WO2023092943A1 - 盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用 - Google Patents

盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用 Download PDF

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WO2023092943A1
WO2023092943A1 PCT/CN2022/089862 CN2022089862W WO2023092943A1 WO 2023092943 A1 WO2023092943 A1 WO 2023092943A1 CN 2022089862 W CN2022089862 W CN 2022089862W WO 2023092943 A1 WO2023092943 A1 WO 2023092943A1
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fluorouracil
dronedarone hydrochloride
liver cancer
tumor
preparation
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PCT/CN2022/089862
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English (en)
French (fr)
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柴进
张晓珣
潘琼
瞿家权
谭雅
江忠勇
赵楠
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中国人民解放军陆军军医大学第一附属医院
成都市第七人民医院
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Publication of WO2023092943A1 publication Critical patent/WO2023092943A1/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
    • A61K31/395—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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the invention relates to the field of biomedicine, in particular to the application of dronedarone hydrochloride combined with 5-fluorouracil in the preparation of drugs for treating liver cancer and lung cancer.
  • Liver cancer is a common malignant tumor of the digestive system, and the number of liver cancer patients in China accounts for about half of the world's total. There are about 841,000 new liver cancer patients and 782,000 liver cancer deaths every year. China is a big country with liver cancer.
  • the incidence rate of liver cancer in my country is 26.92/100,000, and the mortality rate is 23.72/100,000.
  • the morbidity and mortality of liver cancer rank fourth and second respectively among malignant tumors in my country.
  • Liver cancer has the characteristics of difficult early diagnosis, rapid progress, and poor prognosis.
  • the overall five-year survival rate of liver cancer in my country is only 12.5%, which seriously threatens the life and health of our people.
  • Lung cancer is currently the malignant tumor with the highest morbidity and mortality in the world. Lung cancer accounts for the first morbidity and mortality of men, and the second morbidity and mortality of women.
  • liver cancer and lung cancer Although surgical resection and effective adjuvant treatment at the early stage of the disease have good therapeutic effects, lung cancer is still a threat to patients due to poor prognosis and low early diagnosis rate, and severe side effects of radiotherapy and chemotherapy on the body. A major cancer of life and health. Therefore, there is an urgent need to discover new treatments for liver cancer and lung cancer.
  • Dronedarone hydrochloride is a drug for the treatment of cardiac arrhythmia, its chemical name is N-(2-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)benzofuran-5- base) methanesulfonamide hydrochloride.
  • the Chinese name is Dronedarone Hydrochloride
  • the English name is Dronedarone Hydrochloride
  • the CAS registration number is 141625-93-6
  • the molecular weight is 593.22. Its pharmacological action is similar to that of amiodarone.
  • Dronedarone hydrochloride is also a multi-channel inhibitor, and it has blocking effects on sodium, potassium, calcium ion channels and ⁇ receptors.
  • Dronedarone hydrochloride can prolong the duration of myocardial action potential, slow down the atrioventricular conduction rate, and slow down the sinus rhythm; at the same time, it also has obvious negative inotropic effect, and can increase the left ventricular diastolic function under the condition of unchanged cardiac output. end pressure without altering or shortening the left ventricular ejection fraction.
  • 5-Fluorouracil is mainly used clinically in the treatment of gastrointestinal tumors, or in larger doses of fluorouracil in the treatment of choriocarcinoma. At the same time, it is often used in the treatment of breast cancer, ovarian cancer, lung cancer, cervical cancer, bladder cancer and skin cancer.
  • the purpose of the present invention is to provide a new drug combination to treat liver cancer and lung cancer.
  • the new application of dronedarone hydrochloride combined with 5-fluorouracil in the preparation of antitumor drugs provides a new solution for clinical treatment of liver cancer and lung cancer, which can reduce the concentration of hydrochloric acid.
  • the doses of nedarone and 5-fluorouracil can improve the anti-tumor effect of dronedarone hydrochloride and 5-fluorouracil, and reduce toxic and side effects.
  • the technical solution adopted in the present invention is the application of dronedarone hydrochloride combined with 5-fluorouracil in the preparation of antitumor drugs, and the antitumor drugs are drugs for treating liver cancer and/or lung cancer.
  • the dosage form of the antitumor drug includes any pharmaceutically acceptable dosage form.
  • the dosage forms include oral dosage forms and injection dosage forms.
  • the two separate preparations of dronedarone hydrochloride and 5-fluorouracil are administered simultaneously or the two separate preparations are administered sequentially.
  • the dosage of dronedarone hydrochloride is 20 mg/kg/day-100 mg/kg/day
  • the dosage of 5-fluorouracil is 20 mg/kg/day-100 mg/kg/day.
  • the present invention also provides an anti-tumor combined pharmaceutical composition, comprising dronedarone hydrochloride and 5-fluorouracil.
  • the dosage ratio of the dronedarone hydrochloride to 5-fluorouracil is 1:1-1:5.
  • Dronedarone hydrochloride combined with 5-fluorouracil of the present invention can effectively inhibit the proliferation of human liver cancer cells HepG2, PLC/PRF/5, and Hep3B, and using dronedarone hydrochloride alone can effectively inhibit human liver cancer cell lines HepG2, PLC/PRF/5, Hep3B proliferation, and dronedarone hydrochloride alone can effectively inhibit the proliferation of human lung cancer cell lines SPC-A1, A549 and mouse lung cancer cell line Lewis.
  • Dronedarone hydrochloride and 5-fluorouracil ratio of 1:4, 1:3, 1:2, 1:1 inhibit the proliferation of human liver cancer cells Huh7 and human lung cancer cells A459 better than dronedarone hydrochloride and 5-fluorouracil alone 5-fluorouracil.
  • dronedarone hydrochloride combined with antineoplastic drugs has an inhibitory effect on liver cancer cells and lung cancer cells.
  • the combined use of dronedarone hydrochloride and 5-fluorouracil can significantly inhibit the growth of tumors in the mouse liver cancer xenograft model, and the effect of inhibiting tumor growth in the mouse liver cancer xenograft model is better than that of 5-fluorouracil alone.
  • the combined application of anti-tumor drugs includes but not limited to 5-fluorouracil, and the tumors include but not limited to liver cancer and lung cancer.
  • Dronedarone hydrochloride combined with 5-fluorouracil within the dosage ratio range of the present invention, the two have obvious synergistic effect, effectively improving the curative effect, which is more significant than the simple curative effect superposition of a single component or two components, and improves the antitumor effect. cell lethality.
  • the combined use of dronedarone hydrochloride and 5-fluorouracil can reduce the dosage of each other, thereby reducing toxic and side effects.
  • the combined use of dronedarone hydrochloride and 5-fluorouracil can also save costs and reduce the economic burden of patients.
  • the invention provides a new way for the prevention and treatment of tumors, and has broad application prospects in the field of medicine.
  • Figure 1 shows that dronedarone hydrochloride can inhibit the proliferation of human liver cancer cells HepG2, PLC/PRF/5, and Hep3B.
  • the bars at each concentration in the figure are HepG2, PLC/PRF/5, and Hep3B from left to right.
  • Figure 2 shows that dronedarone hydrochloride can inhibit the proliferation of human lung cancer cells SPC-A1, A549 and mouse lung cancer cells Lewis.
  • the bars at each concentration in the figure are SPC-A1, A549, and Lewis from left to right.
  • Figure 3 shows that dronedarone hydrochloride combined with 5-fluorouracil can inhibit the proliferation of human liver cancer cells HepG2, PLC/PRF/5, and Hep3B.
  • the bars at each concentration in the figure are HepG2, PLC/PRF/5 from left to right , Hep3B.
  • FIG 4 shows that dronedarone hydrochloride and 5-fluorouracil at different dosage ratios can inhibit the proliferation of human liver cancer cells Huh7.
  • FIG. 5 shows that dronedarone hydrochloride and 5-fluorouracil at different dosage ratios can inhibit the proliferation of human lung cancer cell A549.
  • Figure 6 shows the effect of combined use of dronedarone hydrochloride and 5-fluorouracil on inhibiting tumor growth in a mouse liver cancer xenograft model.
  • Dronedarone hydrochloride was purchased from Huaxia Reagent, batch number 2016031601, CAS number 141625-93-6; 5-fluorouracil was purchased from Beyontian Company, product number was ST1060; DMEM high glucose medium was purchased from Thermo Fisher Company, The product number is 11965092; fetal bovine serum was purchased from Thermo Fisher Company, product number 10099141; DMSO was purchased from Sigma Company, product number D2650; CCK-8 kit was purchased from Boster, product number AR1199.
  • Thermo Fisher's CO 2 cell culture incubator (Heracell, 160i), ThermoFisher's multifunctional microplate reader (Varioskan LUX), cell culture flasks, and 96-well cell culture plates were purchased from Wuxi Nice Life Technology Co., Ltd.
  • Human liver cancer cells HepG2, PLC/PRF/5, Hep3B in logarithmic phase growth, human lung cancer cells SPC-A1, A549 and mouse lung cancer cells Lewis were seeded in 96 wells at 5 ⁇ 10 cells/well for culture. 100 ⁇ l of DMEM high-glucose medium containing 10% FBS per well was placed in a 5% CO 2 , 37° C. cell culture incubator and cultured overnight. Add dronedarone hydrochloride, 100 ⁇ M 5-fluorouracil, and 10 ⁇ M dronedarone hydrochloride + 100 ⁇ M 5-fluorouracil at final concentrations of 5 ⁇ M, 10 ⁇ M, and 20 ⁇ M, respectively.
  • Dronedarone hydrochloride between 5 ⁇ M and 20 ⁇ M could inhibit the proliferation of human liver cancer cells HepG2, PLC/PRF/5, Hep3B, human lung cancer cell lines SPC-A1, A549 and mouse lung cancer cell line Lewis, as shown in Shown in Figure 1 and Figure 2, and in a dose-dependent manner.
  • Dronedarone hydrochloride combined with 5-fluorouracil inhibits liver cancer cells with inhibition rates of HepG2 (93.41%), PLC/PRF/5 (97.06%), and Hep3B (98.10%), as shown in FIG. 3 . It shows that combined use of dronedarone hydrochloride and 5-fluorouracil can effectively inhibit the proliferation of liver cancer cells.
  • Human liver cancer cells Huh7 and human lung cancer cells A549 in the logarithmic phase were seeded at 5 ⁇ 10 cells/well in 96 wells for culture, and 100 ⁇ l of DMEM high-glucose medium containing 10% FBS per well was placed in 5% CO 2 , culture overnight in a 37°C cell culture incubator.
  • dronedarone hydrochloride at a final concentration of 10 ⁇ M, 100 ⁇ M 5-fluorouracil, 10 ⁇ M dronedarone hydrochloride+50 ⁇ M 5-fluorouracil, 10 ⁇ M dronedarone hydrochloride+40 ⁇ M 5-fluorouracil, 10 ⁇ M dronedarone hydrochloride+30 ⁇ M 5-fluorouracil, 10 ⁇ M dronedarone hydrochloride + 20 ⁇ M 5-fluorouracil, 10 ⁇ M dronedarone hydrochloride + 10 ⁇ M 5-fluorouracil, and an equal volume of DMSO was added to the control group.
  • the dosage ratio of dronedarone hydrochloride and 5-fluorouracil is preferably 1:5, 1:4, 1:3, 1:2, 1:1.
  • Dronedarone Hydrochloride Treats Liver Cancer Xenografted Tumor Mouse Model
  • the dosage ratio of dronedarone hydrochloride and 5-fluorouracil was selected to be 1:1.5, and the ability to inhibit tumor proliferation was detected at the in vivo level.
  • Human liver cancer cell Huh7 in logarithmic phase was taken to make a cell suspension, containing 1 ⁇ 10 4 cells per microliter. Inject 100 ⁇ l of cell suspension subcutaneously on the back of nude mice, and when the tumor grows to 15 mm, the tumor-bearing mice are randomly divided into three groups.
  • the dosage ratio of dronedarone hydrochloride to 5-fluorouracil is preferably 1:5-1:1.

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Abstract

本发明提供一种盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，药效学实验证明盐酸决奈达隆联合5-氟尿嘧啶可以有效抑制人肝癌细胞株HepG2，PLC/PRF/5，Hep3B增殖。单独使用盐酸决奈达隆可有效抑制人肝癌细胞株HepG2，PLC/PRF/5，Hep3B增殖，单独使用盐酸决奈达隆可有效抑制人肺癌细胞系SPC-A1、A549以及小鼠肺癌细胞系Lewis增殖。此外，盐酸决奈达隆联合5-氟尿嘧啶可抑制小鼠肝癌移植瘤模型中肿瘤的生长。盐酸决奈达隆联合抗肿瘤药物可用于制备治疗肝癌及肺癌药物。

Description

盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用 技术领域
本发明涉及生物医药领域，具体涉及盐酸决奈达隆联合5-氟尿嘧啶在制备治疗肝癌和肺癌药物中的应用。
背景技术
肝癌是一种常见的消化系统恶性肿瘤，中国的肝癌患者占全球的一半左右。每年大约有84.1万新发肝癌患者，78.2万死亡肝癌患者。中国是肝癌大国，我国肝癌发病率为26.92/10万，死亡率23.72/10万。肝癌的发病率和死亡率在我国恶性肿瘤中分别排列第四位和第二位。肝癌具有早诊困难、进展迅速，预后较差等特征，我国肝癌总体五年生存率仅12.5％，严重威胁我国人民的生命和健康。目前，针对食管癌术后复发的预防以放射治疗和化学疗法为主，但是放射治疗和化学治疗后所带给机体的严重副作用，使得放、化疗在延续患者生命的同时也加重了患者的预后不良情况。并且肝癌患者的5年生存率依旧没有得到显著地提高。肺癌是目前全球发病率和死亡率最高的恶性肿瘤，肺癌占男性发病率和死亡率第一位，女性发病率第二位和死亡率第一位。尽管在疾病早期阶段进行手术切除和有效的辅助有不错的治疗效果，但由于患者预后较差且早期诊断率较低，且放射治疗和化学治疗对机体产生严重的副作用，导致肺癌仍是威胁患者生命健康的一大癌症。因此，目前急需发现新的治疗肝癌和肺癌的治疗手段。
盐酸决奈达隆是治疗心律失常的药物，其化学名为N-(2-丁基-3-(4-(3-二丁基氨基丙氧基)苯甲酰基)苯并呋喃-5-基)甲磺酰胺盐酸盐。中文名为盐酸决奈达隆，英文名为Dronedarone Hydrochloride，CAS登记号141625-93-6，分子量为593.22。其药理作用于胺碘酮相似，盐酸决奈达隆亦为多通道的抑制剂，对钠、钾、钙离子通道和β受体等均有阻滞作用。盐酸决奈达隆可延长心肌动作电位时程，减慢房室传导速率，减慢窦性心律；同时还具有明显的负性肌力作用，在心输出量不变的情况下可增加左室舒末压，但不会改变左室射血分数或缩短分数。5-氟尿嘧啶临床主要用于治疗消化道肿瘤，或较大剂量氟尿嘧啶治疗绒毛膜上皮癌。同时常用于治疗乳腺癌、卵巢癌、肺癌、 宫颈癌、膀胱癌及皮肤癌等。
发明内容
本发明目的在于提供新的联合用药以治疗肝癌和肺癌，盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的新应用，为临床治疗肝癌和肺癌提供了新的方案，可以降低盐酸决奈达隆和5-氟尿嘧啶的用药量，提升盐酸决奈达隆和5-氟尿嘧啶的抗肿瘤作用，减少毒副作用。
为了实现上述目的，本发明采用的技术方案是，盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，所述抗肿瘤药物为治疗肝癌和/或肺癌的药物。
进一步，所述抗肿瘤药物的剂型包括药剂学上可接受的任意一种剂型。
优选地，所述剂型包括口服剂型和注射剂型。
进一步，所述盐酸决奈达隆和5-氟尿嘧啶两种单独的制剂同时施用或两种单独的制剂依次施用。
优选地，所述盐酸决奈达隆用药量为20mg/kg/天～100mg/kg/天，所述5-氟尿嘧啶用药量为20mg/kg/天～100mg/kg/天。
本发明还提供了一种抗肿瘤的联合用药物组合物，包括盐酸决奈达隆和5-氟尿嘧啶。所述盐酸决奈达隆与5-氟尿嘧啶的用量比例为1:1-1:5。
本发明盐酸决奈达隆联合5-氟尿嘧啶可有效抑制人肝癌细胞HepG2、PLC/PRF/5、Hep3B增殖，单独使用盐酸决奈达隆可有效抑制人肝癌细胞株HepG2，PLC/PRF/5，Hep3B增殖，并且单独使用盐酸决奈达隆可有效抑制人肺癌细胞系SPC-A1、A549以及小鼠肺癌细胞系Lewis增殖。盐酸决奈达隆和5-氟尿嘧啶用量比1:4，1:3，1:2，1:1抑制人肝癌细胞Huh7和人肺癌细胞A459细胞增殖的效应优于单独使用盐酸决奈达隆和5-氟尿嘧啶。以上结果表明盐酸决奈达隆联合抗肿瘤药物对肝癌细胞和肺癌细胞具有抑制作用。此外，联合使用盐酸决奈达隆和5-氟尿嘧啶可明显抑制小鼠肝癌移植瘤模型中肿瘤的生长，并抑制小鼠肝癌移植瘤模型中肿瘤生长的效应优于单独使用5-氟尿嘧啶。其中联合应用抗 肿瘤药物包括但不限于5-氟尿嘧啶，肿瘤包括但不限于肝癌、肺癌。
盐酸决奈达隆联合5-氟尿嘧啶，在本发明的用量比例范围内，两者具有明显的协同作用，有效提高疗效，相对于单一组分或两组分简单疗效叠加更显著，提高了对肿瘤细胞的杀伤性。在保证同样治疗效果的情况下，盐酸决奈达隆和5-氟尿嘧啶的联合使用可以降低彼此的用药量，从而减少毒副作用。此外，盐酸决奈达隆和5-氟尿嘧啶的联合使用还可节约成本，减轻病人的经济负担，本发明为肿瘤的防治提供了一条新途径，在医药学领域的应用前景广阔。
附图说明
图1为盐酸决奈达隆可抑制人肝癌细胞HepG2、PLC/PRF/5、Hep3B增殖，图中各浓度下的柱形条从左到右依次是HepG2、PLC/PRF/5、Hep3B。
图2为盐酸决奈达隆可抑制人肺癌细胞SPC-A1、A549以及小鼠肺癌细胞Lewis增殖，图中各浓度下的柱形条从左到右依次是SPC-A1、A549、Lewis。
图3为盐酸决奈达隆联合5-氟尿嘧啶可抑制人肝癌细胞HepG2、PLC/PRF/5、Hep3B增殖，图中各浓度下的柱形条从左到右依次是HepG2、PLC/PRF/5、Hep3B。
图4为不同用量比的盐酸决奈达隆和5-氟尿嘧啶可抑制人肝癌细胞Huh7增殖。
图5为不同用量比的盐酸决奈达隆和5-氟尿嘧啶可抑制人肺癌细胞A549增殖。
图6为联合使用盐酸决奈达隆和5-氟尿嘧啶可抑制小鼠肝癌移植瘤模型中肿瘤生长的效应。
具体实施方式
以下通过实验例来进一步阐述本发明药物的有益效果，但是本发明不限于这些具体实施例。
实施例中使用的实验材料和仪器
1.实验材料
1.1主要试剂及药物
盐酸决奈达隆购自于华夏试剂，批号为2016031601，CAS号141625-93-6；5-氟尿嘧啶购自于碧云天公司，货号为ST1060；DMEM高糖培养基，购自于Thermo Fisher公司，货号为11965092；胎牛血清购自于Thermo Fisher公司，货号10099141；DMSO购自于Sigma公司，货号为D2650；CCK-8试剂盒购自于博士德，货号为AR1199。
1.2主要仪器和耗材
Thermo Fisher公司CO 2细胞培养箱(Heracell，160i)，ThermoFisher公司多功能微孔板读数仪(Varioskan LUX)，细胞培养瓶、96孔细胞培养板购自于无锡耐思生命科技股份有限公司。
实施例1
细胞增殖实验
取对数期生长的人肝癌细胞HepG2、PLC/PRF/5、Hep3B，人肺癌细胞SPC-A1、A549以及小鼠肺癌细胞Lewis，按照5×10 3个细胞/孔接种于96孔中培养，每孔100μl含有10％FBS的DMEM高糖培养基，置于5％CO 2，37℃的细胞培养箱中培养过夜。分别加入终浓度为5μM，10μM，20μM的盐酸决奈达隆，100μM的5-氟尿嘧啶，以及10μM的盐酸决奈达隆+100μM的5-氟尿嘧啶，对照组加入等体积的DMSO，每孔100μl DMEM高糖培养基。置于5％CO 2，37℃的细胞培养箱中培养24小时。每孔加入10μl CCK-8溶液。在细胞培养箱中继续孵育0.5小时。在450nm处测定吸光度。计算公式：细胞存活率＝[(实验孔-空白孔)/(对照孔-空白孔)]×100％，实验孔(含有细胞的培养基、CCK-8、待测物质)，对照孔(含有细胞的培养基、CCK-8、没有待测物质)，空白孔(不含细胞和待测物质的培养基、CCK-8)。计算统计各组细胞存活率。结果显示，盐酸决奈达隆浓度在5μM-20μM之间，可抑制人肝癌细胞HepG2、PLC/PRF/5、Hep3B和人肺癌细胞系SPC-A1、A549以及小鼠肺癌细胞系Lewis增殖，如图1和图2所示，并且呈剂量依赖性。盐酸决奈达隆联合5-氟尿嘧啶抑制肝癌细胞抑制率为HepG2(93.41％)、PLC/PRF/5(97.06％)、Hep3B(98.10％)，如图3所示。说明联合使用盐酸决奈达隆和5-氟尿嘧啶能够有效抑制肝癌细胞增殖。
取对数期生长的人肝癌细胞Huh7，人肺癌细胞A549，按照5×10 3个细胞/孔接种于96孔中培养，每孔100μl含有10％FBS的DMEM高糖培养基，置于5％CO 2，37℃的细胞培养箱中培养过夜。分别加入终浓度为10μM的盐酸决奈达隆，100μM 5-氟尿嘧啶，10μM盐酸决奈达隆+50μM 5-氟尿嘧啶，10μM盐酸决奈达隆+40μM 5-氟尿嘧啶，10μM盐酸决奈达隆+30μM 5-氟尿嘧啶，10μM盐酸决奈达隆+20μM 5-氟尿嘧啶，10μM盐酸决奈达隆+10μM 5-氟尿嘧啶，对照组加入等体积的DMSO。结果显示，与对照组相比，10μM盐酸决奈达隆+50μM 5-氟尿嘧啶，10μM盐酸决奈达隆+40μM 5-氟尿嘧啶，10μM盐酸决奈达隆+30μM 5-氟尿嘧啶，10μM盐酸决奈达隆+20μM 5-氟尿嘧啶，10μM盐酸决奈达隆+10μM 5-氟尿嘧啶可抑制人肝癌细胞Huh7和人肺癌细胞A459增殖，如图4和图5所示，并且抑制肿瘤细胞增殖效应优于10μM的盐酸决奈达隆以及100μM 5-氟尿嘧啶。盐酸决奈达隆和5-氟尿嘧啶用量比优选于1:5，1:4，1:3，1:2，1:1。
实施例2
盐酸决奈达隆治疗肝癌移植瘤小鼠模型
根据前期细胞实验结果，选取盐酸决奈达隆和5-氟尿嘧啶用量比1:1.5，在体内水平检测抑制肿瘤增殖能力。取对数期生长的人肝癌细胞Huh7，制成细胞悬液，每微升含1×10 4个细胞。注入100μl细胞悬液裸鼠背部皮下，待肿瘤长至15mm，将荷瘤小鼠随机分为三组。一组为溶剂对照组(含5％DMSO的生理盐水)，二组为盐酸决奈达隆联合5-氟尿嘧啶组(20mg/kg盐酸决奈达隆，30mg/kg 5-氟尿嘧啶，盐酸决奈达隆、5-氟尿嘧啶溶于含5％DMSO的生理盐水中)，三组为5-氟尿嘧啶组(30mg/kg，盐酸决奈达隆溶于含5％DMSO的生理盐水中)。按照分组每天腹腔注射药物进行治疗，每隔一天测量瘤体积。瘤体积＝(长径×短径×短径)/2。当对照组小鼠瘤组织达到1000mm 3时，终止实验，取出肿瘤组织，称量肿瘤重量并拍照记录。如图6所示。单独使用30mg/kg 5-氟尿嘧啶可抑制肿瘤体积，而联合使用20mg/kg盐酸决奈达隆和30mg/kg 5-氟尿嘧啶能够明显抑制肿瘤体积。说明联合使用盐酸决奈达隆和5-氟尿嘧啶可有效抑制瘤体积，发挥抗肿瘤作用。盐酸决奈达隆与5-氟尿嘧啶的用量比例优选1:5-1:1。

Claims (9)

  1. 盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用。
  2. 根据权利要求1所述盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，其特征在于：所述抗肿瘤药物为治疗肝癌和/或肺癌的药物。
  3. 根据权利要求1或2所述盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，其特征在于：所述抗肿瘤药物的剂型包括药剂学上可接受的任意一种剂型。
  4. 根据权利要求3所述盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，其特征在于：所述剂型包括口服剂型和注射剂型。
  5. 根据权利要求1或2所述盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，其特征在于：所述盐酸决奈达隆和5-氟尿嘧啶两种单独的制剂同时施用或两种单独的制剂依次施用。
  6. 根据权利要求5所述盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用，其特征在于：所述盐酸决奈达隆用药量为20mg/kg/天～100mg/kg/天，所述5-氟尿嘧啶用药量为20mg/kg/天～100mg/kg/天。
  7. 一种抗肿瘤的联合用药物组合物，其特征在于：包括盐酸决奈达隆和5-氟尿嘧啶。
  8. 根据权利要求7所述一种抗肿瘤的联合用药物组合物，其特征在于：所述肿瘤包括肝癌和肺癌。
  9. 根据权利要求7所述一种抗肿瘤的联合用药物组合物，其特征在于：所述盐酸决奈达隆与5-氟尿嘧啶的用量比例为1:1-1:5。
PCT/CN2022/089862 2021-11-23 2022-04-28 盐酸决奈达隆联合5-氟尿嘧啶在制备抗肿瘤药物中的应用 WO2023092943A1 (zh)

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