WO2017118114A1 - 一种由常山酮和青蒿倍半萜内酯类化合物组成的抗癌组合物及其应用 - Google Patents

一种由常山酮和青蒿倍半萜内酯类化合物组成的抗癌组合物及其应用 Download PDF

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WO2017118114A1
WO2017118114A1 PCT/CN2016/100329 CN2016100329W WO2017118114A1 WO 2017118114 A1 WO2017118114 A1 WO 2017118114A1 CN 2016100329 W CN2016100329 W CN 2016100329W WO 2017118114 A1 WO2017118114 A1 WO 2017118114A1
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artemisinin
sesquiterpene lactone
combination
cancer
ketone
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PCT/CN2016/100329
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French (fr)
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卞兆祥
陈国庆
龚锐洪
杨大坚
吕爱平
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香港浸会大学
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Priority to US16/067,839 priority Critical patent/US10973823B2/en
Priority to EP16883244.2A priority patent/EP3400936B1/en
Publication of WO2017118114A1 publication Critical patent/WO2017118114A1/zh

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/282—Artemisia, e.g. wormwood or sagebrush
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to an anticancer combination drug, and more particularly to a composition for an anticancer drug, anthraquinone, and a sesquiterpene lactone compound, and use thereof.
  • Halof ⁇ ginone is an alkaloid and a derivative of Changshan base, an active ingredient of traditional Chinese medicine. Its molecular formula is C16H17BrCIN3O3 ⁇ HBr, which is a white or light gray crystalline powder, odorless and bitter.
  • Research on HF began in 1975 and has been used as a broad-spectrum anticoccidial drug for a long time. In recent years, with the in-depth study of HF, it has been found that HF can promote wound repair and inhibit tissue fibrosis, which is particularly prominent in preclinical studies of anti-tumor, for liver cancer, sarcoma, brain cancer, bladder cancer, breast cancer and prostate. Many cancer models such as cancer have significant inhibitory effects.
  • Artemisinin, dihydroartemisinin, artesunate or artemether are all sesquiterpene lactone drugs and compounds thereof which are extracted from the stems and leaves of the plant Artemisia annua.
  • Artemisinin sesquiterpene lactones and their compounds have good activity in anticancer, and there may be two applications as anticancer drugs: one is antitumor drug used alone; One is an anti-tumor drug used as a sensitizer in combination with other tumor chemotherapy drugs.
  • the present invention provides a composition for the anticancer composition of the dexamethasone sesquiterpene lactone compound for anticancer. It is composed of two components of benzoate and sesquiterpene lactone.
  • the sesquiterpene lactone compound is a sesquiterpene lactone and an Artemisia annua L. extracted from Artemisia annua L. a derivative of the hormone.
  • the sesquiterpene lactone is one of artemisinin, dihydroartemisinin, artesunate or artemether.
  • composition for the anticancer agent of the amphibious sesquiterpene lactone compound for the preparation of a medicament for treating cancer.
  • composition of the anti-cancer, sylvestrein, sesquiterpene lactone compound for the preparation of a medicament for treating colon cancer.
  • composition of the anti-cancer, sylvestrein, sesquiterpene lactone compound for the preparation of a medicament for treating breast cancer.
  • composition of the anti-cancer, sylvestrein, sesquiterpene lactone compound for the preparation of a medicament for treating liver cancer.
  • composition for the anticancer agent of the amphibious sesquiterpene lactone compound for the preparation of a medicament for treating gastric cancer.
  • composition for the anti-cancer, sylvestrein, sesquiterpene lactone compound for the preparation of a medicament for treating melanoma.
  • the beneficial technical effect of the present invention is that the combination of the ketone and the artemisinin, artemisinin or artemether, and the sesquiterpene lactone compound have a remarkable coordination effect.
  • the combination of Changshan ketone and artemisinin has similar activity and even better than the anticancer activity of the anticancer drug 5-Fu.
  • Human colon cancer cell line HCT-116 was inoculated into a 96-well plate with 100 ⁇ L of cell suspension per well.
  • the culture medium was DMEM medium supplemented with 10% FBS and 2 mM glutamate.
  • 24 hours after inoculation add Changshan ketone, artemisinin, dihydroartemisinin, artesunate, artemether, Changshan ketone and artemisinin, Changshan ketone and dihydroartemisinin, Changshan ketone and artemisia
  • cell viability was assessed using the MTT method; the synergistic index (CI) of the combination of benzoate and artemisinin was calculated using Calcusyn software. The results are shown in Table 1.
  • Tumor cell survival rate experimental group OD value / control group OD ⁇ 100%
  • Hepatoma cells HepG2 were seeded into 96-well plates at 100 ⁇ L of cell suspension per well.
  • the culture medium was DMEM medium supplemented with 10% FBS and 2 mM glutamate.
  • 24 hours after inoculation add Changshan ketone, artemisinin, dihydroartemisinin, artesunate, artemether, Changshan ketone and artemisinin, Changshan ketone and dihydroartemisinin, Changshan ketone and artemisia
  • cell viability was assessed using the MTT method; the synergistic index (CI) of the combination of benzoate and artemisinin was calculated using Calcusyn software. The details are shown in Table 3.
  • Gastric cancer cells MGC803 were inoculated into 96-well plates at 100 ⁇ L of cell suspension per well.
  • the culture medium was DMEM medium supplemented with 10% FBS and 2 mM glutamate.
  • 24 hours after inoculation add Changshan ketone, artemisinin, dihydroartemisinin, artesunate, artemether, Changshan ketone and artemisinin, Changshan ketone and dihydroartemisinin, Changshan ketone and artemisia
  • cell viability was assessed using the MTT method; the synergistic index (CI) of the combination of benzoate and artemisinin was calculated using Calcusyn software. The details are shown in Table 4.
  • the CI of the combination of Changshanone and artemisinin was 0.37-0.86, and the synergistic effect increased with the increase of the concentration of the drug; the combination of Changshanone and dihydroartemisinin The CIs were 0.84, 0.77, and 0.71, respectively, which were low-level synergistic effects; the CIs of the combination of Changshan ketone and artesunate were 0.91, 0.76, and 0.71, respectively; synergistic effect; in Changshan ketone and artemisia The CI of the ether combination drug pair was 0.88, 0.77, and 0.77, respectively, with moderate synergy.
  • the CI of the combination of the ketone and the artemether combination is 0.67, 0.38, 0.39, respectively, with moderate synergistic effect.
  • the CI of the combination of Changshan ketone and artemisinin was 0.20-0.42.
  • the synergistic effect increased with the increase of the concentration of the drug; the combination of benzoyl ketone and artemisinin could Understand that the same effect.
  • the CI of the combination of Changshan ketone and dihydroartemisinin was 0.75-0.38, respectively, and the synergistic effect increased with the increase of the concentration of the drug; it was a medium-high synergistic effect; in combination with the ketone and artesunate
  • the CI of the drug pair was 0.62-0.21, respectively, and the synergistic effect showed an increasing trend with the increase of the concentration of the drug; it was a moderately high synergistic effect; it can be understood as the synergy of high and intensity; in the combination of Changshanone and artemether
  • the CIs were 0.79, 0.57, and 0.41, respectively, with moderate synergy.
  • the CI of the combination of dextroxan and artemisinin was 0.20-0.42, and the synergistic effect increased with the increase of the concentration of the drug; the combination drug of ketone and artemisinin It can be understood as a high degree of synergistic effect; the CI of the combination of Changshan ketone and dihydroartemisinin is 0.74-0.31, respectively, and the synergistic effect increases with the increase of the concentration of the drug; it is a synergistic effect at medium and low levels; The CI of the combination of Changshan ketone and artesunate was 0.62, 0.80, and 0.21, respectively, which was a moderate to low synergistic effect; the CI of the combination of Changshan ketone and artemether was 0.89, 0.57, and 0.42, respectively. Association The same effect.
  • the data on the inhibition rate of the combination of Changshan ketone and sesquiterpene lactone on five kinds of cancer cells shows that the activity of the combination of dextrogonone and artemisinin and derivatives is significantly better than that of Changshan ketone alone. It is administered alone with sesquiterpene lactone. Among them, the combination of Artemisia annua and Changshanone has the most significant activity.
  • the combination drug of artemisinin and tyrosone, artemisinin and tyrosone were subjected to animal experiments, and 5-Fu was used as a control drug.
  • 5-Fu was used as a control drug.
  • Using the colon cancer cells HCT116 female nude mice inoculated subcutaneously inoculated with 1x10 6 cells each, 5 days until tumors grow to about the volume of 100mm 3, is administered.
  • the dose of tamsone was 5 ⁇ g/kg
  • the dose of artemisinin was 50 mg/kg.
  • the combination of the two was the sum of the two doses, and the dose of 5-Fu was 10 mg/kg.
  • Each group was administered intraperitoneally once a day.
  • a combination of two different mass ratios of artemisinin and dextrozine was carried out in an animal experiment, wherein the first group was administered with a dose of 100 ⁇ g/kg, and the artemisinin was administered at a dose of 20 mg/kg; In the second group, the dose of Changshanone was 2 ⁇ g/kg, and the dose of artemisinin was 100 mg/kg.
  • the activity of the combination of artemisinin and Changshanone in different weight ratio groups was similar to that of 5-Fu. Its efficacy is still superior to artemisinin or dextran.
  • the combination of artemisinin and tyrosone has a significant therapeutic effect on colon cancer; the activity of the combination drug of artemisinin and dextroxan is similar to that of 5-Fu; the ketone and artemisinin are at 0.1 In the range of 20 to 0.002:100 (the mass ratio of the ketone: artemisinin is 1:2 ⁇ 10 2 to 5 ⁇ 10 5 ), the ketone and the artemisinin have a good synergistic effect. It is a viable combination drug technology solution.

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Abstract

本发明提供了一种抗癌组合物，其中活性成分由常山酮和青蒿倍半萜内酯类化合物组成。常山酮和青蒿倍半萜内酯类化合物的组合具有显著的协同抗癌效果，所述效果接近或高于5-Fu的抗癌效果。

Description

[根据细则37.2由ISA制定的发明名称]　一种由常山酮和青蒿倍半萜内酯类化合物组成的抗癌组合物及其应用 技术领域
本发明涉及一种抗癌组合药物，更具体的说涉及一种用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物及其应用。
背景技术
常山酮(halofμginone,HF)是一种生物碱，是中药有效成分常山碱的衍生物，其分子式是C16H17BrCIN3O3·HBr，为白色或淡灰色结晶性粉末，无臭，味苦。关于HF的研究最早始于1975年，很长一段时间其一直作为广谱抗球虫药使用。近年来，随着对HF的深入研究，发现HF可促进伤口修复、抑制组织纤维化，其在抗肿瘤临床前研究中表现尤为突出，对肝癌、肉瘤、脑癌、膀胱癌、乳腺癌及前列腺癌等诸多癌症模型有显著的抑制作用。
青蒿素、二氢青蒿素、青蒿琥酯或蒿甲醚等都是从植物黄花蒿茎叶中提取的有过氧基团的倍半萜内酯药物及其化合物。近年来，研究发现青蒿倍半萜内酯类药物及其化合物在抗癌方面具有良好的活性，具体作为抗癌药物可能有两种应用方式：一种是作为单独使用的抗肿瘤药物；另一种是与其他肿瘤化疗药物联合使用，作为一种增敏剂的抗肿瘤药物。
发明内容
为提供一种低毒且具有良好的抗癌活性抗癌组合药物，本发明提供了一种用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物所述组合药物的活性成分为常山酮和青蒿倍半萜内酯类化合物两种成分组成。
所述青蒿倍半萜内酯类化合物为从黄花蒿中提取的倍半萜内酯及青蒿 素的衍生物。
所述青蒿倍半萜内酯为青蒿素、二氢青蒿素、青蒿琥酯或蒿甲醚中的一种。
其中最优的方案是青蒿素和常山酮的组合。
所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗癌症的药物中的应用。
所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗结肠癌的药物中的应用。
所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗乳腺癌的药物中的应用。
所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗肝癌的药物中的应用。
所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗胃癌的药物中的应用。
所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗黑色素瘤的药物中的应用。
本发明的有益技术效果是：常山酮与青蒿素、二氢青蒿素、青蒿琥酯或蒿甲醚等青蒿倍半萜内酯类化合物组合具有显著的协调作用。其中常山酮与青蒿素的组合药物的活性相近甚至优于抗癌药物5-Fu的抗癌活性。
附图说明
图1肿瘤组织的体积比较；
图2动物切片试验-HE染色；
图3青蒿素和常山酮的组合药物与单独用药的活性比较。
具体实施方式
实施例1常山酮与青蒿素组合药物抗癌活性的体外模型考察
将人结肠癌细胞HCT-116系接种入96孔板中，每孔100μL细胞悬液。培养介质为DMEM培养液，并添加有10％FBS和2mM谷氨酸盐。接种24小时后，分别添加常山酮、青蒿素、二氢青蒿素、青蒿琥酯、蒿甲醚、常山酮与青蒿素、常山酮与二氢青蒿素、常山酮与蒿甲醚和常山酮与青蒿琥酯的组合物，对照组培养基不加药物。添加化合物24小时后，细胞存活率采用MTT法来评估；采用Calcusyn软件计算常山酮与青蒿素组合药物的协同指数(CI)。结果如表1所示。
肿瘤细胞存活率＝实验组OD值/对照组OD×100％
表1 常山酮与青蒿素组合药物对结肠癌细胞HCT116的抑制作用
Figure PCTCN2016100329-appb-000001
将乳腺癌细胞MCF-7接种入96孔板中，每孔100μL细胞悬液。培养介质为DMEM培养液，并添加有10％FBS和2mM谷氨酸盐。接种24小时后，分别添加常山酮、青蒿素、二氢青蒿素、青蒿琥酯、蒿甲醚、常山酮与青蒿素、常山酮与二氢青蒿素、常山酮与蒿甲醚和常山酮与青蒿琥酯 的组合物，对照组培养基不加药物。添加化合物24小时后，细胞存活率采用MTT法来评估；采用Calcusyn软件计算常山酮与青蒿素组合药物的协同指数(CI)。具体如表2所示。
表2 常山酮与青蒿素组合药物对乳腺癌细胞MCF-7的抑制作用
Figure PCTCN2016100329-appb-000002
将肝癌细胞HepG2接种入96孔板中，每孔100μL细胞悬液。培养介质为DMEM培养液，并添加有10％FBS和2mM谷氨酸盐。接种24小时后，分别添加常山酮、青蒿素、二氢青蒿素、青蒿琥酯、蒿甲醚、常山酮与青蒿素、常山酮与二氢青蒿素、常山酮与蒿甲醚和常山酮与青蒿琥酯的组合物，对照组培养基不加药物。添加化合物24小时后，细胞存活率采用MTT法来评估；采用Calcusyn软件计算常山酮与青蒿素组合药物的协同指数(CI)。具体如表3所示。
表3 常山酮与青蒿素组合药物对肝癌细胞HepG2的抑制作用
Figure PCTCN2016100329-appb-000003
将胃癌细胞MGC803接种入96孔板中，每孔100μL细胞悬液。培养介质为DMEM培养液，并添加有10％FBS和2mM谷氨酸盐。接种24小时后，分别添加常山酮、青蒿素、二氢青蒿素、青蒿琥酯、蒿甲醚、常山酮与青蒿素、常山酮与二氢青蒿素、常山酮与蒿甲醚和常山酮与青蒿琥酯的组合物，对照组培养基不加药物。添加化合物24小时后，细胞存活率采用MTT法来评估；采用Calcusyn软件计算常山酮与青蒿素组合药物的协同指数(CI)。具体如表4所示。
表4 常山酮与青蒿素组合药物对胃癌细胞MGC803的抑制作用
Figure PCTCN2016100329-appb-000004
将黑色素瘤细胞A375接种入96孔板中，每孔100μL细胞悬液。培养 介质为DMEM培养液，并添加有10％FBS和2mM谷氨酸盐。接种24小时后，分别添加常山酮、青蒿素、二氢青蒿素、青蒿琥酯、蒿甲醚、常山酮与青蒿素、常山酮与二氢青蒿素、常山酮与蒿甲醚和常山酮与青蒿琥酯的组合物，对照组培养基不加药物。添加化合物24小时后，细胞存活率采用MTT法来评估；采用Calcusyn软件计算常山酮与青蒿素组合药物的协同指数(CI)。具体如表5所示。
表5 常山酮与青蒿素组合药物对黑色素瘤细胞A375的抑制作用
Figure PCTCN2016100329-appb-000005
参照Soriano AF等发表在《Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against hμMan lung cancer cell lines》(Cancer Res，1999,59(24):6178-6184.)中的方法，在对结肠癌细胞HCT116的抑制作用的考察中，常山酮与青蒿素组合药物CI为0.55-0.7，随着给药浓度的增加，协同作用呈现下降趋势，为中度协同作用；在常山酮与二氢青蒿素组合药物对的CI为分别为0.75、0.61、0.81，为中低度协同作用；在常山酮与青蒿琥酯组合药物对的CI为分别为0.62-0.77，随着给药浓度的增加，协同作用呈现下降趋势，为中度协同作用，在常山酮与蒿甲醚组合药物对的CI为分别为0.50-0.78，有中度协同作用。在对乳腺癌细胞 MCF-7的抑制作用的考察中，常山酮与青蒿素组合药物的CI为0.37-0.86，随着给药浓度的增加，协同作用呈现上升趋势；在常山酮与二氢青蒿素组合药物对的CI为分别为0.84、0.77、0.71，为低度协同作用；在常山酮与青蒿琥酯组合药物对的CI为分别为0.91、0.76、0.71，有协同作用；在常山酮与蒿甲醚组合药物对的CI为分别为0.88、0.77、0.77，有中度协同作用。在对肝癌细胞HepG2的抑制作用的考察中，常山酮与青蒿素组合药物CI为0.08-0.18，随着给药浓度的增加，协同作用呈现上升趋势；常山酮与青蒿素组合药物可以理解为强协同作用。在常山酮与二氢青蒿素组合药物对的CI为分别为0.45-0.22，为高度和强度协同作用；在常山酮与青蒿琥酯组合药物对的CI为分别为0.62、0.55、0.48，可以理解为高度协同；在常山酮与蒿甲醚组合药物对的CI为分别为0.67、0.38、0.39，有中度协同作用。在对胃癌细胞MGC803的抑制作用的考察中，常山酮与青蒿素组合药物的CI为0.20-0.42，随着给药浓度的增加，协同作用呈现上升趋势；常山酮与青蒿素组合药物可以理解为高度同作用。在常山酮与二氢青蒿素组合药物对的CI为分别为0.75-0.38，随着给药浓度的增加，协同作用呈现上升趋势；为中高度协同作用；在常山酮与青蒿琥酯组合药物对的CI为分别为0.62-0.21，随着给药浓度的增加，协同作用呈现上升趋势；为中高度协同作用；可以理解为高和强度协同；在常山酮与蒿甲醚组合药物对的CI为分别为0.79、0.57、0.41，有中度协同作用。在对黑色素瘤细胞A375的抑制作用的考察中，常山酮与青蒿素组合药物的CI为0.20-0.42，随着给药浓度的增加，协同作用呈现上升趋势；常山酮与青蒿素组合药物可以理解为高度同作用；在常山酮与二氢青蒿素组合药物对的CI为分别为0.74-0.31，随着给药浓度的增加，协同作用呈现上升趋势；为中低度协同作用；在常山酮与青蒿琥酯组合药物对的CI为分别为0.62、0.80、0.21，为中低度协同作用；在常山酮与蒿甲醚组合药物对的CI为分别为0.89、0.57、0.42，有协 同作用。
综上所述的常山酮与青蒿倍半萜内酯的组合药物对5种癌细胞的抑制率数据可知，常山酮与青蒿素及衍生物组合用药的活性，明显优于常山酮单独用药和青蒿倍半萜内酯单独用药。其中，青蒿及常山酮的组合药物的活性最为显著。
实施例2常山酮与青蒿素组合药物抑制结肠癌的动物实验考察
将青蒿素和常山酮的组合药物、青蒿素和常山酮进行动物实验，以5-Fu作为对照药物。采用结肠癌细胞HCT116，接种于雌性裸鼠皮下，每只接种1x106个细胞，待5天后，肿瘤体积长到100mm3左右，给药。常山酮给药剂量为5μg/kg，青蒿素的给药剂量为50mg/kg，两者联用为这两个剂量之和，5-Fu的给药剂量为10mg/kg。各组均为每天腹腔注射给药一次。15d后，切除肿瘤细胞(具体如图1所示)，进行病理切片检查(如图2所示)，发现青蒿素和常山酮的组合药物具有明显的协同作用，其作用明显优于单独使用青蒿素或单独使用常山酮(如图3所示)。并且青蒿素和常山酮的组合药物的活性优于5-Fu。
依据上述方法进行两组不同质量比的青蒿素和常山酮的组合药物进行动物实验，其中第一组中常山酮给药剂量为100μg/kg，青蒿素的给药剂量为20mg/kg；第二组中常山酮给药剂量为2μg/kg，青蒿素的给药剂量为100mg/kg；不同重量配比组的青蒿素和常山酮的组合药物的活性与5-Fu效果相近，其疗效仍然优于青蒿素或常山酮单独给药。
综上所述，青蒿素和常山酮的组合物对于结肠癌具有明显的治疗效果；在青蒿素和常山酮的组合药物的活性与5-Fu效果相近；常山酮和青蒿素在0.1:20～0.002:100(常山酮:青蒿素的质量比为1:2×102-5×105)的范围内,常山酮和青蒿素是具有良好的协同作用的。是可行的组合药物技术方案。

Claims (10)

  1. 一种用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物，其特征在于：所述组合药物的活性成分为常山酮和青蒿倍半萜内酯类化合物组成。
  2. 根据权利要求1所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物，其特征在于：所述青蒿倍半萜内酯类化合物为从黄花蒿中提取的倍半萜内酯及青蒿素的衍生物。
  3. 根据权利要求1所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物，其特征在于：所述青蒿倍半萜内酯为青蒿素、二氢青蒿素、青蒿琥酯或蒿甲醚中的一种。
  4. 根据权利要求1所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物，其特征在于：所述方案为常山酮和青蒿素的组合。
  5. 根据权利要求3所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗癌症的药物中的应用。
  6. 根据权利要求3所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗结肠癌的药物中的应用。
  7. 根据权利要求3所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗乳腺癌的药物中的应用。
  8. 根据权利要求3所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗肝癌的药物中的应用。
  9. 根据权利要求3所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗胃癌的药物中的应用。
  10. 根据权利要求3所述的用于抗癌的常山酮青蒿倍半萜内酯类化合物的组合物在制备治疗黑色素瘤的药物中的应用。
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