WO2016062277A1 - 驱虫药用于制备抗癌医药组合物中的应用 - Google Patents

驱虫药用于制备抗癌医药组合物中的应用 Download PDF

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WO2016062277A1
WO2016062277A1 PCT/CN2015/092746 CN2015092746W WO2016062277A1 WO 2016062277 A1 WO2016062277 A1 WO 2016062277A1 CN 2015092746 W CN2015092746 W CN 2015092746W WO 2016062277 A1 WO2016062277 A1 WO 2016062277A1
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cancer
drug
use according
anthelmintic
group
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French (fr)
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陈丘泓
庄秀美
萧乃文
梁瑞岳
陈筱彤
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朗齐生物医学股份有限公司
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Definitions

  • the present invention is an application of new indications for various anthelmintic drugs, in particular, the plurality of drugs are approved drugs marketed by the Department of Health and have the use of inhibiting various cancers.
  • Cancer has long been the leading cause of death worldwide, and the number of cancer patients has increased year by year. Therefore, treating cancer has become an important issue.
  • the treatment of cancer can be divided into surgical treatment, radiation therapy, chemotherapy and target treatment.
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • chemotherapy chemotherapy or target treatment
  • cancer drug treatment is intended to prevent cancer cells from replicating and dividing to block the spread and spread of tumors.
  • chemotherapeutic drugs and target treatment hoping to kill cancer cells by different mechanisms to improve the therapeutic effect, but in fact, patients often react to the treatment of drugs Not good.
  • many cancer cells have developed resistance, which has led to a significant reduction in the effectiveness of drug use, which ultimately leads to failure of cancer treatment.
  • the present invention aims at the development of new indications for a variety of drugs that have undergone clinical trials and have no adverse reactions to the human body, and achieves the goal of new use of old drugs.
  • cancer cells have different performance traits than normal cells, and their differences in morphology or changes in action can also be regarded as an external invader. Similarly, therefore, the inventive concept of using an anthelmintic agent to inhibit cancer cells is proposed and an experiment is conducted.
  • the present invention provides an anthelmintic for use in the preparation of an anti-cancer pharmaceutical composition, wherein the pharmaceutical composition is selected from the group consisting of an effective amount of an anthelmintic and a pharmaceutically acceptable salt.
  • the anthelmintic medicine of the present invention is an FDA-approved medicine, and has been used in human or animal body for decades, and has a large number of drug machine transfer and human body research results data, so if applied to cancer, this new development It will save time, reduce costs, and combine with other treatments to improve results.
  • the cost of cancer drugs today is tens of thousands to millions of dollars, and the anthelmintic drugs of the present invention have therapeutic effects on cancer cells, so for patients who cannot afford expensive treatment, these inexpensive and long-established drugs will bring Come to new hopes.
  • the anthelmintic is selected from one or more of the group consisting of an anti-nematode, an anti-aphid, an anti-liver, an anti-amnesi, an anti-parasitic, and other anti-parasitic drugs.
  • the composition of the drug is selected from one or more of the group consisting of an anti-nematode, an anti-aphid, an anti-liver, an anti-amnesi, an anti-parasitic, and other anti-parasitic drugs.
  • the anti-nematode drug is a drug selected from the group consisting of one or more of Ivermectin, Albendazole, Thiabendazole, Oxfendazole, Flubendazole, Oxibendazole, Levamisole Hydrochloride, Tetramisole HCl, Bephenium Hydroxynaphthoate.
  • the anti-aphid drug is a drug selected from the group consisting of one or more of Praziquantel and Nitazoxanide.
  • the anti-liver drug is selected from the group consisting of Praziquantel, Closantel A drug consisting of one or more of Sodium, Closantel, and Triclabendazole.
  • the anti-althyroid agent is Broxyquinoline.
  • the anti-protozoal drug is a drug selected from the group consisting of one or more of Diminazene Aceturate and Decoquinate.
  • the other antiparasitic drug is a drug selected from the group consisting of one or more of Cyromazine, Uridine, Fleroxacin (Quinodis), Guanidine HCl.
  • the cancer is one or more selected from the group consisting of lung cancer, intestinal cancer, colorectal cancer, prostate cancer, bladder cancer, cervical cancer, breast cancer, and blood cancer.
  • the effective dose is 20-500 mg/kg/day.
  • Fig. 1 shows the results of analysis of an anthelmintic of the present invention for inhibiting various cancer cells.
  • the original culture solution in the 96-well plate was aspirated, and a commercially available anthelmintic drug having a concentration of 10 ⁇ M and a volume of 100 ul was added to each well. After 72 hours, 100 ul of diluted WST-1 reagent was added to each well, and the dilution ratio was cultured. The volume ratio of the liquid to the WST-1 stock solution is 9:1, and finally the total volume of each well is 200 ul, and then the 96-well plate is placed at 37 ° C for 30-90 minutes using an elisa reader (ELISA) The absorbance was measured at OD450 and the survival rate of each cancer cell line was calculated.
  • ELISA elisa reader
  • Anthelmintic drugs are used to inhibit cancer cell analysis results
  • the anthelmintic according to the present invention can be classified into anti-nematode, anti-aphid, anti-inhalation, anti-ammunosis, anti-protozoal and other anti-parasitic drugs according to the parasitic species to be treated.
  • Tetramisole HCl could not effectively inhibit lung cancer cell lines (H1650, A549), gastric cancer cell lines (AGS, MKN-45), liver cancer cell lines (HepG2), rectal cancer cell lines (HCT116, LoVo). , skin cancer cell line (A375), cervical cancer cell line (HeLa), prostate cancer cell line (PC3), bladder cancer cell line (TSGH-8301), breast cancer cell line (MCF7), and blood cancer cell line (HL-60) ) growth.
  • Ivermectin has inhibitory effects on lung cancer, gastric cancer, rectal cancer, colon cancer, skin cancer, prostate cancer, bladder cancer, and blood cancer;
  • Nitazoxanide (Alinia, Annita) has inhibitory effects on lung cancer, gastric cancer, bladder cancer, and breast cancer.
  • Albendazole has inhibitory effects on lung cancer, gastric cancer, rectal cancer, skin cancer, bladder cancer, and breast cancer
  • Praziquantel has inhibitory effects on lung cancer, gastric cancer, and bladder cancer
  • Thiabendazole has inhibitory effect on breast cancer
  • Oxfendazole on lung cancer, Gastric cancer, colon cancer, skin cancer, breast cancer have inhibitory effects
  • Flubendazole Flubendazole (Flutelmium) has inhibitory effects on lung cancer, gastric cancer, rectal cancer, colon cancer, skin cancer, prostate cancer, breast cancer
  • Oxibendazole for lung cancer, stomach cancer, rectal cancer, colon cancer , skin cancer, prostate cancer, breast cancer has inhibitory effect
  • Levamisole Hydrochloride Ergamisol
  • Uridine has inhibitory effect on lung cancer, breast cancer
  • Fleroxacin Quinodis has inhibitory effects on lung cancer, gastric cancer, rectal cancer, colon
  • the anthelmintic drugs include Ivermectin, Nitazoxanide (Alinia, Annita), Albendazole (Albenza), Oxfendazole, Flubendazole (Flutelmium), Oxibendazole, Levamisole Hydrochloride (Ergamisol), Fleroxacin (Quinodis), Cyromazine. It has obvious inhibitory effects on different types of cancer cells.
  • the experimental design results show that the anthelmintic has no or only minimal toxicity to normal cells, but as to whether the anthelmintic has a selective effect between normal cells and tumor cells, more research is needed. Clear, and not all anthelmintics can effectively inhibit tumor cells under the same conditions.

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Abstract

驱虫药在制备抗癌医药组合物中的应用，所述驱虫药选自抗线虫药、抗绦虫药、抗吸虫药、抗变形虫药、抗原虫药、其他抗寄生虫用药中的一种或多种。

Description

驱虫药用于制备抗癌医药组合物中的应用 技术领域
本发明为多种驱虫药的新适应症的应用，尤其该多种药物为卫生署核准上市的药物且具有抑制多种癌症的用途。
背景技术
癌症长期高居全球死因之首，且罹患癌症人数更是逐年攀升，因此治疗癌症俨然成为重要的课题。癌症的治疗可区分为手术治疗、放射线治疗、化学治疗及标靶治疗。
一般来说，癌症药物治疗无论是化学治疗或标靶治疗，目的多是让癌细胞无法复制、分裂，来阻断肿瘤的蔓延扩张。在临床治疗选择上，通常会结合一到数种化疗药物以及标靶治疗，希望能藉由不同机制来杀死癌细胞以提高治疗效果，但事实上，还是常遇到患者对于治疗药物的反应不佳。此外，许多癌细胞相继产生抗药性，使药物的使用成效大幅降低，最终导致癌症治疗失败。
尽管如此，癌症药物开发依然是重要的医学议题，开发过程必须经过繁复的临床前试验才能进入临床试验，根据统计，平均每一万个新药约只有五个能够进入第一期临床试验。此外，除了药物本身是否能大量制造的难题外，还需克服药物安全性、病人筛选、试用剂量等问题，即便药物已经通过FDA的核准并上市，亦有可能因上市后于人体发现不良反应而强制下架回收，由此可见药物开发具有一定的困难程度。
发明内容
有鉴于此，本发明是针对通过临床实验且对人体无不良反应的多种药物进行新适应症的研发，而达到老药新用的目标。
发明人依据长年的研究经验，证实癌症细胞较正常细胞具有不同的表现性状，且其型态上的差异或是作用机转的变化亦可视为一种外来的侵入者，此与寄生虫相似，因此，提出使用驱虫药抑制癌症细胞的发明概念并且进行实验。
本发明提供一种驱虫药用于制备抗癌医药组合物中的应用，其中所述医药组合物是选自由有效剂量的驱虫药及药学上可接受的盐类所组成。
本发明所述驱虫药是FDA所认可的用药，且已于人体或动物体中使用数十年，具有大量药物机转及人体研究成果数据，因此，若应用在癌症方面，这项新发展会更省时、减少成本，也能和其他治疗方式结合来提高效果。此外，现今癌症药物费用动辄上万至数百万元，而本发明所述驱虫药对癌症细胞具有治疗功效，因此对于无法负担昂贵治疗的患者们，这些便宜而历史悠久的药物，会带来新希望。
本发明一实施例中，其中所述驱虫药是选自由抗线虫药、抗绦虫药、抗吸虫药、抗变形虫药、抗原虫药及其他抗寄生虫用药中的一种或多种所组成的药物。
本发明一实施例中，其中所述抗线虫药是选自由Ivermectin、Albendazole、Thiabendazole、Oxfendazole、Flubendazole、Oxibendazole、Levamisole Hydrochloride、Tetramisole HCl、Bephenium Hydroxynaphthoate中的一种或多种所组成的药物。
本发明一实施例中，其中所述抗绦虫药是选自由Praziquantel、Nitazoxanide中的一种或多种所组成的药物。
本发明一实施例中，其中所述抗吸虫药是选自由Praziquantel、Closantel  Sodium、Closantel、Triclabendazole中的一种或多种所组成的药物。
本发明一实施例中，其中所述抗变形虫药是Broxyquinoline。
本发明一实施例中，其中所述抗原虫药是选自由Diminazene Aceturate、Decoquinate中的一种或多种所组成的药物。
本发明一实施例中，其中所述其他抗寄生虫用药是选自由Cyromazine、Uridine、Fleroxacin(Quinodis)、Guanidine HCl中的一种或多种所组成的药物。
本发明一实施例中，其中所述癌症是选自由肺癌、肠道癌、大肠直肠癌、前列腺癌、膀胱癌、子宫颈癌、乳癌及血癌中的一种或多种。
本发明一实施例中，其中所述有效剂量为20-500mg/kg/天。
附图说明
图1显示本发明驱虫药应用于抑制各种癌细胞的分析结果。
具体实施方式
建立细胞株
参照表一，将不同类型的癌症细胞株进行继代培养，计算细胞数目后，回种2×106细胞数，然后加入培养该细胞株的培养液补至体积为10ml，继续培养2-3天。之后将细胞计数，并分装至96孔盘，其中每孔的细胞数目固定为3000个，且体积为100ul。
表一、细胞株及其培养所用的培养液
Figure PCTCN2015092746-appb-000001
Figure PCTCN2015092746-appb-000002
细胞存活分析方法
将96孔盘中原有的培养液吸掉，每孔加入浓度10μM、体积100ul的市售驱虫药物，放置72小时后，每孔再加入100ul已稀释的WST-1试剂，该稀释比例为培养液与WST-1原液的体积比为9：1，最后每个孔盘的总体积为200ul，然后将96孔盘放置于37℃，30～90分钟，利用elisa reader(酶联免疫检测仪)于OD450侦测吸光值，并计算各癌症细胞株的存活率。
驱虫药应用于抑制癌细胞分析结果
本发明所述驱虫药可依其治疗的寄生虫种类区分为抗线虫药、抗绦虫药、抗吸虫药、抗变形虫药、抗原虫药及其他抗寄生虫用药。
参照表二，实验结果显示Tetramisole HCl并无法有效的抑制肺癌细胞株(H1650、A549)、胃癌细胞株(AGS、MKN-45)、肝癌细胞株(HepG2)、直肠癌细胞株(HCT116、LoVo)、皮肤癌细胞株(A375)、子宫颈癌细胞株(HeLa)、前列腺癌细胞株(PC3)、膀胱癌细胞株(TSGH-8301)、乳癌细胞株(MCF7)及血癌细胞株(HL-60)的生长。
表二、对癌症细胞株无抑制效果之驱虫药
驱虫药 抑制癌症细胞株数量
Tetramisole HCl 0
而其他驱虫药对于各种癌症细胞的抑制效果也不尽相同，参照表三，表三中的数值是以IC50表示，灰色标记表示该驱虫药物对于该细胞株有明显抑制的功效。
Figure PCTCN2015092746-appb-000003
Figure PCTCN2015092746-appb-000004
如表三所示，Ivermectin对肺癌,胃癌,直肠癌,结肠癌,皮肤癌,前列腺癌,膀胱癌,血癌有抑制效果；Nitazoxanide(Alinia,Annita)对肺癌,胃癌,膀胱癌,乳癌有抑制效果；Albendazole(Albenza)对肺癌,胃癌,直肠癌,皮肤癌,膀胱癌,乳癌有抑制效果；Praziquantel(Biltricide)对肺癌,胃癌,膀胱癌有抑制效果；Thiabendazole对乳癌有抑制效果；Oxfendazole对肺癌,胃癌,结肠癌,皮肤癌,乳癌有抑制效果；Flubendazole(Flutelmium)对肺癌,胃癌,直肠癌,结肠癌,皮肤癌,前列腺癌,乳癌有抑制效果；Oxibendazole对肺癌,胃癌,直肠癌,结肠癌,皮肤癌,前列腺癌,乳癌有抑制效果；Levamisole Hydrochloride(Ergamisol)对肺癌,胃癌,结肠癌,皮肤癌,前列腺癌,膀胱癌,乳癌有抑制效果；Uridine对肺癌,乳癌有抑制效果；Fleroxacin(Quinodis)对肺癌,胃癌,直肠癌，结肠癌,皮肤癌,前列腺癌,膀胱癌有抑制效果；Guanidine HCl对胃癌有抑制效果；Diminazene Aceturate对前列腺癌,乳癌有抑制效果；Closantel Sodium对乳癌有抑制效果；Closantel对直肠癌,乳癌有抑制效果；Triclabendazole对肺癌,乳癌有抑制效果；Decoquinate对肺癌,胃癌,直肠癌,乳癌有抑制效果；Cyromazine对肺癌,胃癌,直肠癌,皮肤癌,前列腺癌,膀胱癌,乳癌有抑制效果；Broxyquinoline对直肠癌,皮肤癌,血癌有抑制效果；Bephenium Hydroxynaphthoate(羟萘苄芬宁)对皮肤癌,乳癌有抑制效果。
请参考第一图，由实验结果可知，驱虫药包括Ivermectin、Nitazoxanide(Alinia,Annita)、Albendazole(Albenza)、Oxfendazole、Flubendazole(Flutelmium)、Oxibendazole、Levamisole Hydrochloride(Ergamisol)、Fleroxacin(Quinodis)、Cyromazine对于不同类型的癌症细胞均有明显的抑制效果。
而实验设计的结果显示驱虫药对正常细胞没有或仅有微小的毒性，但至于驱虫药在正常细胞与肿瘤细胞之间是否具有选择性的影响，还待更多的研究厘 清，而且并非所有的驱虫药在相同的条件下均能有效的抑制肿瘤细胞。
上列详细说明是针对本发明之一可行实施例的具体说明，惟该实施例并非用以限制本发明的专利范围，凡未脱离本发明技艺精神所为的等效实施或变更，均应包含于本发明的专利范围中。

Claims (10)

  1. 一种驱虫药用于制备抗癌医药组合物中的应用，其特征是，所述医药组合物是选自由有效剂量的驱虫药及药学上可接受的盐类所组成。
  2. 如权利要求1所述的应用，其特征是，所述驱虫药为抗线虫药、抗绦虫药、抗吸虫药、抗变形虫药、抗原虫药、其他抗寄生虫用药中的一种或多种。
  3. 如权利要求2所述的应用，其特征是，所述抗线虫药是选自由Ivermectin、Albendazole、Thiabendazole、Oxfendazole、Flubendazole、Oxibendazole、Levamisole Hydrochloride、Tetramisole HCl、Bephenium Hydroxynaphthoate中的一种或多种所组成的药物。
  4. 如权利要求2所述的应用，其特征是，所述抗绦虫药是选自由Praziquantel、Nitazoxanide中的一种或多种所组成的药物。
  5. 如权利要求2所述的应用，其特征是，所述抗吸虫药是选自由Praziquantel、Closantel Sodium、Closantel、Triclabendazole中的一种或多种所组成的药物。
  6. 如权利要求2所述的应用，其特征是，所述抗变形虫药是Broxyquinoline。
  7. 如权利要求2所述的应用，其特征是，所述抗原虫药是选自由Diminazene Aceturate、Decoquinate中的一种或多种所组成的药物。
  8. 如权利要求2所述的应用，其特征是，所述其他抗寄生虫用药是选自由Cyromazine、Uridine、Fleroxacin(Quinodis)、Guanidine HCl中的一种或多种所组成的药物。
  9. 如权利要求1所述的应用，其特征是，所述癌症选自肺癌、肠道癌、大肠直肠癌、前列腺癌、膀胱癌、子宫颈癌、乳癌、血癌中的一种或多种。
  10. 如权利要求1所述的应用，其特征是，所述有效剂量是20-500mg/kg/天。
PCT/CN2015/092746 2014-10-24 2015-10-23 驱虫药用于制备抗癌医药组合物中的应用 WO2016062277A1 (zh)

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PCT/CN2015/092771 WO2016062283A1 (zh) 2014-10-24 2015-10-23 抗发炎用药物在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092776 WO2016062286A1 (zh) 2014-10-24 2015-10-23 脱克钙药物在用于制备治疗癌症的医药组合物中的用途
PCT/CN2015/092782 WO2016062291A1 (zh) 2014-10-24 2015-10-23 千忧解药物在用于制备治疗癌症的医药组合物中的用途
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PCT/CN2015/092777 WO2016062287A1 (zh) 2014-10-24 2015-10-23 山喜多药物在用于制备抑制癌症的医药组合物中的用途
PCT/CN2015/092781 WO2016062290A1 (zh) 2014-10-24 2015-10-23 氨苯蝶啶药物在用于制备治疗癌症的医药组合物中的用途
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PCT/CN2015/092779 WO2016062288A1 (zh) 2014-10-24 2015-10-23 代谢性疾病药物用于制备抑制癌症的医药组合物的用途
PCT/CN2015/092768 WO2016062281A1 (zh) 2014-10-24 2015-10-23 心血管疾病用药物在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092753 WO2016062278A1 (zh) 2014-10-24 2015-10-23 内分泌疾病用药在制备抑制癌症的医药组合物中的应用
PCT/CN2015/092653 WO2016062267A1 (zh) 2014-10-24 2015-10-23 奈必洛尔在制备抑制癌症的医药组合物中的用途
PCT/CN2015/092714 WO2016062275A1 (zh) 2014-10-24 2015-10-23 阿折地平在制备治疗癌症的医药组合物中的用途
PCT/CN2015/092632 WO2016062266A1 (zh) 2014-10-24 2015-10-23 氨氯地平在制备抑制癌症的医药组合物中的用途
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EP3235497A4 (en) 2018-06-13
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US20170304388A1 (en) 2017-10-26
JP6539345B2 (ja) 2019-07-03
JP2017532351A (ja) 2017-11-02
TW201615224A (zh) 2016-05-01
EP3210604A1 (en) 2017-08-30
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US10045962B2 (en) 2018-08-14
WO2016062291A1 (zh) 2016-04-28
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US10105357B2 (en) 2018-10-23
US20170304228A1 (en) 2017-10-26
WO2016062275A1 (zh) 2016-04-28
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WO2016062283A1 (zh) 2016-04-28
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TWI621434B (zh) 2018-04-21
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EP3222278A1 (en) 2017-09-27
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KR20170084034A (ko) 2017-07-19
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