release formulation containing the active ingredient.

[0053] (Regarding the target population) This compound is expected to have low toxicity and few side effects, and possesses excellent properties as a pharmaceutical. Therefore, this inhibitor can be safely administered to mammals (e.g., humans, dogs, or cats, especially humans).

[0054] (Regarding the route of administration) This enhancer is used in conjunction with and / or concurrently with radiotherapy for cancer in clinical settings, and can be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, ophthalmoscopy, intracerebrally, rectally, vaginally, intraperitoneally, and directly to the lesion). Among these, intravenous administration may be particularly useful.

[0055] (Regarding Dosage) The dosage of this compound varies depending on the target patient, route of administration, and the patient's age and symptoms, but is not particularly limited as long as it is a dosage that can enhance the radiosensitivity of the target cancer in radiotherapy (hereinafter also referred to as the "effective dose"). For example, the effective dose of this compound is 1 to 250 mg when administered orally, and 0.1 to 1000 mg when administered parenterally.

[0056] In one embodiment, this enhancer contains compound (I) as the sole active ingredient.

[0057] This enhancer may be used in combination with other cancer therapies. These other therapies include surgery, chemotherapy, immunotherapy, and photoimmunotherapy. The appropriate combination can be used in clinical practice, taking into account the stage of cancer progression and the patient's condition.

[0058] (Regarding concomitant use with other agents) This enhancer may be used in combination with other active ingredients for enhancing radiosensitivity (hereinafter abbreviated as "concomitant drugs") as needed. Such embodiments are also included in the embodiments of this enhancer. When using the above concomitant combination, the timing of administration of this enhancer and the concomitant drug is not limited, and this enhancer and the concomitant drug (which may be in the form of a pharmaceutical composition) may be administered to the target simultaneously or with a time difference. The dosage of the concomitant drug may, for example, be in accordance with clinically used dosages and can be appropriately selected depending on the target, route of administration, disease, combination, etc. The form of administration of this enhancer and the concomitant drug is not particularly limited, as long as this enhancer and the concomitant drug are combined at the time of administration. Examples of such administration methods include: (1) administration of a single formulation obtained by simultaneously formulating compound (I) or its salt and the concomitant drug; (2) simultaneous administration of two formulations obtained by separately formulating compound (I) or its salt and the concomitant drug via the same route of administration; (3) administration of two formulations obtained by separately formulating compound (I) or its salt and the concomitant drug via the same route of administration with a time difference; (4) simultaneous administration of two formulations obtained by separately formulating compound (I) or its salt and the concomitant drug via different routes of administration; and (5) administration of two formulations obtained by separately formulating compound (I) or its salt and the concomitant drug via different routes of administration with a time difference (for example, administration of compound (I) or its salt followed by the concomitant drug, or in the reverse order).

[0059] Another embodiment of the present invention is "[B] A method for enhancing radiosensitivity in radiotherapy for cancer (Embodiment B), comprising administering an effective amount of at least one compound selected from the compound (Ia) represented by formula (Ia), the compound (Ib) represented by formula (Ib), and the compound (Ic) represented by formula (Ic), as well as salts thereof, to a subject requiring such administration (more specifically, including administration to a subject requiring enhanced radiosensitivity of cancer in radiotherapy). Hereinafter also referred to as "the enhancement method." The meaning of each inventive feature ("enhancement of radiosensitivity," "compound (Ia) represented by formula (Ia)," "compound (Ib) represented by formula (Ib)," "compound (Ic) represented by formula (Ic)," "forms of use of compounds (Ia) to (Ic) or their salts") in "the enhancement method" of Embodiment B, etc., and their specific embodiments (preferred embodiments) can be found by referring to the description of the corresponding inventive feature in "the enhancer" of Embodiment A. In this embodiment B, in one particular case, only compound (I) or a salt thereof is administered as a single active ingredient.

[0060] Another embodiment of the present invention is "[C] At least one compound selected from the compound represented by formula (Ia), the compound represented by formula (Ib), and the compound represented by formula (Ic), as defined in Embodiment A above, and their salts, used for enhancing radiosensitivity in radiotherapy for cancer (Embodiment C). Hereinafter also referred to as "the compound / salt"." For the meaning of each inventive feature ("enhancement of radiosensitivity," "compound represented by formula (Ia) (Ia)," "compound represented by formula (Ib) (Ib)," "compound represented by formula (Ic) (Ic)," "forms of use of compounds (Ia) to (Ic) or their salts") in "the compound / salt" of Embodiment C, etc., and specific embodiments (preferred embodiments) thereof, refer to the description of the corresponding inventive feature in "the enhancer" of Embodiment A. In one embodiment of Embodiment C, only compound (I) or its salt is used as a single active ingredient.

[0061] Another embodiment of the present invention is "[D] Use of at least one compound selected from the compound represented by formula (Ia), the compound represented by formula (Ib), and the compound represented by formula (Ic), as defined in Embodiment A above, and their salts, for the manufacture of a pharmaceutical for enhancing radiosensitivity in radiotherapy for cancer (Embodiment D). Hereinafter also referred to as "the present use." The meaning of each inventive feature ("enhancement of radiosensitivity," "compound represented by formula (Ia) (Ia)," "compound represented by formula (Ib) (Ib)," "compound represented by formula (Ic) (Ic)," "forms of use of compounds (Ia) to (Ic) or their salts") in "the present use" of Embodiment D, etc., and their specific embodiments (preferred embodiments) can be found by referring to the description of the corresponding inventive feature in "the present enhancer" of Embodiment A. In one embodiment of Embodiment D, a pharmaceutical is manufactured in which only compound (I) or a salt thereof is a single active ingredient.

[0062] The present invention will be described in detail below based on reference examples and embodiments, but the present invention is not limited to these. Those skilled in the art can modify embodiments of the present invention in various ways without departing from the meaning of the present invention, and such modifications are also included within the scope of the present invention.

[0063] In the following description, the results of statistical analysis are reported as mean ± standard deviation (SD). Differences between groups were evaluated using a two-sided, unpaired Student's t-test. Reference Example 1: Cell Culture The prostate cancer cell lines were obtained and cultured as follows: DU145 (RRID: CVCL_0105) was obtained from RIKEN BRC CELL BANK. PC-3 (RRID: CVCL_0035) was obtained from the American Type Culture Collection. LNCaP-MLuc cells were established according to the method described in the literature (Lupold SE et al. PLoS One 2012). These cell lines were cultured in RPMI-1640 (Nacalai Tesque, Kyoto, Japan) supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic (in humidified air at 37°C with 5% CO2). LNCaP cells are recognized by those skilled in the art as the cells that most closely resemble actual prostate cancer. MLuc (Metrdia luciferase) is a secreted reporter gene, and it is known that there is a linear relationship between luciferase activity in the supernatant of cultured cells into which it has been introduced and the number of (live) cells.

[0064] Example 1: Screening of compounds (I) with radiosensitivity-enhancing effects from a compound library The selection of cladribine, albendazole, and norethindrone used in the embodiments of the present invention was definitively made based on the results of tests using an evaluation system with LNCaP-MLuc cells, which are cells derived from LNCaP cells, recognized by those skilled in the art as the most realistic mimics of prostate cancer cells. The outline is as follows: (1) 1st screening Screening was performed using a 2 mM compound library consisting of 1134 FDA-approved drugs. Compounds were added to a 96-well plate beforehand, and 1 × 10⁻¹⁶ samples were taken using Multidrop COMBI (Thermo Fisher Scientific). 3LNCaP-MLuc cells were seeded. As a control, plates containing 6 cells each, with only DMSO added instead of the compound, were prepared. Cells were cultured in 100 μl of medium, and the final compound concentrations were 2 μM and 0.2 μM. Screening was performed using duplicates to create two groups: an irradiated group and a no-treatment group. The day after seeding, the irradiated group received 6 Gy of radiation using a gamma cell, while the no-treatment group did not receive irradiation. After 11 days of culture, luciferase activity in the supernatant was measured. Dual-Luciferase was used to measure luciferase activity. TM Reporter Assay System (Promega) was used. Stop & Glo TM Buffer and Stop & Glo TM A solution of Substrate mixed in a 50:1 ratio was dispensed in 20 μl portions into 384-well, flat-bottom Lumitrac, med binding, white (greiner bio-one 781075) plates using Nano Liquid Flex 5 (Gyger Fluidics). Then, 4 μl of the culture supernatant was injected from the 96-well plate into the 384-well plate using Fluent (TECAN). Thirty minutes after injection, Lenilla luciferase activity was measured using GloMax GM300 (Promega). Compounds that reduced viability by more than 50% (compared to DMSO) without irradiation were excluded as cytotoxic agents. Subsequently, 19 compounds that reduced viability by more than 50% (compared to DMSO) with irradiation were extracted as candidate compounds showing radiosensitizing effects and subjected to 2nd screening.

[0065] (2) 2nd screening Using the 19 candidate compounds that showed radiosensitizing effects in the screening (1st screening) from the compound library described above, a 2nd screening was performed by varying the radiation dose. Six different concentrations of the compound (6.3 μM, 2 μM, 630 nM, 200 nM, 65 nM, and 20 nM) were pre-added to a 96-well plate, and 1 × 10⁻¹⁶ samples were taken as before.3 LNCaP-MLuc cells were seeded. As a control, plates containing only DMSO (without any compounds) were prepared, with six cells per plate. Second screening was performed in a triplicate manner. The cells were irradiated with 4 Gy or 6 Gy of radiation the day after seeding, or left untreated. After 11 days of culture, luciferase activity was measured as before, and viability was calculated. The radiosensitization profile of each compound was comprehensively evaluated, taking into account the correlation with compound concentration and radiation dose. Three compounds (cladribine, albendazole, and norethindrone) that showed desirable radiosensitization profiles were selected as compounds for enhancing radiosensitivity. The experimental results of the second screening for the three compounds are shown in Figure 1. Figure A shows the experimental results for cladribine, Figure B shows the experimental results for albendazole, and Figure C shows the experimental results for norethindrone. Cladribine and albendazole were selected because they exhibited concentration-dependent and dose-dependent effects, and at either concentration, the relative cell viability at 4 Gy or 6 Gy was less than half that of 0 Gy. Norethindrone was selected because it showed no concentration-dependent effects or cytotoxicity, and exhibited properties different from the other 18 compounds.

[0066] Examples 2 and 3 below show, for reference, the results of further investigations into the radiosensitivity-enhancing effect of cladribine.

[0067] Example 2: Cloning Assay DU145 cells, PC3 cells, and 22Rv1 cells were cultured for 24 hours with DMSO or cladribine (0.2 μM), respectively, then plated and immediately irradiated with different doses. The medium was changed the day after irradiation, and the cells were cultured for a further 10 days. After fixing, the cells were stained with crystal violet. Colonies with 30 or more cells were counted, and the viability was calculated. The experimental results are shown in Figure 2. Figure A shows the results for DU145 cells, Figure B shows the results for PC3 cells, and Figure C shows the results for 22Rv1 cells. The results of this test confirmed that cladribine enhances the inhibitory effect on the proliferation of prostate cancer cells induced by radiation in all three cell types: DU145 cells, PC3 cells, and 22Rv1 cells.

[0068] Example 3: γ-H2AX assay (evaluation using DU145 cells) The γ-H2AX assay was performed using 8.0 × 10⁶ cells. ４ DU145 cells were seeded on glass slides and incubated with DMSO or cladribine for 24 hours, followed by irradiation (4 Gy) or no treatment. Four hours after irradiation, the formation of γ-H2AX lesions was evaluated. Cells were fixed with 4% paraformaldehyde for 15 minutes, treated with 0.2% Triton X-100 for 10 minutes, blocked with 1% BSA for 1 hour, and incubated with γ-H2AX antibody (1:500) for 30 minutes. Cells were labeled with Alexa Fluor antibody (Invitrogen) for 30 minutes and counterstained with Prolong Gold containing DAPI (Invitrogen). Lesions were visualized using a BZ-X710 fluorescence microscope (KEYENCE). Images were taken with the same exposure time in each experiment. In each experiment, more than 100 cells were counted from three or more random fields, and the percentage of cells containing 10 or more fluorescent lesions was calculated. The experimental results are shown in Figure 3. Figure A shows the imaging results described above, and Figure B shows the percentage of cells containing the fluorescent lesions described above. The results of this study confirmed that cladribine enhances the DNA damage effect of radiation on prostate cancer cells.

[0069] Example 4: γ-H2AX assay (evaluation using PC3 cells) The γ-H2AX assay was performed using 8.0 × 10⁶ cells. ４ PC3 cells were seeded on glass slides and incubated with DMSO or cladribine for 24 hours, followed by irradiation (4 Gy) or no treatment. Four hours after irradiation, the formation of γ-H2AX lesions was evaluated. Cells were fixed with 4% paraformaldehyde for 15 minutes, treated with 0.2% Triton X-100 for 10 minutes, blocked with 1% BSA for 1 hour, and incubated with γ-H2AX antibody (1:500) for 30 minutes. Cells were labeled with Alexa Fluor antibody (Invitrogen) for 30 minutes and counterstained with Prolong Gold containing DAPI (Invitrogen). Lesions were visualized using a BZ-X710 fluorescence microscope (KEYENCE). Images were taken with the same exposure time in each experiment. In each experiment, more than 100 cells were counted from three or more random fields, and the percentage of cells containing 10 or more fluorescent lesions was calculated. The experimental results are shown in Figure 4. In the figures, Figure A shows the results of the imaging described above, and Figure B shows the percentage of cells containing the fluorescent lesions described above.

[0070] The results of the γ-H2AX assay described above (Examples 3 and 4) showed that cladribine enhances the radiosensitivity of prostate cancer cells by inhibiting DNA damage repair. The DNA damage repair pathway significantly affects radiosensitivity. Specifically, radiation exerts cytotoxic effects mainly through DNA double-strand breaks (DSBs). The inventors evaluated the effect of cladribine on DSB repair using phosphorylated H2AX (γH2AX), a marker for DSBs. Using DU145 cells, the effect of cladribine on γH2AX foci formation under no-radiation conditions and 4 hours after 4 Gy irradiation was investigated. Under no-radiation conditions, γH2AX foci formation was minimal in both the DMSO group and the cladribine group, and no significant difference was observed between the two groups. However, 4 hours after irradiation, γH2AX foci formation was significantly higher in the cladribine group than in the DMSO group (Figure 3). Similar results were observed in PC3 cells (Figure 4).

[0071] Example 5: γ-H2AX assay (evaluation using 22Rv1 cells) The γ-H2AX assay was performed using 8.0 × 10⁶ cells. ４ 22Rv1 cells were seeded on glass slides and incubated with DMSO or cladribine for 24 hours, followed by irradiation (4 Gy) or no treatment. Four hours after irradiation, the formation of γ-H2AX lesions was evaluated. Cells were fixed with 4% paraformaldehyde for 15 minutes, treated with 0.2% Triton X-100 for 10 minutes, blocked with 1% BSA for 1 hour, and incubated with γ-H2AX antibody (1:500) for 30 minutes. Cells were labeled with Alexa Fluor antibody (Invitrogen) for 30 minutes and counterstained with Prolong Gold with DAPI (Invitrogen). Lesions were visualized using a BZ-X710 fluorescence microscope (KEYENCE). Images were taken with the same exposure time in each experiment. In each experiment, more than 100 cells were counted from three or more random fields, and the percentage of cells containing 10 or more fluorescent lesions was calculated. The experimental results are shown in Figure 5. In the figure, Figure A shows the imaging results described above, and Figure B shows the percentage of cells containing the fluorescent lesions described above. Similar results were observed in 22Rv1 cells as in DU145 cells and PC3 cells (Figure 5).

[0072] The experimental results described above (Examples 3-5) demonstrate that cladribine enhances radiosensitivity by suppressing the repair of DNA damage after radiation exposure.

[0073] Example 6: Cell Cycle Assay The cell cycle, which is closely related to DNA repair, was also analyzed. Cells (DU145 cells and PC3 cells) were treated with DMSO or cladribine for 24 hours, followed by irradiation with 4 Gy of radiation. The culture medium was changed 24 hours after irradiation. Cell cycle assays were performed before irradiation and at 6, 24, and 48 hours after irradiation. After treatment, the cells were washed with PBS and precipitated by centrifugation. The supernatant was removed, and 0.5 mL of PBS and 5 μL of Cell Cycle Assay Solution (Dojindo Laboratories, Kumamoto, Japan) were added to the precipitate. The samples were thoroughly mixed with a vortex mixer and cultured in the dark at 37°C for 15 minutes. The samples were then passed through a cell strainer and BD FACSCanto TM The analysis was performed using a FlowCytometer II (Becton, Dickinson and Company, Tokyo, Japan). The cell cycle distribution was analyzed using FlowJo TM The calculations were performed using software (Becton, Dickinson and Company, Tokyo, Japan). The cell cycle distribution calculated above is shown in Figure 6. Figure A shows the assay results for DU145 cells, and Figure B shows the assay results for PC3 cells. The graphs in each figure show the proportion of each cell cycle analyzed by flow cytometry, with the left peak representing the G1 phase, the right peak representing the G2 and M phases, and the area in between representing S phase cells. The graphs in each figure show that cladribine causes S phase arrest in each cell. Figure 7 shows the data from Figure 6 summarized by cell cycle as a line graph. In all cell types, in the DMSO group, little change was observed in the proportion of S phase cells from before irradiation to 48 hours after irradiation. However, in the cladribine group, the proportion of S phase cells, which was already high before irradiation in DU145 cells, increased further 6 hours after irradiation, and in PC3 cells, although it was no different from the DMSO group before irradiation, it began to increase 6 hours after irradiation, and a significant increase was observed at 24 hours. From the above, it was shown that in all cell types, the combined administration of cladribine and radiation increased the proportion of S-phase cells.

[0074] Example 7: Radiation Sensitization Effect (in vivo) The radiation sensitization effect of cladribine was verified in vivo. SCID mice (CB-17 / Icr-scid / scidJcl) were purchased from CLEA Japan, Inc. (Tokyo, Japan). DU145 cells 1 × 10⁶ 6 A mixture of 50 μl of PBS containing [specific cells] and 50 μl of Matrigel was subcutaneously administered to the right lower limb of mice. Tumors were measured three times a week, and the tumor volume was 0.52 × long diameter × (short diameter). 2 The calculation was performed when the tumor was 300 cm 3 Treatment was initiated when the tumor size reached a certain point. DMSO or cladribine was administered intraperitoneally for three consecutive days from the start of treatment, and the radiation group received 6 Gy of radiation on the second day of administration. The results of this study are shown in Figure 8. In Figure A, the horizontal axis represents the number of days since the start of treatment, and the vertical axis represents the ratio of tumor volume to the volume at the start of treatment. The DMSO monotherapy group and the cladribine monotherapy group showed almost the same growth rate, but the cladribine and radiation combination group showed significantly suppressed tumor growth compared to the radiation alone group. Figure B shows the Kaplan-Meier curve. The DMSO and cladribine monotherapy groups dropped out at almost the same time, but the cladribine and radiation combination group showed a significantly longer period until the tumor tripled compared to the radiation alone group.

[0075] Example 8: Radiation sensitization effect (in vivo) SCID mice (CB-17 / Icr-scid / scidJcl) were purchased from CLEA Japan Inc. (Tokyo, Japan). 2 × 10⁶ mice in 50 μL of phosphate-buffered saline. 6 A mixture of 22Rv1 cells and 50 μL of Matrigel was subcutaneously injected into the right lower limb of a mouse. In experiments using DU145 cells, a similar result was obtained: 1 × 10⁶ 6 Individual DU145 cells were injected. Tumor dimensions were measured at least three times a week, and the volume was calculated as follows: Tumor volume = 0.52 × major diameter × minor diameter 2 Tumor volume is 300 mm 3Treatment was initiated when the tumor size reached a certain level. DMSO or cladribine was administered intraperitoneally for three consecutive days from the start of treatment. In the irradiation group, irradiation was performed on the second day of administration (6 Gy for DU145, 5 Gy for 22Rv1). Body weight was monitored to assess treatment-related toxicity. The results of the study are shown in Figure 9. In Figure A, the horizontal axis represents the number of days since the start of treatment, and the vertical axis represents the ratio of tumor volume to the volume at the start of treatment. The DMSO monotherapy group and the cladribine monotherapy group showed almost the same growth rate, but tumor growth was significantly suppressed in the cladribine and radiation combination group compared to the radiation alone group. Figure B shows the Kaplan-Meier curve. The DMSO and cladribine monotherapy groups dropped out at almost the same time, but it was found that the time to three times the tumor size was significantly longer in the cladribine and radiation combination group compared to the radiation alone group. Figure C shows the results of body weight monitoring. It was shown that the cladribine and radiation combination did not show any specific toxicity. For γH2AX analysis, subcutaneous tumors were excised 4 hours after irradiation, and a γH2AX assay was performed according to previously reported methods (Tani M, et al. Cancer Sci. 2025 Dec;116(12):3403-3416). The test results are shown in Figure 10. Figures A and B show the test results using DU145 cells, and Figures C and D show the results using 22Rv1 cells. Similar to the in vitro study, it was found that cladribine increased the percentage of γH2AX-positive cells after radiation irradiation.

[0076] Example 9: MTS Cell Viability Assay Cells were seeded in a 96-well plate (DU145: 1.5 × 10⁻⁶). 3 PC3: 2.0×10 3 pcs, LNCaP: 2.0×10 3(1 cell). After 24 hours of incubation, cladribine or solvent was added to reach the specified concentration, and the cells were incubated for a further 72 hours. Subsequently, 20 μL of CellTiter 96 AQueous One Solution Reagent (Catalog No. G3580, Promega) was added to each well, and the plates were incubated at 37°C under 5% CO2 for 1 hour (DU145), 2 hours (PC3), or 4 hours (22Rv1). Absorbance was measured at 490 nm using a microplate reader (Bio-Rad, Hercules, California, USA). The test results are shown in Figure 11. In all cell types, cladribine alone did not suppress tumor growth.

[0077] Example 10: Western blot analysis Cells (DU145 cells or PC3 cells) were treated with DMSO or cladribine for 24 hours and irradiated with 6 Gy of radiation. Proteins were collected immediately before irradiation and at 1, 4, 8, and 24 hours after irradiation for protein extraction. Protein samples were separated by polyacrylamide gel electrophoresis and transferred to polyvinylidene fluoride membranes. The membranes were blocked with Bullet Blocking One for Western Blotting (Nacalai Tesque, Kyoto, Japan) and incubated overnight at 4°C with anti-phosphorylated Chk1 (Ser345) antibody (1:1000 dilution). After washing, the membranes were incubated with anti-rabbit IgG HRP-labeled antibody at room temperature for approximately 1 hour. Signals were detected using the ChemiDoc XRS+ imaging system (Bio-Rad). Immunoblotting of CHK1 and ACTB was performed in a similar manner, and the percentage of phosphorylated CHK1 was quantified using ImageJ software (National Institutes of Health, Bethesda, Maryland). The test results are shown in Figure 12. Figures A and B show the test results in DU145 cells, and Figures C and D show the test results in PC3 cells. pCHK1(S345) reflects a sensitive response to replication stress. In the cladribine group, this was increased in all cells from the pre-irradiation stage. This result suggests that cladribine induces a response to replication stress, and this action is understood to be involved in the sensitization mechanism in this study.

[0078] As one embodiment thereof, the present invention discloses a radiosensitivity enhancer for cancer radiotherapy, which is useful, for example, in the pharmaceutical field. This application is based on Japanese Patent Application No. 2025-009378 (filed on January 22, 2025) and Japanese Patent Application No. 2025-136397 (filed on August 19, 2025), the contents of which are fully incorporated herein.

Claims

1. A radiosensitizer for cancer radiotherapy, containing at least one compound selected from the compound (Ia) represented by the following formula (Ia), the compound (Ib) represented by the formula (Ib), and the compound (Ic) represented by the formula (Ic), and salts thereof, as an active ingredient. Formula (Ia) (In the formula, R １ represents a hydroxy group or an acyloxy group, R ２ represents a hydroxy group or an acyloxy group, R ３ represents a hydrogen atom, a hydroxy group, or an acyloxy group, R ４ represents a halogen atom, and R ５ represents an amino group or an acylamino group.) Formula (Ib) (In the formula, R ６ represents a C １－６ alkylthio group, and R ７ represents an acylamino group.) Formula (Ic) (In the formula, R ８ represents a hydrogen atom, a hydroxy group, or an acyloxy group, and R ９ [[ID=2&]] represents a C １－６ hydrocarbon group.) 2. Compound (Ia) is, in formula (Ia), R １ However, it is a hydroxyl group, R ２ However, it is a hydroxyl group, R ３ However, it is a hydrogen atom, R ４ However, it is a halogen atom, and R ５ However, it is an amino group, a compound; compound (Ib) is, in formula (Ib), R ６ However, C １－６ It is an alkylthio group, and R ７ However, C １－６ It is a compound that has an alkoxycarbonyl-amino group; compound (Ic) is in formula (Ic), R ８ However, it is a hydroxyl group, and R ９ However, C ２－６ A radiosensitivity enhancer according to claim 1, which is a compound having an alkynyl group.

3. A radiosensitivity enhancer according to claim 1 or 2, comprising at least one compound selected from cladribine, albendazole, and norethindrone, and salts thereof, as an active ingredient.

4. A radiosensitivity enhancer according to claim 1 or 2, comprising cladribine or a salt thereof as an active ingredient.

5. A radiosensitivity enhancer according to claim 1 or 2, comprising albendazole or a salt thereof as an active ingredient.

6. A radiosensitivity enhancer according to claim 1 or 2, comprising norethindrone or a salt thereof as an active ingredient.

7. A radiosensitivity enhancer according to claim 1 or 2, which is administered to a subject in radiotherapy who requires enhanced sensitivity of cancer to radiation.

8. The radiosensitivity enhancer according to claim 1 or 2, wherein the enhancement of radiosensitivity is due to the enhancement of DNA damage in cancer cells.

9. The radiosensitivity enhancer according to claim 1 or 2, wherein the enhancement of radiosensitivity is for the purpose of curing cancer, enhancing the therapeutic effect of palliative irradiation for metastatic cancer, or enhancing the therapeutic effect of internal radiotherapy for metastatic cancer.

10. A radiosensitizer according to claim 1 or 2, wherein radiotherapy for cancer is performed in combination with other cancer therapies.

11. The radiosensitivity enhancer according to claim 1 or 2, wherein the cancer is prostate cancer or colorectal cancer.

12. A method for enhancing radiosensitivity in radiotherapy for cancer, comprising administering an effective amount of at least one compound selected from the compound represented by formula (Ia) as defined in claim 1, the compound represented by formula (Ib) as (Ib), and the compound represented by formula (Ic) as (Ic), and salts thereof, to a subject requiring such administration.

13. A compound selected from the compounds represented by formula (Ia), formula (Ib), and formula (Ic), as defined in claim 1, and their salts, for use in enhancing radiosensitivity in radiotherapy for cancer.

14. Use of at least one compound selected from the compound represented by formula (Ia), the compound represented by formula (Ib), and the compound represented by formula (Ic), as defined in claim 1, and their salts, for the manufacture of a pharmaceutical for enhancing radiosensitivity in radiotherapy for cancer.

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