WO2014068972A1

WO2014068972A1 - Side effect reducing agent for sorafenib

Info

Publication number: WO2014068972A1
Application number: PCT/JP2013/006424
Authority: WO
Inventors: 功坂井田; 山本　直樹; 隆弘山崎
Original assignee: 国立大学法人山口大学
Priority date: 2012-11-05
Filing date: 2013-10-30
Publication date: 2014-05-08
Also published as: JPWO2014068972A1; JP6179904B2

Abstract

The present invention addresses the problem of providing an agent for reducing side effects of cancer treatment that is based on administering sorafenib or a pharmacologically acceptable salt thereof, and a potentiator of anticancer activity from administering of sorafenib or a pharmacologically acceptable salt thereof. As a means of solving the problem, the following are prepared: a reducing agent of side effects caused by administering sorafenib or a pharmacologically acceptable salt thereof in cancer treatment, the reducing agent comprising as active ingredients thereof deferasirox or a pharmaceutically acceptable salt thereof; and a potentiator of anticancer activity from administering sorafenib or a pharmacologically acceptable salt thereof, the potentiator comprising deferasirox or a pharmaceutically acceptable salt thereof.

Description

Side effects of sorafenib

The present invention relates to 4- [4- [3- [4-chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide (hereinafter also referred to as “sorafenib”). For more details on side effect reducing agents, agents for enhancing anticancer action by sorafenib, and the like, more specifically, 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl ] Side effects caused by administration of sorafenib or pharmacologically acceptable salt thereof in the treatment of cancer comprising benzoic acid (hereinafter also referred to as “deferacilox”) or a pharmacologically acceptable salt thereof as an active ingredient And a potentiator of anticancer action by administration of sorafenib or a pharmacologically acceptable salt thereof, comprising deferasirox or a pharmacologically acceptable salt thereof. That.

The top cause of death in Japan is cancer, and countermeasures are the most important from the viewpoint of the health of the people. Current cancer treatment methods include surgical treatment, radiotherapy, chemotherapy, immunotherapy, etc. Among them, chemotherapy using an anticancer agent is widely used. However, many anti-cancer drugs have the problem of many side effects because they damage not only cancer cells but also normal cells, and the development of effective therapeutic agents that can effectively treat cancer It is not easy, and sufficient therapeutic agents are not yet obtained.

Among cancers, hepatocellular carcinoma is one of the most frequent solid cancers in the world, and the death rate from hepatocellular carcinoma in Japan in 2011 was the fourth highest death rate due to malignant neoplasm ( About 35,000 people a year). Hepatocellular carcinoma is a cancer that recurs at an annual rate of 15 to 20% even if it is detected at an early stage. Eventually, fibrosis progresses and the number and size of the cancers increase, and the cells progress to advanced hepatocytes. Treatment becomes difficult. Currently, there are only treatments for advanced hepatocellular carcinoma, in which anticancer drugs are injected directly into the liver from the arteries (hepatic arterial infusion chemotherapy) or ingestion. There is currently no effective treatment for advanced hepatocellular carcinoma that does not respond to these treatments.

Sorafenib, one of the anticancer drugs, is a molecularly-targeted drug that can be administered orally. It directly inhibits Raf activity in the MAP kinase pathway that acts on cancer cell proliferation and acts on angiogenesis. It is a kinase inhibitor that simultaneously inhibits VEGF receptor and PDGF receptor activities. This sorafenib was developed by Bayer Yakuhin and Onyx Pharmaceuticals, Inc., and sorafenib tosyl salt (BAY43-9006) was formulated. As of September 2009, hepatocellular Approved in over 70 countries for cancer. In Japan, it is marketed by Bayer Yakuhin as Nexavar® and is the only approved treatment for systemic chemotherapy for unresectable hepatocellular carcinoma.

However, in the actual administration of sorafenib or pharmacologically acceptable salt thereof, hand-foot syndrome, deprivation dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding Cause serious side effects such as hematoma, tumor bleeding, loss of appetite, weight loss, liver weight, and liver function, not only significantly lowering the patient's quality of life but also decreasing early after the start of medication Cases where drugs or withdrawal are often a problem.

On the other hand, in recent years, iron chelating agents have attracted attention as cancer chemotherapeutic agents. The present inventors have found that an iron chelator, deferoxamine, has a remarkable antitumor effect, and it is clear that intraarterial infusion chemotherapy can be one of new treatments for advanced liver cancer ineffective in clinical practice. (For example, refer to Patent Document 1 and Non-Patent Document 1). However, since deferoxamine has a short effective half-life in blood, since the administration method for treatment is intravenous administration, continuous administration is necessary, and there is a problem that the stage is limited.

In addition, it is known that deferasirox alone, which is an iron chelator, suppresses liver fibrosis and liver cancer (see, for example, Non-Patent Document 2), but the liver fibrosis and liver cancer. The generation suppressing effect was not sufficient.

Furthermore, diseases associated with the growth and / or proliferation of neoplastic cells and / or tissues in mammals, especially humans, and / or triggered by refractory angiogenesis are: (a) iron chelators; and (b) one species A method for preventing or treating with a combination of medicines containing the above pharmaceutically active agents is known (see, for example, Patent Document 2). However, this method only shows anti-proliferative activity at the cellular level in combination with deferasirox and 5-fluorouracil, mitomycin C, cisplatin, leucovorin and Tumdex.

In addition, as a side effect reduction of sorafenib by a combination of sorafenib and an antibody, a pharmaceutical composition for treating or preventing liver cancer, which is a combination of sorafenib and glypican 3 antibody, is known (for example, Patent Document 3). See), and there are problems in productivity and cost by producing antibodies.

JP 2009-196959 A Special table 2009-536180 gazette No. 2009-122667

An object of the present invention is to reduce an adverse effect in cancer treatment by administering sorafenib or a pharmacologically acceptable salt thereof, or an anticancer effect by administering sorafenib or a pharmacologically acceptable salt thereof. It is to provide an enhancer.

In order to solve the above-mentioned problems, the present inventors have intensively studied, and in studying a concomitant drug with sorafenib or a pharmacologically acceptable salt thereof, the action mechanism of the therapeutic effect on cancer of the iron chelator itself. In spite of the fact that Sorafenib or its pharmacologically acceptable salt was used in combination with an iron chelator, it was accidentally found that sorafenib tosylate and iron chelator deferasirox In addition, the improvement of hand-foot syndrome, which is one of the side effects of sorafenib, was observed.

Therefore, as a result of further research, not only the improvement of hand-foot syndrome was observed, but the use of deferasirox in combination with sorafenib tosylate reduced various side effects caused by sorafenib, and in addition, sorafenib We found that the administration of tosylate suppresses the decrease in survival time, which is considered to be a kind of side effect. We have also found that the combined use of deferasirox with sorafenib tosylate enhances the anticancer effect of sorafenib. The present invention has been completed based on these findings.

That is, the present invention relates to [1] 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof. 4- [4- [3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide, or a pharmacological thereof, which is an active ingredient and is produced in cancer treatment An agent for reducing side effects caused by administration of an acceptable salt, [2] a side effect reducing agent according to [1] above, wherein the cancer treatment is treatment of hepatocellular carcinoma, and [3] side effects But hand-foot syndrome, deprivation dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding, hematoma, tumor bleeding, loss of appetite, weight loss, liver weight reduction, That one of the liver function decline The side effect reducing agent described in [1] or [2] above, or [4] the side effect reducing agent described in any one of [1] to [3] above, which is an oral drug, [5] 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof, [4- [3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide or a pharmacologically acceptable salt thereof for anticancer activity An enhancer, or [6] an anticancer effect enhancer according to [5] above, wherein the [6] anticancer effect is an inhibitory effect on hepatocellular carcinoma, or [7] an anticancer effect. Is an anti-cancer product according to [5] above, which has an action of suppressing fibrosis of liver tissue And [8] 4- [3,5-bis (2-hydroxyphenyl) -1H- [1,2,4] triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof 4- [4- [3- [4-chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide or a pharmaceutically acceptable salt thereof, The present invention relates to a kit for treating or preventing cancer.

According to the side effect reducing agent of the present invention, side effects such as skin symptoms, bleeding, decrease in body weight and liver weight, and decrease in survival time due to administration of sorafenib or a pharmacologically acceptable salt thereof can be improved. . In addition, according to the enhancer of anticancer action of the present invention, by enhancing the carcinogenesis inhibitory effect of hepatocellular carcinoma or the fibrosis inhibitory effect of liver tissue by administration of sorafenib or a pharmacologically acceptable salt thereof, Cancer treatment is possible by administration of a smaller amount of sorafenib or a pharmacologically acceptable salt thereof than before, and it is possible to administer sorafenib or a pharmacologically acceptable salt thereof in an early and long-term manner. Therefore, it becomes possible to suppress hepatic fibrosis of refractory cirrhosis and suppress the development of hepatocellular carcinoma.

It is a figure which shows the result of having investigated the survival rate of the liver fibrosis / liver carcinogenesis rat. The vertical axis represents the survival rate of rats when all the rats are alive in each group, and the horizontal axis represents the number of days (days) from the start of administration of choline-deficient diet (CDAA diet). It is a figure which shows the Azan staining result of a liver fibrosis / liver carcinogenesis rat. The upper left of FIG. 2 is (1) CDAA only continuous administration group (CDAA only 16w), the upper part of FIG. 2 is (2) CDAA + deferasirox single agent continuous administration group (CDAA + Deferairox 16w), and the upper right of FIG. 2 is (4) CDAA + sorafenib + deferasirox combination continuous administration group (CDAA + Sorafenib + Deferairox 16w). In the lower part of FIG. 2, the vertical axis is Azan positive area (%), and the horizontal axis is from the left (1) CDAA only continuous administration group (CDAA16w), (2) CDAA + deferasirox single agent continuous administration group (CDAA + DEF 16w) (3) CDAA + sorafenib single agent continuous administration group (CDAA + SOR 16w), (4) CDAA + sorafenib + deferasirox combination continuous administration group (CDAA + SOR + DEF 16w). “DEF” represents deferasirox, and “SOR” represents sorafenib (the same applies hereinafter). It is a figure which shows the immunohistochemical staining result by the GST-P antibody of a liver fibrosis / liver carcinogenesis rat. In the upper part of FIG. 3, the vertical axis is the tumor area (%) by GST-P staining, the horizontal axis is from the left (1) CDAA only continuous administration group (CDAA16w), (2) CDAA + deferasirox single agent continuous administration group (CDAA + DEF 16w), (3) CDAA + sorafenib single agent continuous administration group (CDAA + SOR 16w), (4) CDAA + sorafenib + deferasirox combination continuous administration group (CDAA + SOR + DEF 16w). In the lower part of FIG. 3, the vertical axis is the number of tumors per unit area (1 cm ² ), and the horizontal axis is the same as in the upper part of FIG.

As an agent for reducing side effects caused by administration of sorafenib or a pharmacologically acceptable salt thereof produced in the cancer treatment of the present invention (hereinafter also simply referred to as “the side effect reducing agent of the present invention”), the following formula (I): 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid (deferasirox) or a pharmaceutically acceptable salt thereof represented by the formula: If it contains as an active ingredient, it will not restrict | limit in particular. By administering the side effect reducing agent of the present invention in combination with sorafenib or a pharmacologically acceptable salt thereof, side effects due to administration of sorafenib or a pharmacologically acceptable salt thereof can be reduced.

The compound represented by the above formula (I) is sold as a chelating agent from Novartis Pharma Co., Ltd. as “XJADE (registered trademark)” in Japan and as “Exjade (registered trademark)” overseas. As this deferasirox or a pharmacologically acceptable salt thereof, a commercially available product may be used, or a known product described in, for example, International Publication No. 97/49395 published on Dec. 31, 1997. It can be manufactured by a method.

Examples of pharmacologically acceptable salts of deferasirox include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and transition metal salts such as zinc salts. Hydroxy-lower alkylamines such as cyclic amine salts, mono-, di- or tri-lower alkylamine salts, mono-, di- or trihydroxy-lower alkylamine salts, polyhydroxy-lower alkylamine salts, etc. And salts thereof and hydroxy-lower alkyl-lower alkylamine salts.

4- [4- [3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide (sorafenib) or a pharmaceutically acceptable salt thereof in the present invention Is not particularly limited as long as it contains a compound represented by the following formula (II) or a pharmacologically acceptable salt thereof as an active ingredient. Sorafenib is a multikinase inhibitor that inhibits Raf kinase, PDGFR kinase, VEGFR kinase, and KIT kinase.

The compound represented by the above formula (II) is sold by Bayer Yakuhin as “Nexavar (registered trademark)” in Japan and “Nexavar (registered trademark)” overseas. This sorafenib or a pharmacologically acceptable salt thereof may be a commercially available product, or can be produced by a known method described in, for example, Japanese Patent No. 3845792.

Examples of pharmacologically acceptable salts of sorafenib include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, sulfate and other inorganic acid salts, acetates, trifluoroacetic acid Salt, succinate, oxalate, lactate, tartrate, glycolate, butyrate, valerate, citrate, fumarate, maleate, malate, p-toluenesulfonic acid (tosyl) Acid) salts, methane sulfonates, trifluoromethane sulfonates, benzene sulfonates, 1-naphthalene sulfonates, 2-naphthalene sulfonates, and the like. Can be preferably mentioned.

In the present invention, side effects are not particularly limited as long as they are caused by administration of sorafenib or a pharmacologically acceptable salt thereof, but skin symptoms (hand-foot syndrome, deprivation dermatitis, eczema, hair loss, erythema), bleeding ( Gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding, hematoma, tumor bleeding), loss of appetite, weight loss, liver weight reduction, liver function decline, oxidative stress, especially limb syndrome Preferable examples include, exfoliative dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, loss of appetite, weight loss, and liver weight reduction.

Here, the reduction of side effects means that the symptoms of the above side effects such as skin symptoms, bleeding, loss of appetite, etc. are reduced. For example, if the symptoms are skin symptoms, the area where the symptoms occur is reduced, or if bleeding This means that the bleeding site and the amount of bleeding decrease. Furthermore, as a result of increased side effects caused by excessive administration of sorafenib or a pharmacologically acceptable salt thereof, the survival rate within a predetermined period may be reduced. However, the increase of such side effects can also be improved.

The anticancer activity enhancer (hereinafter also referred to as “the anticancer activity enhancer of the present invention”) by sorafenib or a pharmaceutically acceptable salt thereof of the present invention is represented by the above formula (I). There is no particular limitation as long as it contains deferasirox or a pharmacologically acceptable salt thereof as an active ingredient. As the pharmacologically acceptable salt of deferasirox or sorafenib or the pharmacologically acceptable salt thereof in the anticancer activity enhancer of the present invention, the same as the case of the side effect reducing agent of the present invention described above. Mention may be made of salts.

The cancer to be the subject of the present invention is not particularly limited as long as sorafenib or a pharmacologically acceptable salt thereof exhibits an anti-cancer effect. For example, hepatocellular carcinoma, renal cell carcinoma, Breast cancer can be mentioned, and hepatocellular carcinoma can be mentioned more suitably.

The anti-cancer effect of the anti-cancer effect enhancer of the present invention is not particularly limited, but it suppresses carcinogenesis such as hepatocellular carcinoma, suppresses fibrosis of liver tissue, suppresses oxidative stress, and improves the function of organs such as liver. Suitable examples include suppression of hepatocellular carcinoma carcinogenesis or suppression of liver tissue fibrosis.

Deferasirox or a pharmacologically acceptable salt thereof in the side effect reducing agent of the present invention or the anticancer activity enhancing agent of the present invention reduces side effects caused by administration of sorafenib or a pharmacologically acceptable salt thereof. Can be provided as a single preparation together with a package insert etc. to the effect of sorafenib or a pharmacologically acceptable salt thereof to enhance the anticancer effect. It may be a mixed preparation of ferrasilox or a pharmacologically acceptable salt thereof and sorafenib or a pharmacologically acceptable salt thereof.

The kit for the treatment or prevention of cancer of the present invention includes deferasirox or a pharmacologically acceptable salt thereof, and sorafenib or a pharmacologically acceptable salt thereof as individual active ingredients. The kit is not particularly limited as long as it is a kit containing a combination of preparations (combination preparation), and may include a package insert or the like describing a method for treating or preventing cancer using the kit, and treating or preventing such cancer. Because the side effect of sorafenib is reduced and the anticancer effect is enhanced, long-lasting administration is possible from an early stage, which suppresses liver fibrosis of refractory cirrhosis, It becomes possible to suppress the onset of cell cancer.

Preferred examples of the administration target of the side effect reducing agent of the present invention, the anticancer agent enhancing agent of the present invention, and the kit for treating or preventing cancer of the present invention include mammals or mammalian cells. Among such mammals, humans, mice, rats, guinea pigs, rabbits, birds, sheep, pigs, cows, horses, cats, dogs, monkeys, chimpanzees can be more preferably mentioned, and humans are particularly preferred. Can be mentioned.

Each combination of the side effect reducing agent of the present invention (single preparation or mixed preparation), the anti-cancer activity enhancer of the present invention (single preparation or mixed preparation), and the kit for treating or preventing cancer of the present invention Examples of the dosage form of the preparation include powders, granules, tablets, solutions, emulsions, suspensions, syrups, capsules, suppositories, injections and the like. These preparations are prepared according to the necessity of the preparation, as appropriate pharmacologically acceptable carriers such as solvents, excipients, binders, solubilizers, suspending agents, emulsifiers, tonicity agents, Manufactured by blending optional ingredients such as buffers, stabilizers, soothing agents, preservatives, antioxidants, colorants, lubricants, disintegrants, wetting agents, adsorbents, sweeteners, diluents, etc. be able to.

The method for administering each component of the kit for reducing or reducing the side effect of the present invention, the enhancer of anticancer activity of the present invention, and the kit for treating or preventing cancer of the present invention comprises the effect of reducing the side effect of the present invention, Although it is not particularly limited as long as it has an effect of enhancing the anticancer action of the invention, oral administration or parenteral administration such as rectal administration, buccal administration, subcutaneous administration, intramuscular administration, intravenous administration, etc. can be mentioned, Oral administration is preferred in that it does not require heavy continuous infusion treatment. Furthermore, each component of the agent for reducing side effects of the present invention (single preparation), the enhancer of anticancer action of the present invention (single preparation), and the kit for treating or preventing cancer of the present invention comprises sorafenib or It may be administered at the same time as its pharmacologically acceptable salt, either one may be administered first, but from the viewpoint of obtaining a better side effect reducing effect or enhancing anticancer effect of the present invention. It is preferable to administer sorafenib or a pharmaceutically acceptable salt thereof.

The dose of deferasirox in the kit for reducing side effects of the present invention, the enhancer of anticancer activity of the present invention, and the kit for treating or preventing cancer of the present invention includes the reduction of the side effects of the present invention. Although it is not particularly limited as long as it has the effect of enhancing the anticancer action of the present invention, for example, in the case of a human adult, it is 20 to 500% by mass, preferably 50 to 300% by mass, more preferably to sorafenib. A preferred example is 100 to 200% by mass, more preferably 130 to 170% by mass. The daily dose of deferasirox can be appropriately adjusted according to the dose of sorafenib. For example, in the case of a human adult, 5 to 30 mg / kg, preferably 10 to 25 mg / kg, more preferably Can be 18 to 22 mg / kg.

On the other hand, the daily dose of sorafenib is not particularly limited. For example, in the case of a human adult, it is preferable not to exceed 14 mg / kg.

The administration time zone of deferasirox in the kit for reducing side effects of the present invention, the enhancer of anticancer activity of the present invention, and the kit for treating or preventing cancer of the present invention is not particularly limited, even in the morning. Evening may be possible, but when the dose is large, it is preferable to administer it in multiple doses per day.

The present invention will be described in detail by the following examples, but the present invention is not limited to these examples.

[Observation of rats with liver fibrosis / carcinogenesis]
(Production of rats with liver fibrosis / liver carcinogenesis)
Continued choline-deficient L-amino acid-defined: CDAA (518752 Choline Deficient Diet: Dyets Inc.) to 80 6-week-old Wister male rats (SLC) (20 rats in each group) After administration, the rats were bred for 12 weeks at 25 ° C. for 16 weeks (112 days), and the following four groups of liver fibrosis / liver carcinogenesis rats were prepared as shown in (1) to (4) below. Rats with fibrosis and liver carcinogenesis caused by the CDAA diet are the only models that can develop a liver cancer onset state from cirrhosis encountered in clinical practice.
(1) CDAA-only continuous administration group (2) CDAA + deferasirox 20 mg / kg / day single agent continuous administration group (hereinafter also referred to as “CDAA + deferasirox single agent continuous administration group”)
(3) CDAA + sorafenib 13.3 mg / kg / day single agent continuous administration group (hereinafter also referred to as “CDAA + sorafenib single agent continuous administration group”)
(4) CDAA + sorafenib 13.3 mg / kg / day + deferasirox 20 mg / kg / day combination continuous administration group (hereinafter also referred to as “CDAA + sorafenib + deferasirox combination continuous administration group”)

As the deferasirox, XJade (registered trademark) manufactured by Novartis was used, and Nexavar (registered trademark) manufactured by Bayer Yakuhin was used as the sorafenib. Nexavar 1 mg contains 1 mg of sorafenib (1.37 mg as sorafenib tosylate). All the administration methods were oral administration, and in the above (4) CDAA + sorafenib + deferasirox combination continuous administration group, sorafenib and deferasirox were administered simultaneously.

(result)
The following three items (a) to (c) were observed in the four groups (1) to (4) of the liver fibrosis / liver carcinogenic rat.

(A) Skin symptoms (3) In the CDAA + sorafenib single agent continuous administration group, compared with the (1) CDAA only continuous administration group and (2) CDAA + deferasirox single agent continuous administration group, limb syndrome, deprivation as skin symptoms Idiopathic dermatitis, eczema, hair loss and erythema were observed. (4) In the continuous administration group of CDAA + sorafenib + deferasirox, the above skin symptoms were significantly suppressed.

(B) Bleeding (3) Gastrointestinal bleeding was observed in the (1) CDAA + sorafenib single agent continuous administration group compared to the (1) CDAA only continuous administration group and (2) CDAA + deferasirox single agent continuous administration group (4) In the continuous administration group of CDAA + sorafenib + deferasirox combined use, gastrointestinal bleeding was significantly suppressed.

(C) Appetite (3) In the CDAA + sorafenib single agent continuous administration group, (1) CDAA only continuous administration group and (2) CDAA + deferasirox single agent continuous administration group, (4) In the CDAA + sorafenib + deferasirox combination continuous administration group, anorexia was significantly improved.

From the above observation results, it was found that the side effect reducing agent of the present invention significantly reduces the side effects caused by sorafenib.

[Examination of body weight and liver weight]
(Measurement item)
The body weight and liver weight of the rats of the 16th week (day 112) of the four groups (1) to (4) prepared in Example 1 were measured.

(result)
In terms of body weight, the (3) CDAA + sorafenib single agent continuous administration group had a decrease of 32% (166.2 ± 18.18) compared to the (1) CDAA alone continuous administration group (245.1 ± 7.7 g). 8g), however, (4) CDAA + sorafenib + deferasirox combined continuous administration group (1) CDAA alone decreased only 10% compared to the continuous administration group (221.4 ± 5.1 g). In addition, the liver weight was reduced by 50% in the (3) CDAA + sorafenib single agent continuous administration group as compared with the (1) CDAA alone continuous administration group (14.7 ± 0.8 g) (7.3). (± 1.8 g), but (4) CDAA + sorafenib + deferasirox combined continuous administration group (1) CDAA alone decreased only 11% compared to the continuous administration group (13.1 ± 0.1 g) . Therefore, (4) the continuous administration group of CDAA + sorafenib + deferasirox was found to reduce body weight loss and liver weight reduction, which are side effects due to sorafenib. In addition, the CDAA + deferasirox single agent continuous administration group (1) CDAA only continuous administration group, body weight (240.5 ± 3.8 g), liver weight (13.9 ± 0.1 g) were almost the same. .

[Examination of survival time in each treatment group]
(Production of rats with liver fibrosis / liver carcinogenesis)
Continued choline-deficient L-amino acid-defined: CDAA (518752 Choline Deficient Diet: Dyets Inc.) to 36 6-week-old male Wister rats (9 manufactured by SLC). After administration, the mice were bred at 25 ° C. for 12 hours, and the survival period was examined by dividing into four groups of liver fibrosis / liver carcinogenesis rats (1) to (4) as in Example 1. The deferasirox and sorafenib used and their doses are the same as those in groups (1) to (4) of Example 1. Sorafenib is the upper limit of the dose to be administered to human adults. (13.3 mg / kg / day), and this dose is often problematic in cases where even human adults are forced to reduce or discontinue early after the start of medication by causing serious side effects. This is the amount.

(result)
As is clear from FIG. 1, (3) in the CDAA + sorafenib single-drug continuous administration group (••••), rats that die from the 90th day were produced, and about half of the rats died on the 100th day. On the day, all rats died. On the other hand, in the (4) CDAA + sorafenib + deferasirox continuous administration group (− ▲ −), all rats survived until the 200th day, and more than half of the rats survived even on the 280th day. More than 30% of the rats were alive. From this, it became clear that the combined use of deferasirox with sorafenib markedly improved the “decrease in survival time”, which is considered to be one of the side effects of sorafenib. In the figure, the solid line (-) is (1) the CDAA-only continuous administration group, and (2) the CDAA + deferasirox single-drug continuous administration group.

[Examination of liver function fibrosis inhibitory effect]
(Preparation of paraffin-embedded undyed specimen)
Azan staining was performed on liver fibrosis / carcinogenesis rats of the 16th week (112 days) of the four groups (1) to (4) obtained in Example 1. A small amount of liver tissue was collected from each group of rats (1) to (4), the collected liver tissue was immersed in formalin, and a paraffin-embedded unstained sample was prepared from the formalin-fixed tissue.

(Azan staining)
The above-mentioned paraffin-embedded unstained specimen was subjected to Azan staining for fiber tissue staining according to a conventional method. That is, after deparaffinization of the paraffin section, it was mordanted for 20 minutes in a mixed solution of 10% potassium dichromate / 10% trichloroacetic acid and washed with distilled water (5 minutes). It was immersed in an 8% orange G aqueous solution for 10 minutes. After washing with distilled water (about 10 seconds, the same applies hereinafter), the sample was immersed in azocarmine G solution for 60 minutes, washed with distilled water and then immersed in aniline / alcohol for 3 seconds for fractionation. After washing with distilled water, it was treated in acetic alcohol for 1 minute, washed with distilled water, and further treated in 2.5% phosphotungstic acid solution for 20 minutes. This was washed with distilled water and then stained in an aniline blue / orange G mixed solution for 20 to 60 minutes under a microscopic examination. After dyeing, it was washed with water, dehydrated, transparent, and sealed. The Azan positive area ratio was analyzed using a fluorescence microscope image processing system Meta Morph (manufactured by Olympus). The results are shown in FIG.

(result)
As is clear from the photograph in the upper part of FIG. 2, liver fibrosis was suppressed to some extent in the (1) CDAA-only continuous administration group (2) CDAA + deferasirox single-agent continuous administration group, but (4) In the continuous administration group of CDAA + sorafenib + deferasirox combination, liver fibrosis was suppressed to such an extent that hepatic fibrosis was hardly observed. In addition, in the Azan positive area in the lower part of FIG. 2, (1) CDAA only continuous administration group, (3) CDAA + sorafenib single agent continuous administration group, the Azan positive area is reduced by about 1 / 7.5, (2) The CDAA + deferasirox single agent continuous administration group had decreased by about 1/4. However, in the (4) CDAA + sorafenib + deferasirox continuous administration group in which this deferasirox was used in combination with sorafenib, the Azan positive area was surprisingly reduced to approximately 1/30. From these results, it was revealed that the combined use of deferasirox with sorafenib enhances the effect of sorafenib on inhibiting fibrosis of the liver as a synergistic effect as well as an additive effect.

[Examination of liver carcinogenesis suppression effect]
(Immunohistochemical staining with GST-P antibody)
Immunohistochemical staining with GST-P antibody was performed on the liver fibrosis / carcinogenesis rats of the 16th week (112 days) of the four groups (1) to (4) obtained in Example 1. First, a paraffin-embedded unstained specimen was prepared in the same manner as in Example 4, and the paraffin section was deparaffinized. Then, using an anti-rat GST-P antibody (manufactured by ABCAM), avidin-biotin-peroxidase The composite (ABC) method was performed, and then GST-P staining was observed with a high-magnification microscope (Olympus). The ratio (%) of the GST-P positive area per area of the tissue piece and the number of tumors per unit area (1 cm ² ) were determined by a fluorescence microscope image processing system Meta Morph (manufactured by Olympus). The results are shown in FIG.

(result)
In the upper part of FIG. 3, the tumor area is reduced by about 1/30 in (3) CDAA + sorafenib single agent continuous administration group compared with (1) CDAA only continuous administration group, but (2) CDAA + deferasirox single In the continuous administration group, only about 1 / 6.5 was decreased. However, in the (4) CDAA + sorafenib + deferasirox combination continuous administration group in which this deferasirox is used in combination with sorafenib, the tumor area is reduced to about 1/46 compared to the (1) CDAA alone continuous administration group. It was. From this result, it was clarified that the combined use of sorafenib and deferasirox enhances the liver fibrosis inhibitory effect of sorafenib as a synergistic effect as well as an additive effect.

In the lower part of FIG. 3, the number of tumors decreased by about 1/7 in the (3) CDAA + sorafenib single agent continuous administration group compared to (1) the CDAA only continuous administration group. The Rocks single-dose continuous administration group had decreased only about 1/3. However, in the (4) CDAA + sorafenib + deferasirox combination continuous administration group in which this deferasirox was used in combination with sorafenib, the number of tumors was surprisingly about 1/20 of that of the group administered with (1) CDAA alone. It had fallen to. From this result, it became clear that the combined use of deferasirox with sorafenib enhances the liver carcinogenesis-suppressing effect of sorafenib as a synergistic effect as well as an additive effect.

The side effect reducing agent of the present invention, the anticancer agent enhancing agent of the present invention, and the kit for treating or preventing cancer of the present invention can be advantageously used in the fields of medicine and medicine.

Claims

In treating cancer, comprising 4- [3,5-bis (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof as an active ingredient The side effects of administration of the resulting 4- [4- [3- [4-chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide or a pharmaceutically acceptable salt thereof. Reducing agent.
The agent for reducing side effects according to claim 1, wherein the cancer treatment is treatment of hepatocellular carcinoma.
Side effects include limb syndrome, deprivation dermatitis, eczema, hair loss, erythema, gastrointestinal bleeding, respiratory tract bleeding, cerebral bleeding, oral bleeding, nasal bleeding, nail bed bleeding, hematoma, tumor bleeding, loss of appetite, weight loss, liver weight reduction 3. The side-effect reducing agent according to claim 1 or 2, wherein the side-effect-reducing agent is a decrease in liver function.
The side-effect reducing agent according to any one of claims 1 to 3, which is an oral drug.
4- [4-5- (4-hydroxy (2-hydroxyphenyl) -1H-1,2,4-triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof, [3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide or a pharmacologically acceptable salt thereof for enhancing an anticancer effect.
6. The agent for enhancing anti-cancer activity according to claim 5, wherein the anti-cancer activity is a carcinogenesis-inhibiting effect on hepatocellular carcinoma.
6. The agent for enhancing anticancer action according to claim 5, wherein the anticancer action is an action of suppressing fibrosis of liver tissue.
4- [3,5-bis (2-hydroxyphenyl) -1H- [1,2,4] triazol-1-yl] benzoic acid or a pharmaceutically acceptable salt thereof and 4- [4- [3- [4-Chloro-3- (trifluoromethyl) phenyl] ureido] phenoxy] -N-methylpyridine-2-carboxamide or a pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer Kit.