WO2022033465A1 - 具有协同抗癌功效的氯硝柳胺和双硫仑医药组合物及其用途 - Google Patents

具有协同抗癌功效的氯硝柳胺和双硫仑医药组合物及其用途 Download PDF

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WO2022033465A1
WO2022033465A1 PCT/CN2021/111752 CN2021111752W WO2022033465A1 WO 2022033465 A1 WO2022033465 A1 WO 2022033465A1 CN 2021111752 W CN2021111752 W CN 2021111752W WO 2022033465 A1 WO2022033465 A1 WO 2022033465A1
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cancer
disulfiram
niclosamide
pharmaceutical composition
synergistic
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French (fr)
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萧乃文
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萧乃文
石贵中
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    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention provides a novel use with synergistic effects for treating cancer or/and improving the side effects of treating cancer.
  • Niclosamide is an eelicide (Iampricide) and a molluscicide, which can affect the respiration and carbohydrate metabolism of the worm, and can kill many kinds of snails, tapeworms, beef Tapeworm (Taeniasaginata), Pork Tapeworm (Taeniasolium) and Cercariae (Cercariae).
  • Fushou snails also known as big bottle snails, apple snails, English Pomaceacanaliculata
  • it is used to kill snails (the intermediate host of schistosomiasis).
  • the disadvantage of niclosamide is its low absorption rate, which reduces the efficacy of the drug due to the lower dose reaching the target tissue.
  • Disulfiram is an alcohol withdrawal drug used for the treatment of chronic alcoholism and alcohol toxicity psychosis, and has been used in many countries as an alcohol withdrawal drug. After taking this drug, serious reactions such as nausea, vomiting, and fear will occur when drinking alcohol, which makes alcoholics afraid of drinking, thus playing a role in quitting alcohol.
  • the combination of drug therapy can inhibit the growth of cancer cells at multiple targets and improve the success rate of cancer treatment. Therefore, in order to solve the clinical treatment failure caused by drug resistance, it is urgent to test whether different drug combination treatments have synergistic effects to avoid the generation of drug resistance and effectively inhibit the possibility of cancer cell proliferation.
  • the present invention provides a novel pharmaceutical composition, which can achieve synergistic effects to treat cancer or/and improve the new use of old drugs for the treatment of cancer side effects.
  • the "Synergism” mentioned in the present invention means that when two drugs are used together, the effect is greater than the algebraic sum of the individual drug effects, and there is a synergistic effect (synergistic therapeutic effect).
  • the therapeutic effect is worse than that of the single drug; the additive effect is that the effect of the combination drug treatment is not much different than that of the single drug; The therapeutic effect not only reduces the individual dosage of the combined drug, but also reduces the harm caused by the side effects.
  • the " ⁇ value” means that the ⁇ value of the combined drug is greater than 1.5; wherein “survival rate” means that the survival rate of cancer cells is lower than 0.6 (excluding 0.6).
  • “Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are compounds described herein with compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and Acid reactions such as these are obtained.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein having an acidic group with a base to form salts such as: ammonium salts; alkali metal salts, such as sodium or potassium salts; alkaline earth salts Metal salts, such as calcium or magnesium salts; salts of organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, bis(hydroxymethyl)methylamine, and salts with organic bases such as arginine, lysine ( Also known as lysine, Lysine) and salts of such amino acids; or obtained by other methods previously determined.
  • the pharmacologically acceptable salt is not particularly limited as long as it can be used in pharmaceuticals.
  • salts of the compounds described herein with bases include the following: salts with inorganic bases, such as sodium, potassium, magnesium, calcium, and aluminum; and organic bases such as methylamine, ethylamine, and ethanolamine salts with basic amino acids such as lysine and ornithine; and ammonium salts.
  • Salts may be acid addition salts, which are specifically exemplified by acid addition salts formed with mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acids; organic acids, For example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; acidic amino acids such as aspartic acid acid and glutamic acid.
  • mineral acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acids
  • organic acids For example, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulf
  • a "pharmaceutical composition” as used in the present invention refers to a mixture of the drugs described herein and other chemical components such as carriers, stabilizers, diluents, dispersing agents, suspending agents and/or thickening agents.
  • Pharmaceutical compositions facilitate the administration (ie, administration) of a compound to an organism.
  • Various techniques for administering a compound exist in the related art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration (administration).
  • the active compounds of the present invention are preferably administered orally, for example, with an inert diluent or with an ingestible edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be Compressed into lozenges, or they can be incorporated directly into the food of the daily diet.
  • the active compounds can be combined with excipients to form ingestible lozenges, buccal troches, tablets, capsules, elixirs, suspensions, syrups, cachets, and the like.
  • Lozenges, tablets, pills, capsules and the like may also contain the following: binding agents such as tragacanth (tragacanth), acacia gum, cornstarch or gelatin may be added; excipients such as lactose or dicalcium phosphate; disintegration Detergents such as corn starch, potato starch, alginic acid and the like; humectants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin, or flavors such as mint, oil of wintergreen or cherry flavors.
  • Capsule dosage forms may contain liquid carriers in addition to the aforementioned agents.
  • a pharmaceutical composition of niclosamide (Niclosamide) and disulfiram (Disulfiram) with synergistic anticancer efficacy is used for preparing the use of treating a cancer
  • the pharmaceutical composition comprises (A) Niclosamide or/and pharmaceutically acceptable salts, and (B) Disulfiram, Paroxetine, Pyrvinium, Zidovudine ), Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Fasudil, bisphosphonates such as clodronate ( Clodronate) or the group (one or more of the above); wherein the pharmaceutical composition has a synergistic effect in alleviating or/and treating cancer compared to the efficacy of the cancer treatment drug alone.
  • a pharmaceutical composition of niclosamide (Niclosamide) and disulfiram (Disulfiram) with synergistic anticancer efficacy is used for the preparation of the use of treating a cancer, wherein the pharmaceutical composition comprises ( A) disulfiram or/and pharmaceutically acceptable salts, and (B) Niclosamide, Paroxetine, Pyrvinium, Zidovudine , Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lova Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Fasudil, Bisphosphonates such as Clodronate ) or a group(s) of the above; wherein the pharmaceutical composition has a synergistic effect for alleviating or/and treating cancer compared to the efficacy of the cancer treatment drug alone.
  • the synergistic efficacy of the pharmaceutical composition of the present invention is defined as the synergistic effect index ⁇ of the composition is greater than 1.5.
  • composition of the present invention can alleviate or/and treat cancer means that the survival rate of cancer cells is reduced to below 60%.
  • the pharmaceutical composition of the present invention is a drug composed of Niclosamide and disulfiram.
  • the cancer comprises lung cancer, gastric cancer, liver cancer, rectal cancer, kidney cancer, skin cancer, cervical cancer, prostate cancer, bladder cancer, breast cancer, and blood cancer.
  • the effective dose ranges from 100 to 50 nM.
  • DMEM type cell line culture medium lung glands A549 DMEM breast cancer MCF-7 DMEM liver cancer HepG2 DMEM non-small cell carcinoma H460 DMEM Pancreatic cancer BxPC-3 DMEM colorectal cancer HCT116 DMEM ovarian cell carcinoma TOV-21G DMEM triple negative breast cancer MDA-MB-231 DMEM
  • Lung cancer cells A549), breast cancer cells (MCF-7), liver cancer cells (HepG2), non-small cell cancer cells (H460), pancreatic cancer cells (BxPC-3), colorectal cancer cells (HCT116), ovarian cancer cells (TOV-21G) and triple negative breast cancer cell line (MDA-MB-231), cultured in 10% (v/v) fetal bovine serum (Fetal Bovine Serum, Penicillin-Streptomycin Solution) (100X) (ACE Biolabs, CC1009 ) and Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen Carlsbad, CA, USA) medium containing glutamine (Glutamine), and then individual cell lines were placed in a 5% CO 2 , 37°C incubator (Astec-SCA -165DS).
  • fetal bovine serum Fetal Bovine Serum, Penicillin-Streptomycin Solution
  • 100X ACE Biolabs, CC1009
  • DMEM Dulbecco's
  • ⁇ SFA ⁇ SFB/SF(A+B), where SFA represents the survival rate of cells under the action of drug A , SFB is the survival rate of cells under the action of drug B, and SF(A+B) is the survival rate of cells under the action of combined A and B drugs.

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

一种具有协同抗癌功效的氯硝柳胺(Niclosamide)和双硫仑(Disulfiram)新医药组合物及其用途，该医药组合物包括一种以上药物合并使用，以产生协同作用，用于治疗癌症或/及改善治疗癌症副作用的效果。

Description

具有协同抗癌功效的氯硝柳胺和双硫仑医药组合物及其用途 【技术领域】
本发明提供一种新用途，具有协同作用以治疗癌症或/及改善治疗癌症副作用的效果。
【背景技术】
由于癌症病变的机制极其复杂性，单一抗癌药物的治疗并不一定能有效的抑制其治疗的标靶及其下游的讯息传导路径，对该药物的抗药性常随之而生，因而导致病人的癌症复发。
此外，临床上非癌症治疗老药显示，比起化疗药物显著的降低不良的副作用，这代表老药更加适合对于化疗副作用耐受程度较差的患者。
氯硝柳胺(niclosamide)是一种杀鳗剂(Iampricide)，也是一种灭螺剂(molluscicide)，它可影响虫体的呼吸和糖类代谢活动，能杀死很多种蜗牛、绦虫、牛肉绦虫(Taeniasaginata)、猪肉绦虫(Taeniasolium)和尾蚴(Cercariae)。在农业上主要用于杀灭稻田中的福寿螺(又称大瓶螺、苹果螺，英文Pomaceacanaliculata)。同时在公共卫生防治方面，用于杀灭蜗牛(血吸虫的中间宿主)。然而，氯硝柳胺的缺点为吸收率低，由于到达目标组织的剂量较低而削弱了药物的效力。
双硫仑(disulfiram)是一种戒酒药物，用于治疗慢性乙醇中毒和乙醇中毒性精神病的药物，作为一种戒酒药物已在很多国家使用。服用本药后饮酒会出现恶心、呕吐、恐惧等严重反应，而使酗酒者惧怕饮酒，从而 起到戒酒作用。
由于，若以单一药物治疗癌症，可能因为单一疗效而造成治疗效果不佳，因此使用联合药物治疗的方式，可以多靶点的抑制癌细胞的生长，提高癌症治疗的成功率。因此，欲解决抗药性所导致的临床治疗失效，不同的药物组合治疗急需被测试是否具有协同作用能避免抗药性的产生，并有效地抑制癌症细胞增生的可能性。
【发明内容】
有鉴于此，本发明内容提供了一种新颖医药组合物，达到协同效应以治疗癌症或/及改善治疗癌症副作用的老药新用目标。
发明内容旨在提供本揭示内容的简化摘要，以使阅读者对本揭示内容具备基本的理解。此发明内容并非本揭示内容的完整概述，且其用意并非在界定本发明的范围。
本发明中所述的“相乘作用(Synergism)”是指，当两种药物并用后，其效果大于各药单独药效的代数和，具有协同作用(协同治疗功效)。
本发明中所述的「α值」，系指为α＝1，＞1且＜1分别表示加成，协同和拮抗作用，其中拮抗作用是药物相互作用中效果最差的，表示联合药物的治疗效果比单一用药的成效差；加成作用是联合药物治疗的效果相比单一用药的成效差异不大；协同是药物相互作用中效果最好的，表示联合药物比起单一用药更显著的增加治疗效果，不单减低了组合药物个别的使用剂量，同时也减少副作用带来的伤害。
在较佳的实施例中，其「α值」是指组合药物的α值大于1.5以上；其中「存活率」是指癌细胞的存活率低于0.6(不包含0.6)。
本发明中所述的「医药上可接受的盐」是系指化合物的调配物，其 不会对其投与的生物体造成显著刺激且不会消除该化合物的生物活性及性质。在某些情况下，医药上可接受的盐，是本文所阐述的化合物与诸如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、柳酸及诸如此类的酸反应来获得。在一些情况下，医药上可接受的盐是由使本文所阐述具有酸性基团的化合物与碱反应以形成诸如以下等盐来获得：铵盐；碱金属盐，例如钠盐或钾盐；碱土金属盐，例如钙盐或镁盐；诸如二环己胺、N-甲基-D-葡萄糖胺、参(羟甲基)甲胺等有机碱的盐及与诸如精氨酸、离氨酸(又称赖氨酸，Lysine)及诸如此类的氨基酸的盐；或由先前确定的其他方法来获得。药理上可接受的盐并无特别限制，只要其可用于药剂中即可。本文所阐述化合物与碱形成的盐的实例包括以下：与无机碱形成的盐，例如钠盐、钾盐、镁盐、钙盐及铝盐；与诸如甲胺、乙胺及乙醇胺等有机碱形成的盐；与诸如离氨酸及鸟氨酸等碱性氨基酸形成的盐；及铵盐。盐可为酸加成盐，其特定而言是由与以下各项所形成的酸加成盐例示：矿物酸，例如盐酸、氢溴酸、氢碘酸、硫酸、硝酸及磷酸；有机酸，例如甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸及乙磺酸；酸性氨基酸，例如天冬氨酸及麸氨酸。
本发明中所述的「医药组合物」是指本文所阐述的药物与其他化学组分(例如载剂、稳定剂、稀释剂、分散剂、悬浮剂及/或增稠剂)的混合物。医药组合物有助于向生物体投与(即给药)化合物。相关技艺存在多种投与化合物的技术，包括(但不限于)经直肠、经口、静脉内、气溶胶、非经肠、经眼、经肺及局部投与(给药)。
本发明活性化合物较佳地，例如与惰性稀释剂或与可吸收可食用的载体一并经口投予，或其可被包封于硬质或软质外壳动物胶胶囊中，或其 可被压制成锭剂，或其可直接被混入日常饮食的食物中。关于经口治疗投药，这些活性化合物可与赋形剂合并而用于形成可消化摄取的锭剂、口腔锭剂、片剂、胶囊、酏剂、悬浮液、糖浆、扁片等。
锭剂、片剂、药丸、胶囊及其类似物亦可包含下列药剂：可添加结合剂诸如黄蓍(黄芪)胶、洋槐胶、玉米淀粉或明胶；赋形剂诸如乳糖或磷酸二钙；崩解剂诸如玉米淀粉、马铃薯淀粉、藻酸及其类似物；润湿剂诸如硬脂酸镁；及甜味剂诸如蔗糖、乳糖或糖精，或香料诸如薄荷、冬青油或樱桃口味。胶囊剂型除上述药剂外可包含液态载剂。
具有协同抗癌功效的氯硝柳胺(Niclosamide)和双硫仑(Disulfiram)医药组合物及其用途(Pharmaceutical Composition of Niclosamide and Disulfiram With Synergistic Anticancer Effect and Uses Thereof)
在本发明一实施例中，一种具有协同抗癌功效的氯硝柳胺(Niclosamide)和双硫仑(Disulfiram)医药组合物用于制备治疗一癌症之用途，其中所述医药组合物其包含(A)氯硝柳胺(Niclosamide)或/及药物可接受的盐类，及(B)双硫仑(disulfiram)、帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、法舒地尔(Fasudil)、双膦酸盐诸如氯屈膦酸盐(Clodronate)或上述所组成之群组(中的一种或多种)；其中所述医药组合物用于减轻或/及治疗癌症上相较于单独使用所述癌症治疗药物的功效具有协同功效。
在另一实施例中，一种具有协同抗癌功效的氯硝柳胺(Niclosamide)和 双硫仑(Disulfiram)医药组合物用于制备治疗一癌症之用途，其中所述医药组合物其包含(A)双硫仑(disulfiram)或/及药物可接受的盐类，及(B)氯硝柳胺(Niclosamide)、帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、法舒地尔(Fasudil)、双膦酸盐诸如氯屈膦酸盐(Clodronate)或上述所组成之群组(中的一种或多种)；其中所述医药组合物用于减轻或/及治疗癌症上相较于单独使用所述癌症治疗药物的功效具有协同功效。
在本发明一实施例中，本发明医药组合物其协同功效定义为所述组成物的协同作用指数α大于1.5。
在本发明一实施例中，本发明医药组合物可减轻或/及治疗癌症是指癌细胞存活率下降至60％以下。
在本发明一较佳实施例中，本发明医药组合物为氯硝柳胺(Niclosamide)、双硫仑(disulfiram)所组成的药物。
在本发明一实施例中，其中所述癌症包含肺癌、胃癌、肝癌、直肠癌、肾脏癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌、血癌。
在本发明一实施例中，其中所述有效剂量范围为100～50nM。
【实施方式】
为了使本揭示内容的叙述更加详尽与完备，下文针对了本发明的实施方式与具体实施例提出了说明性的描述；但这并非实施或运用本发明具体实施例的唯一形式。实施方式中涵盖了多个具体实施例的特征以及用以 操作这些具体实施例的方法与用途，然而，亦可利用其他具体实施例来达成相同或均等的功效。应当理解，这些实施例是用于说明本发明，而非限制本发明的范围。
表一、本发明癌症测试的细胞株
癌症类型 细胞株 培养液
肺腺 A549 DMEM
乳腺癌 MCF-7 DMEM
肝癌 HepG2 DMEM
非小细胞癌 H460 DMEM
胰脏癌 BxPC-3 DMEM
大肠癌 HCT116 DMEM
卵巢细胞癌 TOV-21G DMEM
三阴性乳癌 MDA-MB-231 DMEM
表二、本发明双药测试的种类
代号 中文药名 英文药名
C1 帕罗西汀 Paroxetine
C3 吡维铵 Pyrvinium
C4 氯硝柳胺 Niclosamide
C7 齐多夫定 Zidovudine
C9 阿苯达唑 Albendazole
C10 阿仑膦酸 Alendronic Acid
C11 金诺芬 Auranofin
C13 卡比马唑 Carbimazole
C14 地塞米松 Dexamethasone
C18 氟苯达唑 Flubendazole
C19 洛伐他汀 Lovastatin
C21 乙胺嘧啶 Pyrimethamine
C22 苯磺酸胺氯地平 Amlodipine besylate
C23 阿折地平 Azelnidipine
C25 双硫仑 Disulfiram
C75 法舒地尔 Fasudil
C76 双膦酸盐诸如氯屈膦酸盐 Clodronate
实施例1、细胞培养(Cell culture)
将肺癌细胞(A549)、乳腺癌细胞(MCF-7)、肝癌细胞(HepG2)、非小细胞癌细胞(H460)、胰腺癌细胞(BxPC-3)、大肠癌细胞(HCT116)、卵巢癌细胞(TOV-21G)及三阴性乳癌细胞株(MDA-MB-231)，培养在含10％(v/v)胎牛血清(Fetal Bovine Serum、Penicillin-Streptomycin Solution)(100X)(ACE Biolabs，CC1009)及含有谷氨酰胺(Glutamine)的Dulbecco’s Modified Eagle’s Medium(DMEM)(Invitrogen Carlsbad，CA，USA)培养基中，之后将个别细胞株放入5％CO 2、37℃的培养箱(Astec-SCA-165DS)。
实施例2、细胞活力测验(Cell Viability)
将1×10 4个不同细胞株接种到96-well(96孔板)中24小时，使细胞贴附于底盘后，经由不同的药物联合处理48小时，无药物处理的细胞为对照组，加入10μL WST-1试剂(BioVision，USA)，在37℃下放置三个小时，使用ELISA reader酶标仪(Thermo Scientific Multiskan FC)，在450nm的波长下测定吸光值，评估细胞活性及增殖能力。细胞活力计算公式如下：
Figure PCTCN2021111752-appb-000001
实施例3、本发明医药组合物对癌细胞具协同作用效果试验
算式用于评估联合药物的相互作用，对于癌细胞的毒杀效果是加成、协同或拮抗：α＝SFA×SFB/SF(A+B)，其中SFA表示A药物的作用下细胞的存活率，SFB表示B药物作用下细胞的存活率，及SF(A+B)是联合A与B药物作用下细胞的存活率。
Figure PCTCN2021111752-appb-000002
Figure PCTCN2021111752-appb-000003
Figure PCTCN2021111752-appb-000004
从表四实验结果显示，其α＜1为两药物产生拮抗作用，造成药效作用减弱或消失。以肺癌细胞A549来说，当氯硝柳胺(Niclosamide)与齐多夫定(Zidovudine)或阿仑膦酸(Alendronic Acid)药物结合时，其α＜1；当双硫仑(Disulfiram)与金诺芬(Auranofin)或阿仑膦酸(Alendronic Acid)药物结合时，其α＜1。以MDA-MB-231细胞来说，当氯硝柳胺(Niclosamide)与金诺芬(Auranofin)、吡维铵(Pyrvinium)或帕罗西汀(Paroxetine)药物结合时，其α＜1；当双硫仑(Disulfiram)与吡维铵(Pyrvinium)、Alendronic药物结合时，其α＜1。
综上述实验结果证实，当氯硝柳胺和双硫仑组合时，对所有癌症均有协同效果；然而发现当氯硝柳胺和双硫仑个别与其他药物结合测试时，在不同癌肿上并没有呈现协同效果的事实，甚至出现拮抗作用，使其双药交互作用导致药理活性上的改变，造成治疗效果的降低。
此外，实验结果显示相加性治疗癌症功效但没有副作用或副作用极小的药物组合就临床的角度来看，也是重要的，因为低剂量的组合可提供相同的抗癌作用又可降低其副作用。
上述实验数据为在特定条件下所获得的初步实验结果，其仅用以易于了解或参考本发明的技术内容而已，其尚需进行其他相关实验。该实验数据及其结果并非用以限制本发明的权利范围。
前述较佳实施例仅举例说明本发明及其技术特征，该实施例的技术仍可适当进行各种实质等效修饰及/或替换方式予以实施；因此，本发明的权利范围须视后附申请专利范围所界定的范围为准。

Claims (7)

  1. 一种具有协同抗癌功效的氯硝柳胺(Niclosamide)和双硫仑(Disulfiram)医药组合物用于制备治疗癌症的用途，其特征是，所述医药组合物包含(A)氯硝柳胺(Niclosamide)或/及药物可接受的盐类，及(B)双硫仑(disulfiram)、帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、法舒地尔(Fasudil)、双膦酸盐诸如氯屈膦酸盐(Clodronate)中的一种或多种；其中所述药组合物用于减轻或/及治疗癌症上相较于单独使用所述癌症治疗药物的功效具有协同功效。
  2. 一种具有协同抗癌功效的氯硝柳胺(Niclosamide)和双硫仑(Disulfiram)医药组合物用于制备治疗癌症的用途，其特征是，所述医药组合物包含(A)双硫仑(disulfiram)或/及药物可接受的盐类，及(B)氯硝柳胺(Niclosamide)、帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、法舒地尔(Fasudil)、双膦酸盐诸如氯屈膦酸盐(Clodronate)中的一种或多种；其中所述医药组合物用于减轻或/及治疗癌症上相较于单独使用所述癌症治疗药物的功效系具有协同功效。
  3. 如权利要求1或2所述的用途，其特征是，所述协同功效定义为所述组成物的协同作用指数α大于1.5。
  4. 如权利要求1或2所述的用途，其特征是，所述减轻或/及治疗癌症是指细胞存活率下降至60％以下。
  5. 如权利要求1或2所述的用途，其特征是，所述医药组合物为氯硝柳胺(Niclosamide)、双硫仑(disulfiram)所组成的药物。
  6. 如权利要求1或2所述的用途，其特征是，所述癌症为肺癌、胃癌、肝癌、直肠癌、肾脏癌、皮肤癌、子宫颈癌、前列腺癌、膀胱癌、乳癌或血癌。
  7. 如权利要求1或2所述的用途，其特征是，所述医药组合物的有效剂量的范围为100～50nM。
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