WO2004110488A1

WO2004110488A1 - Drug for overcoming anticancer agent resistance and method of screening the same

Info

Publication number: WO2004110488A1
Application number: PCT/JP2004/008186
Authority: WO
Inventors: Kaori Taniko; Chihiro Hibi
Original assignee: Sanwa Kagaku Kenkyusho Co., Ltd.
Priority date: 2003-06-12
Filing date: 2004-06-11
Publication date: 2004-12-23
Also published as: JP2007015924A

Abstract

A resistance overcoming agent capable of overcoming the resistance to anticancer agents. In particular, an overcoming agent for anticancer agent resistance, comprising an AR inhibiting compound as an active ingredient; use of an AR inhibiting compound for production of an anticancer agent resistance overcoming agent; a pharmaceutical composition comprising an AR inhibiting compound and an anticancer activity having compound; a method of screening an overcoming agent for anticancer agent resistance, comprising assessing a compound having AR inhibiting activity by means of an evaluation system for anticancer agent resistance overcoming to thereby select a highly effective compound; a method of treating resistant cancer through administration of an AR inhibitor combined with an anticancer agent to a patient; etc. Fidarestat is preferably used as the AR inhibiting compound.

Description

Specification

Drug overcoming anticancer drug resistance and screening method thereof

Technical field

The present invention belongs to the field of pharmaceuticals and relates to the use of an aldose reductase inhibitor for overcoming resistance to an anticancer drug.

Background art

[0002] In recent years, cancer has become one of the most socially ill diseases that accounts for one quarter of the deaths of Japanese people. Currently, surgical treatment, radiation therapy, chemotherapy, etc. are being used as treatments for cancer, but these methods alone have not been able to achieve sufficient therapeutic effects. In addition, in cancer chemotherapy, it is a serious problem that cancer cells show resistance to the drugs used, that is, the development of drug resistance.

[0003] One of the main causes of drug resistance is P-glycoprotein. P-glycoprotein is a protein that exists in the cell membrane and acts as a pump that pumps drugs out of the cell, thereby reducing the drug concentration in the cell. It is known that some cancer cells highly express the MDR1 gene encoding this P-glycoprotein and increase the amount of P-glycoprotein on the cell membrane. In such cancer cells, the drug concentration in the cell decreases to below the effective concentration, resulting in resistance to the drug. In addition, P-glycoprotein has low substrate specificity <, and in cancer cells in which MDR1 is overexpressed, it simultaneously acquires resistance to other drugs as well as the drugs previously used, and chemotherapy. Is often impossible. Such a phenomenon is called multidrug resistance. Drugs that cause cancer cells to develop resistance due to multidrug resistance include drugs with different chemical structures and modes of action, such as doxorubicin hydrochloride, actinomycin D, vinblastine sulfate, vincristine sulfate, colchicine, and daunorubicin hydrochloride ( Molecular mechanism of drug resistance, edited by Takashi Tsuruo, pplO-19, 1994, Yodosha). These are typical drugs that are frequently used in chemotherapy, and thus the severity of the multidrug resistance problem can be understood.

[0004] In recent years, it has been reported that 29% of patients with liver cancer express aldose reductase (hereinafter referred to as AR), and 54% express AR-like proteins. ( Cao D, et al, J Biol Chem 1998, 273, ppl 1429-11435). It is also a liver cancer cell

H Mark When osmotic pressure is applied to G2 to forcibly overexpress AR, cytotoxicity after 2 hours of treatment with daunorubicin, an anticancer drug, is reduced, and an AR inhibitor (hereinafter referred to as ARI) must be added. It was also reported that cytotoxicity was significantly increased in this study (Lee KWY, et al. Anti-Cancer Drugs 2001, 12, ppl29-132). ₀ However, this test was performed under very severe hyperosmolarity. However, since it is quite different from the normal state and only evaluates the cytotoxicity of the anticancer drug in a short period of time, it does not suggest the effect of the ARI on overcoming normal anticancer drug resistance.

[0005] On the other hand, it has been reported that when HeLa cells, which are uterine cancer cells, were treated with doxorubicin hydrochloride or cisplatin, which is an anticancer drug, for 12 days with ARI, the number of cell deaths was large in the presence of ARI. (Anti-Cancer Drugs 2002, 13 pp859_868). However, in this report, it was proved that the effect of AR inhibition was as a result of using AR to confirm the AR expression in the cells used. Not. In addition, this report only shows that the effect of the anticancer drug was enhanced, but did not disclose whether or not the cells used were resistant to the anticancer drug. It does not imply an effect.

[0006] Furthermore, it has been reported that AR expression is enhanced in resistant strains prepared under conditions in which the expression of P-glycoprotein and MRP, which is considered to be the cause of multidrug resistance, is suppressed (Biochemical Pharmacology, Vol. 59). Pp. 293-300, 2000), again under special conditions, and do not suggest the effect of ARI on overcoming normal anticancer drug resistance.

[0007] In order to solve the above-mentioned problem in drug resistance, search for and development of a substance that inhibits the function of P-glycoprotein has been attempted. For example, it has been reported that potent antagonists such as veravamil hydrochloride and immunosuppressants such as cyclosporin A inhibit the function of P-glycoprotein S. However, when these drugs are administered for the purpose of overcoming drug resistance, their inherent effects of calcium antagonism and immunosuppression appear as strong side effects, and are not suitable for actual administration. Cyclosporine inducers and quinoline derivatives are also being developed, but have not been applied to clinical applications due to toxicity problems. [0008] By the way, fidarestat is an ARI discovered by the present applicant and has been shown to have an effect on diabetic neuropathy, an effect on diabetic simple retinopathy, and an effect on diabetic keratopathy. Due to its high potential, it is currently undergoing clinical trials as an oral drug.

[0009] Non-patent document 1: Molecular mechanism of drug resistance, edited by Takashi Tsuruo, pplO-19, 1994, Yodosha

Non-Patent Document 2: Cao D, et al, J Biol Chem 1998, 273, ppl 1429-11435

Non-Patent Document 3: Lee KWY, et al. Anti-Cancer Drugs 2001, 12, ppl29-132

Non-patent document 4: Anti-Cancer Drugs 2002, 13u 859-868

Non-Patent Document 5: Biochemical Pharmacology, Vol.59, pp.293-300, 2000

Disclosure of the invention

Problems the invention is trying to solve

[0010] The problem of drug resistance is an important issue to be solved in the treatment of cancer, and the development of drugs that restore anticancer drug resistance means providing a therapeutic means for these diseases for which there is no cure. And significant. Therefore, an object of the present invention is to provide an agent for overcoming resistance to an anticancer drug in a cancer having resistance.

Means for solving the problem

[0011] The present inventors have found that AR is highly expressed in cancer cells exhibiting anticancer drug resistance, and found that a compound that inhibits AR overcomes anticancer drug resistance of cancer cells, and completed the present invention. That is, the present invention relates to an agent for overcoming anticancer drug resistance comprising a compound that inhibits AR as an active ingredient.

[0012] The present invention also provides use of an AR-inhibiting compound for producing an anticancer drug resistance overcoming agent, a pharmaceutical composition comprising an AR-inhibiting compound and a compound having anticancer activity, and an AR-inhibiting activity. A screening method for an agent for overcoming anticancer drug resistance characterized by evaluating a compound in an evaluation system for overcoming anticancer drug resistance and selecting a compound with high efficacy, and a resistant cancer administered to a patient in combination with an ARI and an anticancer agent The method of treatment.

BRIEF DESCRIPTION OF THE FIGURES

[0013] [Fig. 1] Fig. 1 shows the use of MCF7 / WT for adding and removing fidarestat-added kaolin. It is a figure which shows the growth inhibition rate by unorubicin.

[Fig. 2] Fig. 2 is a graph showing the growth inhibition rate of daunorubicin hydrochloride using MCF7 / ADR with and without the addition of fidarestat.

[Fig. 3] Fig. 3 is a graph showing the rate of growth inhibition by daunorubicin hydrochloride using MES-SA with and without fidarestat.

[Fig. 4] Fig. 4 is a graph showing the growth inhibition rate of doxorubicin hydrochloride using MES-SA with and without the addition of fidarestat.

[Fig. 5] Fig. 5 is a graph showing the growth inhibition rate of daunorubicin hydrochloride using MES-SA / Dx with and without the addition of fidarestat.

[Fig. 6] Fig. 6 is a graph showing the growth inhibition rate of doxorubicin hydrochloride using MES_SA / Dx with and without the addition of fidarestat.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail. The present invention is based on the finding that AR is highly expressed in cancer cells exhibiting anticancer drug resistance, and that compounds that inhibit AR overcome the anticancer drug resistance of cancer cells that have acquired resistance to anticancer drugs. . That is, one embodiment of the present invention is an agent for overcoming anticancer drug resistance comprising a compound that inhibits AR as an active ingredient, and another embodiment is the use of an AR inhibitor compound for producing an anticancer drug overcoming agent. Is expressed.

[0015] Compounds that inhibit AR include fidarestat and epalrestat.

(Mark alrestat), tonorestatto (tolrestat), ponorerestatto (ponalrestat), zoponorerestatto zopolrestat), senafustatto (zenarestat), mirestatto umirestat), nanorerestatoto (minalrestat), sonorebinorenorenoil (sorbin) (methosorbinil), ADN_138 (8'-chloro—2, ό'-dihydrospiro [pyrroliine-3, 6 (5 ri) -pyrrolo [l, 2,3-de] [l, 4] benzoxazine] -2,5 , 5 '-trione), AS— 3201

((R) — (—) — 2— (4— bromo— 2— fluorobenzyl) — 1,2,3,4— tetrahydropyrrolo [l, 2— a] pyrazine— 4— s piro-3 '-pyrrolidine-1 , 2 ', 3, 5' -tetrone), ZD5522 (

N- [3,5-dimethyl-4-[(nitromethyl) sulfonyl] phenyl] -2-methylbenzeneacetamide)), SP R— 210 (3,4_dihydro_3_oxo_4 _ [(4,5,7_trifluoro_2_benzothiazolyl) methyl] -2H- 1, 4-benzothiazine-2-acetic acid),

3,4_Dihydro_2,8_diisopropy 3_yhioxo_2H_l, 4_benzoxazine_4_acetic acid, 6-Fluoro-2-methyl-spiro- [chroman-4,4'-imidazolidine] _2,, 5'-dione,

6-Chloro-2-methyl-spiro- [chroman-4,4'-imidazolidine] -2 ', o-dione,

dl-bpiro- (2-fluorofluoren-9,4'-imidazolidine) -2,5'-dione,

Spiro- [2,7-difluorofluoren-9,4'-imidazolidine] -2 ', 5'-dione, d-cis-6'-Chloro-2', 3'-2'-methyl-spiro- [imidazolidine- 4,4 '-4' H-pyrano [2,3-b] pyridine] -dione, Spiro [imidazolidine— 4,5, (6, H) — quinoline] -2,5-dione— 3'—cnloro— 7 ', 8'-dihydro-7'-methy (5'_cis), or salts thereof. Also, these prodrugs may be used. Above all, fidalestat, whose long-term safety has been confirmed, ie, (2S, 4S) _6-fluoro-2,5,5-dioxospiro [chroman-4,4, -imidazoline] -2-carboxamide. preferable.

[0016] Anticancer drugs for overcoming anticancer drug resistance include, but are not particularly limited to, doxorubicin hydrochloride, daunorubicin hydrochloride, pirarubicin, vinblastine sulfate, bintaristin sulfate, actinomycin D, colchicine, conoresemide, puromycin, emetine, and anthracene. Examples include cyclin, noritaxel, and mitomycin C. ARI is effective in overcoming the resistance of cancer cells that have acquired resistance to one or more or more of these anticancer drugs. Among them, ARI is particularly effective for overcoming resistance to doxorubicin hydrochloride, daunorubicin hydrochloride, pirarubicin, anthracycline, and the like. It is also particularly effective in overcoming multidrug resistance. As a mechanism for overcoming resistance, ARI is expected to be effective against anticancer drugs that are deactivated by some metabolism by AR.

[0017] The target cancer is not particularly limited as long as it is a cancer that shows resistance to an anticancer drug, but not only a cancer that has become resistant by administration of an anticancer drug, but also a drug that is originally resistant to an anticancer drug. It may be a cancer that shows, or it may be a multidrug-resistant cancer. Anticancer drug-resistant cancers with high AR expression are suitable targets. In particular, ARI is particularly effective in overcoming resistance to anticancer drug-resistant breast cancer and liver cancer. Whether ARI is really effective as a drug to overcome resistance in patients with resistant cancers is confirmed by collecting cancer tissues and examining their AR expression. be able to. If AR expression is higher than that of a non-resistant cancer, it can be concluded that ARI is effective as a resistance-overcoming agent. That is, the present invention is characterized in that the presence or absence of AR expression in cancer cells of a cancer patient who has become resistant to an anticancer drug is confirmed, and ARI is administered together with the anticancer drug to a resistant cancer patient in which AR expression has been observed. It also provides a method for treating resistant cancer.

[0018] The anticancer drug-resistance overcoming agent according to the present invention can be prepared by conventional techniques, for example, orally as tablets, capsules, powders, granules, solutions, syrups, or parenterally as eye drops, injections, suppositories. Can be administered in a controlled manner. The dose varies depending on symptoms, age, administration method, dosage form, and compound, but if it is a fidarestat, it is usually administered to adults.

It is preferable to administer 0.1-100mg / day once or several times a day every day. The dose generally varies depending on the type of the anticancer drug, the type of the cancer and its symptoms or the administration method, and the dose can be administered outside the above range.

The anticancer drug resistance overcoming agent of the present invention is generally administered simultaneously with an anticancer drug. Therefore, it can also be used as a combination drug in a drug product together with an anticancer drug. That is, a pharmaceutical composition containing ARI and a compound having anticancer activity can be obtained. Further, the anticancer drug resistance overcoming agent of the present invention can be used in combination with another anticancer drug resistance overcoming agent, and can be used as a combination drug with them.

[0020] From another viewpoint, the present invention can be said to be a method for screening a compound that overcomes anticancer drug resistance based on the inhibitory activity of AR. This method consists of the steps of evaluating the AR inhibitory activity of the test compound and the step of evaluating the obtained compound having AR inhibitory activity using an anticancer drug resistance overcoming evaluation system. This is a screening method that selects compounds with high efficacy in the evaluation system as compounds that overcome resistance to anticancer drugs. The step of evaluating the AR inhibitory activity of the test compound can be omitted, and the existing ARI can be used. The system for evaluating AR inhibitory activity is known to those skilled in the art. However, the reaction is carried out using AR or glucose or dariceraldehyde, or a compound capable of recognizing AR as a substrate, and NADPH as a coenzyme. In general, a method for measuring the activity required by using the decrease in NADPH as an index. Also, those skilled in the art are aware of the evaluation system for anticancer drug resistance. However, the anticancer drug and the test compound (here, ARI) are allowed to coexist in resistant cancer cells. This is a screening method in which the effects of anticancer drugs alone are compared using cell viability or cell proliferation rate or cytotoxic activity as an index. Here, it is particularly optimal to use resistant cancer cells with high AR expression.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Example 1

[0022] Intracellular AR activity was measured and compared using MCF7 / WT, a human breast cancer cell, and MCF7 / ADR, a multidrug-resistant cell thereof. For each cultured cell, the medium was removed, the cells were collected by trypsinization, and then centrifuged to remove the supernatant. Subsequently, centrifugation and removal of the supernatant were repeated three times using cold phosphate buffered saline. Further, the buffer system of 20 mM phosphate buffer PH7.5 containing 0.5 mM ethylenediaminetetraacetic acid and 7 mM mercaptoethanol was removed, the cells were disrupted using a cell ultrasonic disruptor, and centrifuged. The supernatant was used as a measurement sample, and the NADPH consumption per unit time was measured as AR activity based on the change in absorbance associated with NADPH consumption when using dalyseraldehyde as a substrate. The AR-like activity was calculated from the protein concentration in the cell extract as the amount of protein. The results are shown in Table 1. At this time, in the cell extract of MCF7 / WT, NADPH consumption was not suppressed even with the addition of 2000 nmol ZL of the ARI fidarestat, confirming that this activity was not due to AR. On the other hand, about 80% of the MCF7 / ADR cell extract was inhibited by 60 nmol ZL-added cucumber of fidarestat, which is an ARI, and it was confirmed that the activity was due to AR. The results showed that MCF7 / ADR expressed much more AR than MCF7ZWT had very low AR expression.

[Table 1] NADPH consumption

nmoiymin / mg protein

MC F 7 / WT 0.5 5 7

MC F 7 / AD R 2.3 1 7 Example 2

[0024] Using a human breast cancer cell MCF7 / WT and its multidrug-resistant cell MCF7ZADR, the expression level of AR mRNA was measured by RT-PCR and compared. MCF7ZWT and MCF7ZADR were cultured in a 6-well plate, and total RNA was extracted and purified. After lxg equivalent of total RNA was reverse-transcribed, the expression level of ARmRNA was measured by real-time PCR. In the same reverse transcription sample, the expression level of G3PDH mRNA was measured, and the AR expression level was corrected based on the obtained G3PDH expression level. Here, it was calculated as the ratio per G3PDH10 ³ copies. The results are shown in Table 2. These results confirmed that the AR expression level of MCF7 / ADR was significantly increased as compared to MCF7 / WT.

[Table 2]

Average value S.D. (n = 3) Example 3

Use the MCF7ZAD R is MCF7 / WT and its multidrug resistance of the cells, a human breast cancer cell Rere, in RPMI1640 medium containing 5 ^_0/0 FBS 4, 000 cells / well in 96-well plates ί Komaki, 37 ° The cells were cultured for 24 hours in an atmosphere containing 5% C and carbon dioxide. Next, remove the medium, , And a medium containing an anticancer agent and fidarestat were added at 100 μL / well. Here, the final concentration of daunorubicin hydrochloride is ^{2 X 10_ 8 - 2 X 10} 4 Μ, final concentration of Fidaresutatsuto was 10 mu Micromax or Ο / i M. This was further cultured for 3-4 days in an atmosphere containing 5% of carbon dioxide at 37 ° C. Measure the background of 450 nm-690 nm in advance, and incubate 3 reagents (10 reagents) for 1 hour at 37 ° C in an atmosphere containing 5% carbon dioxide, and absorbance at 450 nm-690 nm. Was measured. The IC value of daunorubicin hydrochloride was calculated based on the value obtained by subtracting the value measured before the reaction from the value measured after the reaction.

50

The results are shown in Figure 1 (MCF7 / WT), Figure 2 (MCF7 / ADR), and Table 3. In addition, IC

The 50 values were calculated from a few points around 50% inhibition. As can be seen from Figs. 1, 2 and Table 3, fidarestat did not affect the IC value of daunorubicin hydrochloride against MCF7ZWT cells that did not have multidrug resistance, but did not affect the MCF7 / ADR cells that had become multidrug resistant.

50

Showed that daunorubicin hydrochloride reduced the IC value and overcome the tolerance.

50

[Table 3]

Example 4

[0028] Using MES-SA, a cell derived from human uterine cancer, and MES-SA / Dx, a multidrug-resistant cell thereof, the expression level of AR mRNA was measured by RT-PCR and compared. MES-SA and MES-SA / Dx were cultured in a 6-well plate, and the total RNA was extracted and purified. After 1 μg of total RNA was reverse-transcribed, the expression level of ARmRNA was measured by real-time PCR. In the same reverse transcription sample, the expression level of G3PDH mRNA was also measured, and the AR expression level was corrected based on the obtained G3PDH expression level. In this case, it was calculated as the ratio per G3PDH10 ³ copies. The results are shown in Table 4. Based on these results, the AR expression level of MES_SAZDx was significant (P <0.001) compared to MES-SA. It was confirmed that the number increased.

[0029] [Table 4]

Average value ± s. Example 5

[0030] Human uterine cancer cells, MES-SA, and their multidrug-resistant cells, MES-SA / Dx, were used. MES-SA contained 2,000 cells in McCoy's 5a medium containing 5% FBS. , And cultured for 24 hours at 37 ° C in an atmosphere containing 5% carbon dioxide. MES-SA / Dx, on the other hand, was seeded on a 96-well plate at 4,000 cells / well in McCoy's 5a medium containing 10% FBS and cultured for 24 hours in an atmosphere containing 37 ° C and 5% carbon dioxide. . Next, the medium containing the anticancer drug and fidarestat was added at 100 AiL / well, except for the medium. Here, the anticancer agent using hydrochloric acid daunorubicin or doxorubicin hydrochloride, the final concentration, for MES-SA are hydrochloric daunorubicin IX 10- ⁹ - 1X10- ⁶ M, hydrochloric Dokisoru bicine IX 10- ⁸ - 2X10- ⁵ and then, for MES-SA / Dx, both 2X10- ⁸ - 2 X10- ⁴ was M. The final concentration of fidalestat was 10 / iM or {μ}. This was further cultured at 37 ° C in an atmosphere containing 5% carbon dioxide for 6 days. On the third day, the medium was replaced with the same medium. After completion of the culture, the medium was removed, and the cells were rinsed with McCoy's 5a medium. Then, 100 μl of McCoy's 5a medium containing FBS and 10 μL of WST-1 reagent were caloried, and the medium was heated at 37 ° C for 12 hours at 37 ° C. The cells were cultured in an atmosphere containing 5%, and the absorbance at 450 nm to 690 nm was measured. To the wells containing no cells, 100 xL of McCoy's 5a medium and 10 zL of WST-1 reagent were added, and the IC values of daunorubicin hydrochloride and doxorubicin hydrochloride were calculated as blank values. This

50

The results are shown in Figure 3-6 and Table 5. The IC value was calculated from 23 points around 50% inhibition.

50

Issued. As is evident from Fig. 36 and Table 5, fidalestat has an IC value of daunorubicin hydrochloride and doxorubicin hydrochloride against multi-drug resistant MES-SA cells.

50 MES-SAZDx cells that had no effect but became multidrug resistant Unolubicin and doxorubicin hydrochloride showed the effect of lowering IC value and overcoming tolerance [Table 5]

Industrial applicability

The present invention is to provide a new drug for overcoming resistance which is completely different from the conventional drug for overcoming anticancer drug resistance, and is extremely useful in providing a new method for treating resistant cancer and multidrug resistant cancer.

Claims

The scope of the claims

An agent for overcoming anticancer drug resistance comprising a compound that inhibits aldose reductase as an active ingredient. Compound ability to inhibit aldose reductase Minanoreles Tatto (minalrestat), Sonorebininore (sorbinil), Methosorenbininore (methosorbinil), ADN—138 (8-chloro-2 ', 3—dinydrospiro [pyrrolidine—3, (5H) -pyrrolo [l, 2 , 3-de] [l, 4] b enzoxazine] -2, 5, 5 '-trione), AS— 3201

((R) — (—) — 2— (4— bromo— 2— fluorobenzyl) — 1,2,3,4— tetrahydropyrrolo [l, 2— a] pyrazine— 4— s piro-3 -pyrrolidine-1, 2, ό, 5 '-tetrone), ZD5522 (

N- [3,5-dimethyl-4-[(nitromethyl) sulfonyl] phenyl] -2-methylbenzeneacetamide)), S PR-210 (3,4-dihydro-3-oxo-4-[(4,5,7 -trifluoro-2-benzothiazolyl) methyl]

-2H- 1, 4-benzothiazine-2-acetic acid),

6-Chloro-2-methyl-spiro- [chroman-4,4-imidazolidine] -2,, 5'-dione,

dl-Spiro- (2-fluorofluoren-9,4'-imidazolidine) -2 ', 5'-dione,

Spiro- [2, "_ difluorofluoren_9,4'-imidazolidine] _2,, 5'-dione, d-cis-6'-Chloro-2 ', 3'-2'-methyl-spiro- [imidazolidine-4,4' -4 'H-pyrano [2,3-b] pyridine] -dione, Spiro [imidazolidine— 4,5' (ri ri) —quinoline] -2,5-dione—3'—chloro—7 ', 8— 2. The agent for overcoming anticancer drug resistance according to claim 1, which is one or more compounds selected from the group consisting of dihydro-7'-methyl- (5'-cis), salts thereof, and prodrugs thereof.

The agent for overcoming anticancer drug resistance according to claim 2, wherein the compound that inhibits aldose reductase is fidarestat.

Anticancer drug resistance against one or more anticancer drugs selected from the group consisting of doxorubicin hydrochloride, daunorubicin hydrochloride, pyralubicin, vinblastine sulfate, vincristine sulfate, actinonomycin D, colchicine, puromycin, emetine, anthracycline, colcemide, paclitaxel, and mitomycin C 4. Any one of claims 1 to 3, which is resistant to an anticancer drug. An agent for overcoming anticancer drug resistance according to the above item.

5. The agent for overcoming anticancer drug resistance according to claim 4, wherein the anticancer drug resistance is resistance to daunorubicin hydrochloride.

Use of a compound that inhibits aldose reductase for producing an agent for overcoming anticancer drug resistance.

Compound ability to inhibit aldose reductase Minorarestat (minalrestat), sonorebininole (sorbinil), metsonorebininore (methosorbinil), ADN-138 (8-chloro-2,3-dihydrospiro [pyrrolidine- ^, 6 (5H) -pyrrolo [l, 2, 3-de] [l, 4] benzoxazine] -2,5, o -trione), AS— 3201

((R)-(-)-2- (4-bromo-2-fluorobenzyl) -l, 2,3,4-tetrahydropyrrolo [l, 2-a] pyrazine-4-s piro-3 -pyrrolidine- 1, 2, ό, 5 '-tetrone), ZD5522 (

-2H- 1, 4-benzothiazine-2-acetic acid),

6_Chloro_2_methy spiro_ [chroman_4,4-marauder dazolidine] _2 、、 5'-dione,

dl-Spiro- (2-fluorofluoren-9,4'-imidazolidine) _2,, 5'-dione,

Spiro_ [2,7_difluorofluoren_9,4'-imidazolidine] _2,, 5'-dione, d_cis_6'-Chloro-2 ', 3'-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano [2,3-b] pyridine] -dione, Spiro [imidazolidine— 4,5 '(ri ri) —quinoline] -2,5-dione—3'—chloro—7', 8—dihydro—7'-methy 7. The use according to claim 6, which is one or more compounds selected from the group consisting of (5'_cis) and salts thereof, and their prodrugs.

The use according to claim 7, wherein the compound that inhibits aldose reductase is fidarestat.

A compound comprising a compound that inhibits aldose reductase and a compound that has anticancer activity. Drug composition.

Compounds that inhibit aldose reductase (minalrestat), sonorebinin (sorbinil), methosonorebinin (methosorbinil), ADN-138 (8-chloro-2,3-dihydrospiro [pyrrolidine- ^, 6 (5H) -pyrrolo [l, 2,3- de] [l, 4] benzoxazine] -2,5, o -trione), AS— 3201

((R)-(-)-2- (4-bromo-2-fluorobenzyl) -l, 2,3,4-tetrahydropyrrolo [l, 2-a] pyrazine-4-s piro-3 '-pyrrolidine- 1 , 2, ό, 5 '-tetrone), ZD5522 (

N- [3,5-dimethyl-4-[(nitromethyl) sulfonyl] phenyl] -2-methylbenzeneacetamide)), SPR-210 (3,4-dihydro-3-oxo-4-[(4,5,7 -trifluoro-2-benzothiazolyl) methyl]

-2H- 1, 4-benzothiazine-2-acetic acid),

6_Chloro_2_methy spiro_ [chroman_4,4-marauder dazolidine] _2 、、 5'-dione,

dl-Spiro- (2-fluorofluoren-9,4'-imidazolidine) _2,, 5'-dione,

Spiro_ [2,7_difluorofluoren_9,4'-imidazolidine] _2,, 5'-dione, d_cis_6'-Chloro-2 ', 3'-2'-methyl-spiro- [imidazolidine-4,4'-4'H-pyrano [2,3-b] pyridine] -dione, Spiro [imidazolidine-4,5 '(ri ri) _quinoline] _2, 5_dione_3'-chloro-7,, 8'-dihydro-7'-methyl- (5'- 10. The pharmaceutical composition according to claim 9, which is one or more compounds selected from the group consisting of cis) and salts thereof, and prodrugs thereof.

11. The pharmaceutical composition according to claim 10, wherein the compound that inhibits aldose reductase is fidarestat.

The anticancer drug is one or more anticancer drugs selected from the group consisting of doxorubicin hydrochloride, daunorubicin hydrochloride, pyrarubicin, vinblastine sulfate, vincristine sulfate, actinomycin D, conorechitin, puromycin, emetin, anthracycline, colcemid, paclitaxel, and mitomycin C. 12. The pharmaceutical composition according to claim 9-11, wherein: Compounds with aldose reductase inhibitory activity evaluated in an evaluation system for overcoming anticancer drug resistance A screening method for an agent for overcoming resistance to an anticancer drug, which comprises selecting a compound having high potency and high efficacy.

14. The agent for overcoming anticancer drug resistance according to claim 13, wherein a compound having an aldose reductase inhibitory activity is selected in an evaluation system for evaluating the aldose reductase inhibitory activity of a test compound. Screening method.

[15] A method for treating resistant cancer, comprising administering to a patient a combination of an aldose reductase inhibitor and an anticancer drug.