HK1130481B - Potentiator of radiation therapy - Google Patents

Description

Radiation therapy enhancer

Technical Field

The present invention relates to a radiation therapy potentiator which is used in combination with cancer radiation therapy and can reduce the amount of radiation and side effects.

Background

Cancer (malignant tumor) has been treated with surgical therapy, chemotherapy, immunotherapy, thermotherapy and radiotherapy. Radiotherapy is often performed on various cancers such as gastric cancer, rectal cancer, pancreatic cancer, head and neck cancer, esophageal cancer, lung cancer, and breast cancer that have progressed to stages III to IV, but in therapy using radiation alone (currently, the total radiation dose is 40 to 60Gy in clinical practice), it is difficult to perform the radiotherapy for a long period of time due to the toxicity of the blood system and the side effects of the digestive system such as thirst, and therefore, the clinical effect (antitumor effect) is not sufficient. In order to obtain a high antitumor effect, a chemotherapy method using a combination of a chemotherapeutic agent and radiation has recently been adopted as one of the standard treatments, and it is said that the therapeutic effect is better than that of a radiotherapy alone or a chemotherapy alone (non-patent document 1). For example, a combination of carboplatin/fluorouracil and radiation for head and neck cancer (non-patent document 2) and a combination of cisplatin and radiation (non-patent document 3); a combination of fluorouracil/cisplatin and radiation for esophageal cancer (non-patent document 4); combined use of fluorouracil and radiation for pancreatic cancer (non-patent document 5); in the case of non-small cell lung cancer, combined use of cisplatin/vinblastine and radiation (non-patent document 6) significantly prolongs the survival time as compared with the use of radiation alone. In addition, it has been reported that patients who have undergone chemoradiotherapy (chemoradiotherapy) after surgery have a lower recurrence rate and a longer survival time than patients who have not undergone radiotherapy (non-patent document 7). However, in the conventional combination use of a chemotherapeutic agent and radiotherapy, the chemotherapeutic agent itself has side effects, and as a result, medical practice may have to be interrupted. In addition, a sufficient effect for reducing the side effect cannot be obtained.

Various attempts have been made to provide a radiation sensitizer which can reduce the radiation dose and reduce side effects without reducing the therapeutic effect of radiation therapy. For example, some nitroimidazole derivatives are known as radiation sensitizers, and compounds such as misonidazole and etanidazole have been developed, but they have not been put to practical use because of, for example, too high neurotoxicity when used in an amount capable of obtaining sensitizing activity. In the treatment of radiation-resistant tumors, it is desired to use a combined agent for enhancing radiation sensitivity, but many of the radiation sensitivity enhancers (such as radiation sensitizers) reported have had problems in development due to neurotoxicity.

Non-patent document 1: international Journal of Clinical Oncology, Vol.9, No.6, (2004): 414-490

Non-patent document 2: calais et al, j.natl.cancer inst.91 (1999): 2081-2086

Non-patent document 3: jeremic B, et al, j.clin.oncol.18 (2000): 1458-1464

Non-patent document 4: Al-Sarraf M, et Al, j.clin.oncol.15 (1997): 277-284

Non-patent document 5: moortel CG, et al, Cancer48 (1981): 1705-1710

Non-patent document 6: sause W, et al, Chest117 (2000): 358-364

Non-patent document 7: tveit KM, et al, br.j. cancer84 (1997): 1130-1135

Disclosure of Invention

Accordingly, an object of the present invention is to provide a radiation therapy potentiator which can be used in combination with cancer radiation therapy, can reduce the amount of radiation, and can also reduce side effects.

In view of such circumstances, the present inventors have intensively studied, from various viewpoints, on uracil derivatives represented by formula (1) or pharmaceutically acceptable salts thereof, and as a result, have found that the antitumor effect of radiation is enhanced by using these compounds in combination with a low dose of radiation, and that the same or more effects as or than those of treatment with a high dose of radiation alone are exhibited.

Namely, the present invention provides a radiation therapy-enhancing agent comprising a uracil derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient,

in the formula, R¹Represents a halogen atom or a cyano group; r²Represents a 4-to 8-membered heterocyclic group having 1-to 3-nitrogen atoms which may have a lower alkyl group, an imino group, a hydroxyl group, a hydroxymethyl group, a methanesulfonyloxy group or an amino group as a substituent, an amidinothio group in which a hydrogen atom on a nitrogen atom may be substituted with a lower alkyl group, a guanidino group in which a hydrogen atom on a nitrogen atom may be substituted with a lower alkyl group or a cyano group, a lower alkylamidino group or a 1-pyrrolidinylmethyl group.

The present invention also provides use of the uracil derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof for production of a radiation therapy enhancer.

The present invention also provides a method for enhancing radiotherapy, which comprises administering a uracil derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating cancer, which comprises administering a uracil derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof in combination with cancer radiotherapy.

When the radiation therapy potentiator of the present invention is used in combination with radiation therapy, an excellent cancer treatment effect can be obtained with a smaller amount of radiation, and side effects can be reduced, so that cancer treatment can be effectively performed over a long period of time.

Drawings

Fig. 1 is a photograph showing the skin condition of the thighs of the radiation-independent group in test example 3 (day 11 and day 13).

FIG. 2 is a photograph showing the skin condition of the thighs of the group used in test example 3 to which 5-chloro-6- [1- (2-iminopyrrolidinyl) methyl ] uracil hydrochloride and radiation were administered in combination (day 11 and day 13).

Detailed Description

In the above general formula (1), R is¹Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom and a bromine atom are preferable.

As can be at R²Examples of the heterocyclic group, amidinothio group, guanidino group and amidino-substituted lower alkyl group include linear or branched alkyl groups having 1 to 4 carbon atoms, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl groups, and among them, methyl is particularly preferable.

As R²Examples of the 4-to 8-membered heterocyclic group having 1 to 3 nitrogen atoms include a 1-azetidinyl group, a 1-pyrrolidinyl group, a 2-pyrrolin-1-yl group, a 3-pyrrolin-1-yl group, a 1-pyrrolyl group, a 1-pyrazolidinyl group, a 2-pyrazolin-1-yl group, a 3-pyrazolin-1-yl group, a 4-pyrazolin-1-yl group, a 1-pyrazolyl group, a 1-imidazolidinyl group, a 2-imidazolin-1-yl group, a 3-imidazolin-1-yl group, a 4-imidazolin-1-yl group, a 1-imidazolyl group, a 1, 2, 3-triazol-1-yl group, a 1, 2, 4-triazol-1-yl group, a piperidyl group, a piperidine group, and a, 1-piperazinyl, morpholinyl, 1-azepanyl, or 1-azacyclooctyl, and the like. Among them, 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, and 1-imidazolyl are preferable, and 1-pyrrolidinyl is particularly preferable.

The heterocyclic group may have 1 or 2 substituents on the ring, and examples of such substituents include lower alkyl, imino, hydroxy, hydroxymethyl, methanesulfonyloxy and amino. Specific examples of the heterocyclic group which may have such a substituent(s) include 1-azetidinyl, 1-pyrrolidinyl, 2, 5-dimethylpyrrolidin-1-yl, 2-iminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, 3-methanesulfonyloxypyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 2-pyrrolin-1-yl, 3-pyrrolin-1-yl, 2-imino-3-pyrrolin-1-yl, 1-pyrrolyl, 1-pyrazolidinyl, 2-methylpyrazolidin-1-yl, 4-iminopyrazolidin-1-yl, N-oxides, N, 2-pyrazolin-1-yl, 3-pyrazolin-1-yl, 2-methyl-3-pyrazolin-1-yl, 5-imino-3-pyrazolin-1-yl, 4-pyrazolin-1-yl, 2-methyl-4-pyrazolin-1-yl, 3-imino-4-pyrazolin-1-yl, 1-pyrazolyl, 1-imidazolidinyl, 3-methylimidazolidin-1-yl, 2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl, 2-imino-3-ethylimidazolidin-1-yl, pyrazolin-2-methyl-imidazolidin-1-yl, pyrazolin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl, 2-imidazolin-1-yl, 3-imidazolin-1-yl, 4-imidazolin-1-yl, 3-methyl-4-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl, 2-imino-3-isopropyl-4-imidazolin-1-yl, 1-imidazolyl, 2-methylimidazol-1-yl, and the like, 1, 2, 3-triazol-1-yl, 1, 2, 4-triazol-1-yl, piperidinyl, 1-piperazinyl, 4-methylpiperazin-1-yl, morpholinyl, 1-azepanyl, 1-azacyclooctyl and the like. More preferred examples thereof include a 1-azetidinyl group, a 1-pyrrolidinyl group, a 2-iminopyrrolidin-1-yl group, a 2-iminoimidazolidin-1-yl group, a 2-imino-3-methylimidazolidin-1-yl group, a 2-imino-3-ethylimidazolidin-1-yl group, a 2-imino-3-isopropylimidazolidin-1-yl group, a 2-imidazolin-1-yl group, a 2-imino-3-methyl-4-imidazolin-1-yl group, a 2-imino-3-ethyl-4-imidazolin-1-yl group and a 1-imidazolyl group.

R²Amidinothio in which the hydrogen atom on the nitrogen atom may be substituted with a lower alkyl group, 1 to 3 of the 3 hydrogen atoms on the nitrogen atom of the amidinothio may be substituted with the lower alkyl group, and amidinothio and N are particularly preferable¹(iii) methylamidinylthio and N¹，N²-dimethylamidinothio.

As the guanidino group which may be substituted by a lower alkyl group or a cyano group as a hydrogen atom on a nitrogen atom, 1 to 4 of 4 hydrogen atoms of the guanidino group may be substituted by the above-mentioned lower alkyl group or cyano group, and particularly preferred are a 1-guanidino group, a 1-methylguanidino group, a 3-methylguanidino group, a 2, 3-dimethylguanidino group and a 2-cyano-3-methylguanidino group.

The lower alkylamidino group is a group in which 1 or 2 of the above-mentioned lower alkyl groups are bonded to an amidino group, and among them, a methylamidino group, an ethylamidino group, a dimethylamido group or a diethylamidino group is preferable.

In addition, R²Preferred specific examples of the group include 1-azetidinyl, 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl, 2-iminoimidazolidin-1-yl, 2-imino-3-methylimidazolidin-1-yl, 2-imino-3-ethylimidazolidin-1-yl, 2-imino-3-isopropylimidazolidin-1-yl, 2-imidazolin-1-yl, 2-imino-3-methyl-4-imidazolin-1-yl, 2-imino-3-ethyl-4-imidazolin-1-yl, 1-imidazolyl, 1-pyrrolidinyl, and the like, Amidinothio, N¹-methylamidinylthio, N¹，N²-dimethylamidinothio, 1-guanidino, 1-methylguanidino, 3-methylguanidino, 2, 3-dimethylguanidino, methylamidino or 1-azetidinylmethyl, more preferably 1-azetidinyl, 2-iminopyrrolidin-1-yl, amidinothio, 3-methylguanidino or 1-azetidinylmethyl, particularly preferably 2-iminopyrrolidin-1-yl.

As the uracil derivative represented by the general formula (1), R is preferable¹Is a chlorine atom, a bromine atom or a cyano group, R²Uracil derivatives which are 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl, amidinothio, 3-methylguanidino or 1-pyrrolidinylmethyl.

The salt of the uracil derivative (1) is not particularly limited, but an acid addition salt and/or a base salt which allows a pharmaceutically acceptable acid or base compound to act is preferable. Examples of the acid addition salt include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid; and salts with organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, acetic acid, p-toluenesulfonic acid, and methanesulfonic acid, but salts with hydrochloric acid or p-toluenesulfonic acid are preferred. Examples of the basic salt include salts with alkali metals and alkaline earth metals such as sodium, potassium, magnesium, and calcium; and amines such as ammonium, methylamine, dimethylamine, piperidine, cyclohexylamine, and triethylamine.

Preferable specific examples of the uracil derivative (1) or a pharmaceutically acceptable salt thereof include 5-chloro-6- (1-pyrrolidinylmethyl) uracil, 5-bromo-6- (1-pyrrolidinylmethyl) uracil, 5-cyano-6- (1-pyrrolidinylmethyl) uracil, 5-chloro-6- (1-azetidinylmethyl) uracil, 5-chloro-6- [1- (2-iminopyrrolidinyl) methyl ] uracil hydrochloride, 5-bromo-6- [1- (2-iminopyrrolidinyl) methyl ] uracil hydrochloride, 5-cyano-6- [1- (2-iminopyrrolidinyl) methyl ] uracil, and the like, 5-chloro-6- [1- (2-iminoimidazolidinyl) methyl ] uracil, 5-bromo-6- [1- (2-iminoimidazolidinyl) methyl ] uracil, 5-chloro-6- (1-imidazolidinylmethyl) uracil hydrochloride, 5-chloro-6- (3-methylguanidinyl) methyluracil hydrochloride, 5-bromo-6- (3-methylguanidinyl) methyluracil hydrochloride, 5-cyano-6- (3-methylguanidinyl) methyluracil hydrochloride, 5-chloro-6-amidinothiomethyluracil hydrochloride, 5-bromo-6-amidinothiomethyluracil hydrochloride, 5-cyano-6-amidinothiouracil hydrochloride, 5-cyano-iminomethylthiouracil hydrochloride, 5-bromo-6-amidinothiouracil hydrochloride, 5-chloro-6-iminomethylthiouracil hydrochloride, 5-chloro-6- (2-pyrrolidin-1-yl-ethyl) uracil, 5-bromo-6- (2-pyrrolidin-1-yl-ethyl) uracil, 5-cyano-6- (2-pyrrolidin-1-yl-ethyl) uracil and the like, and particularly preferred is 5-chloro-6- [1- (2-iminopyrrolidinyl) methyl ] uracil hydrochloride represented by the following formula.

The compound of formula (1) can be produced, for example, by the method described in the pamphlet of International publication WO 96/30346. The compounds represented by the general formula (1) as the active ingredient of the present invention are known, and regarding the pharmacological actions thereof, thymidine phosphorylase activity inhibitory action and antitumor effect enhancing action (WO 96/30346), cancer metastasis inhibitory action (WO 98/13045), alimentary tract disorder reducing action as an antitumor agent (WO 00/56337), and anti-HIV action (WO 01/34162) are known. However, it is not known at all what effect the compound exhibits on radiotherapy.

If the compound of formula (1) is administered in combination with radiation therapy, the therapeutic effect by the radiation is significantly enhanced as compared with the case of using radiation therapy alone. Therefore, the compound of formula (1) is useful as a radiation therapy enhancer. In addition, as a result of the enhancement of the radiotherapy effect, since a sufficient cancer treatment effect can be obtained with a smaller radiation dose, the compound of formula (1) also functions as a radiation dose-reducing agent in cancer treatment. In addition, conventionally, when a high dose of radiation therapy is continued, there are cases where long-term therapy cannot be performed because side effects such as blood toxicity, digestive organ toxicity, anorexia, tiredness, and weight loss are produced, but if the compound of formula (1) and radiation therapy are used in combination, the radiation dose can be reduced and the side effects can also be reduced, so that longer-term radiation therapy becomes possible, and as a result, the cancer therapeutic effect is improved.

In addition, in the radiation therapy potentiating agent of the present invention, (B) α, α, α -trifluorothymidine may be blended in addition to (a) the uracil derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof.

The α, α, α -trifluorothymidine (hereinafter, abbreviated as FTD) used herein is represented by the following formula (2). The FTD is a nucleic acid derivative obtained by substituting the 5-position methyl group of thymidine synthesized by Heidelberger et al with a trifluoromethyl group (J.Am.chem.Soc., 84: 3597-3598, 1962; J.Med.chem., 7: 1-5, 1964). In addition, an antitumor composition produced by combining the compound of formula (1) with α, α, α -trifluorothymidine is also known (WO 96/30346). However, it is not known at all what effect the composition shows on radiotherapy.

The ratio of the component (A) to the component (B) is not particularly limited, and the component (A) is used in an amount of about 0.1 to 500 mol, more preferably about 0.2 to 10 mol, and particularly preferably about 0.5 mol, based on 1 mol of the component (B).

The uracil derivative in the component (A) is preferably 5-chloro-6- [1- (2-iminopyrrolidinyl) methyl ] uracil or a pharmaceutically acceptable salt thereof.

If a composition containing the component (A) and the component (B) is used in combination with radiation therapy, the effect of cancer treatment by radiation is significantly enhanced as compared with the case of using radiation therapy alone. Therefore, the composition is useful as a radiation therapy enhancer. In addition, since a sufficient cancer therapeutic effect can be obtained with a smaller radiation dose as a result of the enhancement of the radiation therapeutic effect, the composition also functions as a radiation dose reducing agent in cancer therapy. In addition, conventionally, when a high dose of radiation therapy is continued, there are cases where long-term treatment cannot be performed because side effects such as blood toxicity, digestive organ toxicity, anorexia, tiredness, and weight loss are produced, but if the composition and the radiation therapy are used in combination, the dose of radiation can be reduced and the side effects can also be reduced, so that longer-term radiation therapy becomes possible, and as a result, the cancer treatment effect is improved.

The term "radiation therapy enhancer" as used herein refers to a drug (also referred to as a radiation sensitizer or a radiation sensitizer) that enhances (improves) radiation sensitivity without limiting the mechanism of action.

In addition, the radiotherapy to be carried out in the present invention can be carried out according to a protocol known to those skilled in the art generally used in the technical field. For example, the radiotherapy comprises cesium, iridium, iodine or cobalt irradiation. The radiotherapy may be performed by whole body irradiation (for acute leukemia, malignant lymphoma, and partial solid cancer), but is preferably performed by local irradiation of a tumor site or tissue (for solid cancer, in abdomen, lung, liver, lymph node, head, and the like). Typical radiotherapy is performed for 25 to 30 times (about 5 to 6 weeks) in 2 to 3 minutes per 1 day.

The radiotherapy enhancer of the present invention can be used in combination as an auxiliary agent in radiotherapy of a malignant tumor which is not originally highly sensitive to radiation or a malignant tumor which has acquired radiation resistance by radiotherapy. In addition, the radiation therapy potentiator of the present invention can reduce the dose of radiation to be applied to therapy by enhancing the radiation sensitivity of tumor cells, and can prolong the treatment time (exposure time) more than the time specified in the conventional protocol. In addition, side effects (for example, stomatitis, bone marrow damage, radiation ulcer, and radiation pneumonitis) caused by radiation damage, which are inevitably accompanied by radiotherapy, can be reduced.

The radiotherapy enhancer of the present invention is an enhancer administered during radiotherapy, and is administered before or after radiotherapy. The radiotherapy enhancer of the present invention can be used in combination with other antitumor agents because it enhances the radiotherapy effect as described above. Examples of such antitumor agents include platinum agents, taxane agents, vinca alkaloid agents, topoisomerase inhibitors, metabolic antagonists, alkylating agents, and the like. More specifically, there may be mentioned 1 or 2 or more kinds of cisplatin, carboplatin, oxaliplatin, taxol, taxotere, vincristine, vinblastine, vinorelbine, vindesine, irinotecan hydrochloride, topotecan, etoposide, teniposide, doxorubicin, fluorouracil, tegafur, flutolterolone, capecitabine, gemcitabine, cytarabine, methotrexate, pemetrexed, cyclophosphamide, adriamycin, mitomycin and the like. In addition, the antitumor agent is used in combination in consideration of age, sex, symptoms, degree of side effects, incompatibility of patients, and the like.

The radiotherapy enhancer of the present invention can be prepared into a conventional pharmaceutical preparation form using a pharmaceutically acceptable carrier, for example, a filler, an extender, a binder, a humectant, a disintegrant, a surfactant, a lubricant, an excipient, etc. When the pharmaceutical preparation is administered to mammals including humans, various pharmaceutical administration forms can be prepared according to the purpose of treatment, and specific examples thereof include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquid, suspension, etc.), ointments, and the like. When the composition is formed into a tablet form, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, glyceryl monostearate, starch, and lactose; disintegration inhibitors such as white sugar, stearin, cacao butter, and hydrogenated oil; absorption promoters such as quaternary ammonium hydroxide and sodium lauryl sulfate; humectants such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, and lubricants such as refined talc, stearate, boric acid powder and polyethylene glycol. The tablets may be formulated as required into tablets coated with a usual coating, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer tablets or multi-layer tablets. When the composition is formed into a pill form, for example, excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc and the like; acacia powder, tragacanth powder, gelatin, ethanol, and other binders; disintegrating agents such as laminarin powder and agar powder. Capsules are prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture in hard gelatin capsules, soft capsules, and the like according to a conventional method. In the case of molding into a suppository form, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like can be used. In the case of preparing an injection, it is preferable to sterilize a liquid, an emulsion or a suspension and to make the suspension isotonic with blood, and in the case of forming the injection into such a form, a known diluent, for example, water, ethanol, polyethylene glycol, propylene glycol, polyethoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like can be widely used as the diluent. In this case, a sufficient amount of common salt, glucose or glycerin may be contained in the pharmaceutical preparation for the preparation of an isotonic solution, and a usual cosolvent, buffer, soothing agent, and the like may be added. In the case of forming into an ointment, for example, a paste, or a gel, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicon, bentonite, or the like can be used as a diluent. In addition, the pharmaceutical preparations may contain a colorant, a preservative, a perfume, a flavoring agent, a sweetener, and the like, or other medicines, as necessary.

The amount of the active ingredient (a) or the total amount of the ingredient (a) and the ingredient (B) to be contained in the pharmaceutical preparation is not particularly limited, and is appropriately selected from a wide range, and is usually preferably 1 to 70% by mass in the pharmaceutical preparation.

The method of administration of the pharmaceutical preparation is not particularly limited, and is suitably determined in accordance with various preparation forms, other conditions such as age and sex of patients, and the degree of disease. For example, tablets, pills, powders, liquids, suspensions, emulsions, granules and capsules are orally administered. The injection is administered intravenously alone or in admixture with a conventional infusion solution such as glucose or amino acid, and is administered separately, as needed, intraarterially, intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories are administered rectally. The ointment is applied to skin, oral mucosa, etc. Among them, oral administration is particularly preferred.

The dose of each active ingredient of the preparation of the present invention may be suitably determined depending on the administration method, other conditions such as age and sex of the patient, the degree of the disease, and the like, and it is generally preferable to use the uracil derivative (1) or a pharmaceutically acceptable salt thereof in an amount of about 0.01 to 1000 mg/kg/day, preferably about 0.5 to 100 mg/kg/day. When α, α, α -trifluorothymidine is blended, the amount thereof is preferably in the range of about 0.1 to 100 mg/kg/day, preferably about 0.5 to 50 mg/kg/day. In addition, these preparations of the present invention can be administered 1 time or 2 to 4 times or so per day.

By using the radiation therapy enhancer of the present invention and radiation therapy together, an excellent cancer treatment method can be provided. The tumor to which the treatment can be applied is not particularly limited. The potentiator of the present invention is particularly suitable for cancers having high radiation sensitivity, but can improve radiation sensitivity even in cancers having low sensitivity, and therefore, the potentiating effect of radiotherapy can be expected to be improved. Examples of the cancer include those which are difficult to cure by excision, such as head and neck cancer, esophageal cancer, stomach cancer, colorectal cancer, liver cancer, gallbladder/bile duct cancer, pancreatic cancer, lung cancer, breast cancer, bladder cancer, prostate cancer, cervical cancer, brain tumor, malignant lymphoma, acute leukemia, chronic leukemia, medulloblastoma, retinoblastoma, neuroblastoma, Wilms tumor, Hodgkins disease, multiple myeloma, plasmacytoma, thymoma, basal cell carcinoma, squamous cell carcinoma, Ewing tumor, thyroid cancer, ovarian cancer, salivary gland carcinoma, teratoma, malignant melanoma, glioma, renal cell carcinoma, and osteosarcoma, preferably head and neck cancer, esophageal cancer, stomach cancer, colon/rectal cancer, liver cancer, lung cancer, pancreatic cancer, and breast cancer, more preferably head and neck cancer, esophageal cancer, liver cancer, lung cancer, and pancreatic cancer, particularly preferred are lung cancer and head and neck cancer.

Examples

The present invention will be described in more detail below with reference to test examples, but the present invention is not limited to these examples.

(test example 1)

(a) Preparation of test solutions: 5-chloro-6- [1- (2-iminopyrrolidinyl) methyl ] uracil hydrochloride (hereinafter abbreviated as TPI) was suspended in a 0.5% (W/V) hydroxypropylmethylcellulose (hereinafter abbreviated as HPMC) solution at concentrations of 2.5 and 5.0mg/mL, and after stirring with a stirrer at room temperature for about 10 minutes, it was sonicated under ice-cooling for about 5 minutes to obtain TPI solutions of 25 mg/kg/day and 50 mg/kg/day.

(b) Methods of radiation (X-ray) irradiation: irradiation conditions (irradiation positions) were set so that mice were irradiated with 2Gy and 5Gy at a time, using a radiation irradiation apparatus of MBR-1505R2 model manufactured by Hitachi Medical Co., Ltd, and human tumor strains transplanted in the right thigh of the mice were irradiated locally. As a method of irradiation, in order to avoid whole body irradiation, the mice were placed in a storage box made of lead, and only the right leg was exposed to radiation.

(c) And (3) testing: a human lung cancer strain (LC-11) which was grown by grafting onto the subcutaneous surface of the back of a syngeneic mouse in advance was excised, cut into pieces of about 2mm square with scissors in physiological saline, and the pieces were subcutaneously transplanted onto the right thigh of a BALB/cA-nu mouse aged 5 to 6 weeks after birth using a transplantation needle, and after at least 1 to 2 weeks of raising, a control group, a radiation-independent group, a drug-independent group, and a drug-and-radiation combined group were set so that the tumor volumes and standard deviations (S.D.) of the respective groups (6 in 1 group) were as uniform as possible, and then drug administration and radiation irradiation were started. The drug administration groups were orally administered 1 time a day with 0.1mL of TPI administration solution per 10g of body weight using an oral administration probe continuously daily for 14 days. The radiation irradiation group was irradiated with 2Gy and 5Gy in the above manner within about 1 hour after administration of the TPI drug solution on the 1 st and 8 th days from the start of the test. The control group (non-irradiated and non-drug-administered group) and the cancer-bearing mice in the irradiated group were orally administered with 0.5% HPMC solution alone for 14 days in the same manner.

Tumor volumes of mice in each group were calculated by the following mathematical formula 1, Tumor volumes before the start of the treatment experiment, on days 3, 5, 8(1 week later), 11, 15 (2 weeks later), 18, 22 (3 weeks later), 25 and 29 (4 weeks later) were calculated, and a Tumor Volume ratio (Relative Tumor Volume; RTV) to the Tumor Volume at the start was calculated, and the average RTV and standard deviation value (S.D.) of each group are shown in Table 1. The mean tumor growth inhibition rate (IR;) of each treatment group of the control group on the 15 th and 22 th days after the end of the treatment period was obtained by equation 2 and is shown in table 1.

(math formula 1)

Tumor volume (mm)³) Long diameter x (short diameter)²×1/2

(math figure 2)

Tumor proliferation inhibition rate (IR,%) [1 — (average tumor volume in treatment group)/(average tumor volume in control group) ] × 100

[ Table 1]

(d) The results of the test: the anti-tumor effect was 40% on day 15 and 49% on day 22 when 2Gy of X-ray was irradiated to the LC-11 tumor model. TPI showed almost no antitumor effect even at 50mg/kg dose, but TPI of 25mg/kg and 50mg/kg and 2Gy X-ray irradiation were used in combination, respectively, and showed antitumor effects of 61.3% and 61.6% on day 15 and 68.7% and 64.1% on day 22, respectively, and the antitumor effect by 2Gy X-ray irradiation was intentionally increased. Since this effect is comparable to the antitumor effect of 5Gy of X-ray irradiation alone, 56% and 61%, the effect of high dose X-ray irradiation by using TPI in combination with low dose X-ray irradiation was judged.

(test example 2)

(a) Preparation of test solution (1): TPI was suspended in 0.5% (W/V) HPMC solution to a concentration of 1.5 and 5.0mg/mL, stirred at room temperature for about 10 minutes with a stirrer, and then sonicated under ice-cooling for about 5 minutes to give 15 mg/kg/day and 50 mg/kg/day TPI solutions.

(b) Preparation of test solution (2): 5-chloro-6-aminouracil (hereinafter abbreviated as TUPI) was suspended in a 0.5% (W/V) HPMC solution to a concentration of 5.0mg/mL, stirred at room temperature with a stirrer for about 10 minutes, and then sonicated under ice-cooling for about 5 minutes to obtain a TUPI solution at 50 mg/kg/day.

(c) Methods of radiation (X-ray) irradiation: irradiation conditions (irradiation positions) were set so that mice were irradiated with 2Gy and 5Gy at a time, using a radiation irradiation apparatus of MBR-1505R2 model manufactured by Hitachi Medical Co., Ltd, and human tumor strains transplanted in the right thigh of the mice were irradiated locally. As a method of irradiation, in order to avoid whole body irradiation, the mice were placed in a storage box made of lead, and only the right leg was exposed to radiation.

(d) And (3) testing: a human lung cancer strain (LC-11) which was grown by grafting onto the subcutaneous surface of the back of a syngeneic mouse in advance was excised, cut into pieces of about 2mm square with scissors in physiological saline, and the pieces were subcutaneously transplanted onto the right thigh of a BALB/cA-nu mouse aged 5 to 6 weeks after birth using a transplantation needle, and after at least 1 to 2 weeks of raising, a control group, a radiation-independent group, a drug-independent group, and a drug-and-radiation combined group were set so that the tumor volumes and standard deviations (S.D.) of the respective groups (6 in 1 group) were as uniform as possible, and then drug administration and radiation irradiation were started. The TPI drug solution and the TUPI drug solution were each orally administered at a rate of 0.1mL per 10g body weight using an oral administration probe at a rate of 1 time per day for a drug administration group continuously daily for 14 days. The radiation irradiation group was irradiated with 2Gy and 5Gy in the above manner within about 1 hour after administration of TPI and TUPI liquid medicines on the 1 st and 8 th days from the start of the test. The control group (non-irradiated and non-drug-administered group) and the cancer-bearing mice in the irradiated group were orally administered with 0.5% HPMC solution alone for 14 days in the same manner.

Tumor volumes of mice of each group were obtained by using equation 1 of test example 1, and Tumor volumes before the start of the treatment experiment, on days 3, 5, 8 (after 1 week), 11, 15 (after 2 weeks), 18, 22 (after 3 weeks), 25, and 29 (after 4 weeks) after the end of the administration were calculated, and a Tumor Volume ratio (Relative Tumor Volume; RTV) to the Tumor Volume at the start was obtained, and the average RTV and standard deviation value (s.d.) of each group are shown in table 2. The mean tumor growth inhibition rate (IR;) of each treatment group of the control group on the 15 th, 22 th and 29 th days after the end of the treatment period was determined in the same manner as in test example 1 and is shown in table 2.

[ Table 2]

(e) The results of the test: the anti-tumor effect was 38% on day 15, 45% on day 22 and 45% on day 29 when 2Gy of X-ray was irradiated alone in the LC-11 tumor model. When irradiated with 5Gy of X-ray, the samples showed IR values of 55%, 63.5% and 72.6%, respectively. When 50mg/kg of TUPI was administered alone, it showed almost no antitumor effect in this tumor model, and even when it was used in combination with 2Gy of X-ray, no enhancement of the antitumor effect was observed. On the other hand, TPI alone hardly exhibited any antitumor effect, but the antitumor effect increased depending on the dose by using 2Gy of X-rays in combination, and 50mg/kg of TPI in combination with 2Gy of X-rays gave 50.6% of IR on day 15, 57% of IR on day 22 and 70% of IR on day 29, which was comparable to the antitumor effect of 5Gy of X-rays alone.

(test example 3)

(a) Preparation of test solutions: TPI was suspended in 0.5% (W/V) HPMC solution to a concentration of 10.0mg/mL, stirred at room temperature for about 10 minutes with a stirrer, and then sonicated under ice-cooling for about 5 minutes to give a TPI solution of 100 mg/kg/day.

(b) Methods of radiation (X-ray) irradiation: irradiation conditions (irradiation positions) were set so that the mouse was irradiated with 20Gy of radiation at a time, and the right thigh of the mouse was irradiated locally, using a radiation irradiation apparatus of MBR-1505R2 model manufactured by Hitachi Medical. As a method of irradiation, in order to avoid whole body irradiation, the mice were placed in a storage box made of lead, and only the right leg was exposed to radiation.

(c) And (3) testing: BALB/cA-nu mice 6 to 8 weeks after birth were divided into a control group, a radiation-only group, and a group using a drug and radiation in combination, 1 group consisting of 6 mice, and drug administration and radiation irradiation were started. Since even the agent (TPI) itself does not exhibit an antitumor effect or a side effect by continuous daily oral administration, the agent alone group is omitted. The radiation-irradiated group was irradiated with 10 Gy/mouse on the 1 st, 2 nd and 3 rd days of the start of the test, and the group was irradiated with 3 days of the drug and radiation as described above, and TPI drug solution was continuously administered orally at a rate of 1 time per 1 day over 7 days using a probe for oral administration in an amount of 0.1mL per 10g body weight of the mouse. In the combination group, 10Gy of X-rays was irradiated within about 1 hour after administration of the TPI solution. In normal mice in the control group (non-irradiated and non-drug-administered), only 0.5% HPMC solution was orally administered for 7 days in the same manner.

(d) Determination of the degree of skin damage: 7 days after The start of The test, The degree of damage to The skin of The thigh caused by The irradiation of radiation was evaluated according to The method of Douglas et al (Douglas BG, et al: The effect of multiple small groups of X-ray skin reactions in The micro and a basic interpretive. radiation Res., 66: 401 426, 1976.).

(e) And (3) test results: in the group to which only radiation was applied, skin moisture loss and keratinization (grade 1.0 to 1.5) and skin surface defects (grade 2.5 to 3.0) began to occur in all 6 cases from day 10, and these symptoms reached the maximum on day 13 (fig. 1). On the other hand, mild lesions (redness, swelling, and skin surface keratinization) were observed in the group using the combination of the drug (TPI) and radiation, but no serious symptoms were observed (fig. 2). The control group did not see any skin damage.

From the above results, it was judged that TPI has a reducing effect on tumors, enhances the antitumor effect due to radiation irradiation, and does not enhance the damage due to radiation to normal tissues (here, normal skin).

(test example 4)

(a) Preparation of test solutions I: α, α, α -trifluorothymidine (hereinafter abbreviated as FTD) and TPI were suspended in 0.5% (W/V) HPMC solution at concentrations of 5.0mg/mL and 2.65mg/mL, respectively, and after stirring at room temperature for about 10 minutes, the mixture was sonicated in ice to obtain a formulation (hereinafter abbreviated as TAS-102) of 50 mg/kg/day (FTD equivalent). The TAS-102 solution was administered at the maximum nontoxic level to mice at 14 days of oral administration.

(b) Preparation of test solutions II: FTD was suspended in 0.5% (W/V) HPMC solution to a concentration of 5.0mg/mL, stirred at room temperature for about 10 minutes, and then sonicated under ice-cooling to give 50 mg/kg/day of FTD solution. The amount of FTD is the maximum nontoxic amount when administered orally to mice for 14 days.

(c) Methods of radiation (X-ray) irradiation: irradiation conditions (irradiation positions) were set so that mice were irradiated with 2Gy and 5Gy at a time, using a radiation irradiation apparatus of MBR-1505R2 model manufactured by Hitachi Medical Co., Ltd, and human tumor strains transplanted in the right thigh of the mice were irradiated locally. As a method of irradiation, in order to avoid whole body irradiation, the mice were placed in a storage box made of lead, and only the right leg was exposed to radiation.

(d) And (3) testing: a human lung cancer strain (LC-11) which was grown by grafting onto the subcutaneous surface of the back of a syngeneic mouse in advance was excised, cut into pieces of about 2mm square with scissors in physiological saline, and the pieces were subcutaneously transplanted onto the right thigh of a BALB/cA-nu mouse aged 5 to 6 weeks after birth using a transplantation needle, and after at least 1 to 2 weeks of raising, a control group, a radiation-independent group, a drug-independent group, and a drug-and-radiation combined group were set so that the tumor volumes and standard deviations (S.D.) of the respective groups (6 in 1 group) were as uniform as possible, and then drug administration and radiation irradiation were started. The TAS-102 and FTD solutions were administered orally at a rate of 0.1mL per 10g body weight using an oral administration probe at a rate of 1 time per day for a drug administration group continuously daily over 14 days. The radiation irradiation group was irradiated with 2Gy and 5Gy in the above manner within about 1 hour after administration of TAS-102 and FTD solutions on the 1 st and 8 th days from the start of the test. The control group (non-irradiated and non-drug-administered group) and the cancer-bearing mice in the irradiated group were orally administered with 0.5% HPMC solution alone for 14 days in the same manner.

Tumor volumes of mice in each group were obtained by expression 1 in test example 1, and Tumor volumes before the start of the treatment experiment, on days 3, 5, 8 (after 1 week), 11, 15 (after 2 weeks), 18, 22 (after 3 weeks), 25, and 29 (after 4 weeks) were calculated, and the ratio of Tumor Volume to Tumor Volume at the start (RTV) was obtained, and the average Tumor growth inhibition rate (IR;) in each treatment group was obtained for the control group on days 15, 22, and 29 after 4 weeks as in test example 1, and is shown in Table 3.

[ Table 3]

(e) And (3) test results: in the LC-11 tumor model, 2Gy of X-ray irradiation showed 21% of the antitumor effect on day 15, 16% on day 22, 25.7% on day 29, and TAS-102 alone showed 23%, 32%, and 49% of the antitumor effect, respectively, and the combined use of these two showed an intentionally increased antitumor effect, which was 49% on day 15, 55.5% on day 22, and 61% on day 29. The combined effect is comparable to the antitumor effect of 5Gy of X-ray radiation alone. On the other hand, FTD showed 52%, 57% and 59% effects when administered alone, but its antitumor effect did not increase even when 2Gy of X-ray was used in combination. From the above results, it was judged that the TAS-102 preparation containing TPI had an enhancing effect on the antitumor effect by radiation.

Claims (6)

1. Use of a uracil derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof for production of a radiation therapy enhancer,

in the formula, R¹Represents a halogen atom or a cyano group; r²Represents a linear or branched alkyl group which may have 1 to 4 carbon atoms, an imino group, a hydroxyl group, a hydroxymethyl group, a methanesulfonyloxy group or an amino groupA 4-to 8-membered heterocyclic group containing 1-to 3-nitrogen atoms, or a 1-pyrrolidinylmethyl group as a substituent.

2. Use according to claim 1, characterized in that:

R¹is a chlorine atom, a bromine atom or a cyano group, R²Is 1-pyrrolidinyl, 2-iminopyrrolidin-1-yl or 1-pyrrolidinylmethyl.

3. Use according to claim 2, characterized in that:

the effective component is 5-chloro-6- [1- (2-iminopyrrolidinyl) methyl ] uracil or its pharmaceutically acceptable salt.

4. Use according to any one of claims 1 to 3, wherein:

is used in combination with cancer radiotherapy.

5. Use according to any one of claims 1 to 3, wherein:

the use of α, α, α -trifluorothymidine is also used in combination.

6. Use according to claim 4, characterized in that:

the use of α, α, α -trifluorothymidine is also used in combination.