WO2004110488A1 - Medicament permettant de vaincre une resistance a des agents anticancereux et sa methode de criblage - Google Patents

Medicament permettant de vaincre une resistance a des agents anticancereux et sa methode de criblage Download PDF

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Publication number
WO2004110488A1
WO2004110488A1 PCT/JP2004/008186 JP2004008186W WO2004110488A1 WO 2004110488 A1 WO2004110488 A1 WO 2004110488A1 JP 2004008186 W JP2004008186 W JP 2004008186W WO 2004110488 A1 WO2004110488 A1 WO 2004110488A1
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Prior art keywords
dione
spiro
imidazolidine
compound
anticancer drug
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PCT/JP2004/008186
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English (en)
Japanese (ja)
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Kaori Taniko
Chihiro Hibi
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Sanwa Kagaku Kenkyusho Co., Ltd.
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Publication of WO2004110488A1 publication Critical patent/WO2004110488A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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.
  • cancer has become one of the most socially ill diseases that accounts for one quarter of the deaths of Japanese people.
  • 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.
  • cancer chemotherapy it is a serious problem that cancer cells show resistance to the drugs used, that is, the development of drug resistance.
  • 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.
  • 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.
  • 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.
  • 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
  • an object of the present invention is to provide an agent for overcoming resistance to an anticancer drug in a cancer having resistance.
  • 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.
  • 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.
  • 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 is a graph showing the growth inhibition rate of daunorubicin hydrochloride using MCF7 / ADR with and without the addition of fidarestat.
  • Fig. 3 is a graph showing the rate of growth inhibition by daunorubicin hydrochloride using MES-SA with and without fidarestat.
  • 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 is a graph showing the growth inhibition rate of daunorubicin hydrochloride using MES-SA / Dx with and without the addition of fidarestat.
  • Fig. 6 is a graph showing the growth inhibition rate of doxorubicin hydrochloride using MES_SA / Dx with and without the addition of fidarestat.
  • 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.
  • Compounds that inhibit AR include fidarestat and epalrestat.
  • fidalestat whose long-term safety has been confirmed, ie, (2S, 4S) _6-fluoro-2,5,5-dioxospiro [chroman-4,4, -imidazoline] -2-carboxamide. preferable.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a method for measuring the activity required by using the decrease in NADPH as an index are aware of the evaluation system for anticancer drug resistance.
  • the anticancer drug and the test compound 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.
  • Intracellular AR activity was measured and compared using MCF7 / WT, a human breast cancer cell, and MCF7 / ADR, a multidrug-resistant cell thereof.
  • 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.
  • 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 ⁇ 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 ⁇ L / well.
  • the final concentration of daunorubicin hydrochloride is 2 X 10_ 8 - 2 X 10 4 ⁇
  • final concentration of Fidaresutatsuto was 10 mu Micromax or ⁇ / i M.
  • 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.
  • 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 ⁇ g 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.
  • 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.
  • MES-SA Human uterine cancer cells
  • MES-SA / Dx Human uterine cancer cells
  • MES-SA contained 2,000 cells in McCoy's 5a medium containing 5% FBS.
  • MES-SA / Dx 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.
  • the medium containing the anticancer drug and fidarestat was added at 100 AiL / well, except for the medium.
  • 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 ⁇ . 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.
  • fidalestat has an IC value of daunorubicin hydrochloride and doxorubicin hydrochloride against multi-drug resistant MES-SA cells.
  • 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.

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Abstract

L'invention concerne un agent permettant de vaincre une résistance, notamment la résistance à des agents anticancéreux. En particulier, l'invention concerne un agent permettant de vaincre une résistance à un agent anticancéreux, comprenant un composé d'inhibition AR en tant que principe actif ; l'utilisation d'un composé d'inhibition AR pour la production d'un agent permettant de vaincre une résistance à un agent anticancéreux ; une composition pharmaceutique comprenant un composé d'inhibition AR et un composé présentant une activité anticancéreuse. L'invention concerne une méthode de criblage d'un agent permettant de vaincre une résistance à des agents anticancéreux, consistant à évaluer un composé présentant une activité d'inhibition AR, au moyen d'un système d'évaluation pour vaincre une résistance à un agent anticancéreux, afin de sélectionner un composé hautement efficace. L'invention concerne également une méthode de traitement de cancer résistant, par l'administration d'un inhibiteur AR combiné à un agent anticancéreux, à un patient ; etc. Le fidarestat est de préférence utilisé en tant que composé d'inhibition AR.
PCT/JP2004/008186 2003-06-12 2004-06-11 Medicament permettant de vaincre une resistance a des agents anticancereux et sa methode de criblage WO2004110488A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080255217A1 (en) * 2005-02-22 2008-10-16 Chihiro Yabe Preventive or therapeutic agent for cardiac dysfunction or myocardial injury caused by ischemia or ischemia reperfusion
US20110092566A1 (en) * 2004-11-19 2011-04-21 Srivastava Satish K Treatment of cancer with aldose reductase inhibitors
CN103063794A (zh) * 2012-12-24 2013-04-24 扬子江药业集团南京海陵药业有限公司 一种依帕司他片的含量检测控制方法
CN106362153A (zh) * 2016-01-06 2017-02-01 浙江大学 醛酮还原酶1b1抑制剂在制备抗乳腺癌药物中的应用
EP3226859A4 (fr) * 2014-12-05 2018-12-12 Case Western Reserve University Compositions et procédés de modulation de s-nitrosylation
US11426386B2 (en) 2014-12-05 2022-08-30 Case Western Reserve University Compositions and methods of modulating S-nitrosylation
US11518748B2 (en) 2018-09-21 2022-12-06 Case Western Reserve University Aldoketo reductase inhibitors and uses thereof
US11576900B2 (en) 2017-09-25 2023-02-14 Case Western Reserve University Compositions and methods of reducing serum cholesterol and PCSK9
US11931339B2 (en) 2018-06-25 2024-03-19 Case Western Reserve University Compositions and methods for treating tissue injury

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372268B (zh) * 2021-07-06 2023-10-17 宁夏康亚药业股份有限公司 4-氧代-6-甲氧基-3-(2,3-二氯苯基)甲基-1(4h)喹啉乙酸代谢产物

Citations (1)

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JP2001163805A (ja) * 1999-12-07 2001-06-19 Pfizer Prod Inc 糖尿病性合併症治療用のアルドース還元酵素阻害剤と抗高血圧剤の組合せ

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110092566A1 (en) * 2004-11-19 2011-04-21 Srivastava Satish K Treatment of cancer with aldose reductase inhibitors
US20080255217A1 (en) * 2005-02-22 2008-10-16 Chihiro Yabe Preventive or therapeutic agent for cardiac dysfunction or myocardial injury caused by ischemia or ischemia reperfusion
CN103063794A (zh) * 2012-12-24 2013-04-24 扬子江药业集团南京海陵药业有限公司 一种依帕司他片的含量检测控制方法
CN103063794B (zh) * 2012-12-24 2014-08-06 扬子江药业集团南京海陵药业有限公司 一种依帕司他片的含量检测控制方法
EP3226859A4 (fr) * 2014-12-05 2018-12-12 Case Western Reserve University Compositions et procédés de modulation de s-nitrosylation
US11351155B2 (en) 2014-12-05 2022-06-07 Case Western Reserve University Compositions and methods of modulating s-nitrosylation
US11426386B2 (en) 2014-12-05 2022-08-30 Case Western Reserve University Compositions and methods of modulating S-nitrosylation
CN106362153A (zh) * 2016-01-06 2017-02-01 浙江大学 醛酮还原酶1b1抑制剂在制备抗乳腺癌药物中的应用
US11576900B2 (en) 2017-09-25 2023-02-14 Case Western Reserve University Compositions and methods of reducing serum cholesterol and PCSK9
US11931339B2 (en) 2018-06-25 2024-03-19 Case Western Reserve University Compositions and methods for treating tissue injury
US11518748B2 (en) 2018-09-21 2022-12-06 Case Western Reserve University Aldoketo reductase inhibitors and uses thereof

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