WO2020186392A1 - 甘氨胆酸在制备抗肿瘤药物中的应用 - Google Patents

甘氨胆酸在制备抗肿瘤药物中的应用 Download PDF

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WO2020186392A1
WO2020186392A1 PCT/CN2019/078305 CN2019078305W WO2020186392A1 WO 2020186392 A1 WO2020186392 A1 WO 2020186392A1 CN 2019078305 W CN2019078305 W CN 2019078305W WO 2020186392 A1 WO2020186392 A1 WO 2020186392A1
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glycocholic acid
tumor
breast cancer
drugs
application
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梁文波
项蓉蓉
江一鸣
童玉春
宋捷
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大连大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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  • the invention relates to the application of chemical drugs in the medical field, in particular to the application of glycocholic acid in antitumor drugs.
  • Malignant tumors are one of the major diseases that seriously endanger human health. According to the World Health Organization (WHO), 8.4 million people died of malignant tumors worldwide in 2010, and it is estimated that it may increase to 10 million by 2020. The number of new malignant tumors in my country is about 1.8 million every year, and about 1.3 million people die from malignant tumors. Malignant tumors have become the leading cause of death in our population.
  • WHO World Health Organization
  • Glycocholic acid is a kind of combined cholic acid, which is produced by combining cholic acid and glycine, a metabolite of cholesterol in the liver. Its physiological function is mainly to promote the digestion and absorption of fat in the intestine, but it has not been reported as a medicine, especially its application in anti-tumor drugs.
  • the purpose of the present invention is to provide the application of glycocholic acid in the preparation of antitumor drugs.
  • the present invention provides the application of glycocholic acid in antineoplastic drugs, wherein the molecular structural formula of glycocholic acid is:
  • the antitumor drugs are human antitumor drugs.
  • the antitumor drugs are antitumor drugs for animals.
  • the animals to which the anti-tumor drugs are applied are primates and rodents.
  • the tumors involved are breast cancer, ovarian cancer, endometrial cancer and other malignant tumors.
  • Glycocholic acid is used in the preparation of anti-tumor drugs, and the application of anti-tumor drugs includes the application in tumor cell growth inhibitors.
  • the invention also provides an anti-tumor drug containing glycocholic acid and its derivatives.
  • the anti-tumor drug containing glycocholic acid and its derivatives
  • the anti-tumor drug comprises an effective therapeutic amount of glycocholic acid and the remainder of a pharmaceutically acceptable carrier.
  • the effective therapeutic dose is 0.4-1.6 nmol/L for 4T1 (mouse breast cancer cells), and 0.16-1.28 ⁇ mol for MCF-7 (human breast cancer cells) /L, MDA-MB-468 (human breast cancer cells) is 0.08-1.32 ⁇ mol/L.
  • the above-mentioned anti-tumor drugs containing glycocholic acid and its derivatives are oral preparations, suppositories, injections or transdermal agents.
  • the present invention provides a new application field of glycocholic acid, which can be used in the preparation of anti-tumor drugs.
  • the main applicable tumors are breast cancer (such as 4T1, MCF-7, MDA-MB-468), ovarian Cancer (such as NIH: OVCAR-3), endometrial cancer (such as RL95-2) or their combination
  • glycocholic acid is an effective active ingredient of anti-tumor drugs, and its effective therapeutic dose is 4T10.4 ⁇ 1.6nmol/ L
  • MCF-7 is 0.16 to 1.28 ⁇ mol/L
  • MDA-MB-468 is 0.08 to 1.32 ⁇ mol/L; the present invention is helpful for the development of new anti-tumor drugs.
  • Figure 1 4T1 mouse breast cancer cell glycocholic acid 0.8nmol/L group, the inhibition rate of each time period (compared with the negative control group, * P ⁇ 0.05).
  • Figure 2 Inhibition rate of 4T1 mouse breast cancer cells in each group at 12 hours (compared with the negative control group, * P ⁇ 0.05).
  • FIG. 3 MCF-7 human breast cancer cell 1.28 ⁇ mol/L group, the inhibition rate of each time period (compared with the negative control group, * P ⁇ 0.05).
  • Figure 4 Inhibition rate of MCF-7 human breast cancer cells in each group at 36 hours (compared with the negative control group, * P ⁇ 0.05).
  • FIG. 5 MDA-MB-468 human breast cancer cell 1.32 ⁇ mol/L group, the inhibition rate of each time period (compared with the negative control group, * P ⁇ 0.05).
  • Figure 6 Inhibition rate of MDA-MB-468 human breast cancer cells in each group at 36 hours (compared with the negative control group, * P ⁇ 0.05).
  • Figure 7 NIH:OVCAR-3 human ovarian cancer cell 1.28 ⁇ mol/L group, the inhibition rate of each time period (compared with the negative control group, * P ⁇ 0.05).
  • Figure 8 The inhibition rate of each group of NIH:OVCAR-3 human ovarian cancer cells at 48 hours (compared with the negative control group, * P ⁇ 0.05).
  • Figure 9 Inhibition rate of RL95-2 human endometrial cancer cell 1.28 ⁇ mol/L group at each time period (compared with the negative control group, * P ⁇ 0.05).
  • Figure 10 Inhibition rate of RL95-2 human endometrial cancer cells in each group at 36 hours (compared with the negative control group, * P ⁇ 0.05).
  • Figure 11 Inhibition rate of 4T1 mouse breast cancer cell sodium glycocholate 0.7nmol/L group at each time period (compared with the negative control group, * P ⁇ 0.05).
  • Figure 12 Inhibition rate of 4T1 mouse breast cancer cells in each group at 12 hours (compared with the negative control group, * P ⁇ 0.05).
  • Figure 13 FXR gene expression curve at 12h in the 0.8nmol/L group of 4T1 mouse breast cancer cells
  • Figure 14 Histogram of FXR gene expression at 12h in the 0.8nmol/L group of 4T1 mouse breast cancer cells (compared with the negative control group, * P ⁇ 0.05).
  • Figure 15 FXR protein expression in the 0.8nmol/L group of 4T1 mouse breast cancer cells at 12h
  • Figure 16 Histogram of FXR protein expression in the 0.8nmol/L group of 4T1 mouse breast cancer cells at 12h (compared with the negative control group, * P ⁇ 0.05).
  • glycocholic acid used in the examples was purchased from Aladdin reagent, product number G131002.
  • MCF-7 cells concentration gradient of MCF-7 cells is (0.02 ⁇ mol/L, 0.04 ⁇ mol/L, 0.08 ⁇ mol/L, 0.16 ⁇ mol/L, 0.32 ⁇ mol/L, 0.64 ⁇ mol/L , 1.28 ⁇ mol/L)
  • MDA-MB-468 cells were added with a concentration gradient of (0.02 ⁇ mol/L, 0.04 ⁇ mol/L, 0.08 ⁇ mol/L, 0.16 ⁇ mol/L, 0.33 ⁇ mol/L, 0.66 ⁇ mol/L, 1.32 ⁇ mol /L)
  • NIH OVCAR-3 cells were added with a concentration gradient of (0.02 ⁇ mol/L, 0.04 ⁇ mol/L, 0.08 ⁇ mol/L, 0.16 ⁇ mol/L, 0.32 ⁇ mol/L, 0.
  • inhibition rate (control well OD-dosing hole OD)/(control well OD-blank hole OD) ⁇ 100%
  • the highest point of inhibition reached by 4T1 mouse breast cancer cells in 12 hours was the concentration of glycocholic acid 0.8nmol/L, as shown in Figure 1 and Figure 2, and its IC50 was between 0.01nmol/L-0.1nmol/L
  • MCF-7 cells reached the highest point of inhibition rate of 1.28 ⁇ mol/L at 36 hours, as shown in Figures 3 and 4, their IC50 was between 0.64 ⁇ mol/L-1.00 ⁇ mol/L
  • MDA-MB-468 cells The highest point of inhibition rate reached at 36 hours was 1.32 ⁇ mol/L, as shown in Figure 5 and Figure 6, and its IC50 was between 0.33 ⁇ mol/L-0.66 ⁇ mol/L.
  • NIH:OVCAR-3 cells reached the inhibition rate at 48 hours.
  • the highest point is 1.28 ⁇ mol/L, as shown in Figure 7 and Figure 8. Its IC50 is between 0.16 ⁇ mol/L-0.32 ⁇ mol/L, RL95-2 cells reach the highest point of inhibition rate at 1.28 ⁇ mol/L at 36 hours. See Figure 9 and Figure 10, the IC50 is between 0.32 ⁇ mol/L-0.64 ⁇ mol/L.
  • Cell line: 4T1 (mouse breast cancer cells) (all the above were purchased from Shanghai Cell Bank of Chinese Academy of Sciences)
  • inhibition rate (control well OD-dosing hole OD)/(control well OD-blank hole OD) ⁇ 100%
  • mice in the experimental group 0.247 ⁇ 0.08g
  • mice in the control group 0.431 ⁇ 0.167g
  • the tumors in the experimental group were significantly smaller than those in the control group, and the tumor inhibition rate reached 42.83%.
  • 4T1 mouse breast cancer cells were purchased from Shanghai Cell Bank of Chinese Academy of Sciences.
  • Method Extract the RNA of 4T1 cells after the intervention of glycocholic acid, perform Real-time PCR after reverse transcription to determine the changes in the RNA expression of the specific target of glycocholic acid.
  • Example 5 Western blot experiment to determine changes in the expression of glycocholic acid-specific target protein in tumor cells after the intervention of glycocholic acid
  • 4T1 mouse breast cancer cells were purchased from Shanghai Cell Bank of Chinese Academy of Sciences.

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Abstract

本发明涉及化学药物在医药领域中的用途，具体是甘氨胆酸在制备抗肿瘤药物中的应用。本发明提供了甘氨胆酸的新的应用领域，甘氨胆酸可应用在制备抗肿瘤药物中，主要适用的肿瘤有乳腺癌、卵巢癌、子宫内膜癌或它们的组合，甘氨胆酸作为抗肿瘤药物的有效活性成分，本发明有助于开发出新型的抗肿瘤药物。

Description

甘氨胆酸在制备抗肿瘤药物中的应用 技术领域
本发明涉及化学药物在医药领域中的用途，具体是甘氨胆酸在抗肿瘤药物中的应用。
背景技术
恶性肿瘤是严重危害人类健康的重大疾病之一，据世界卫生组织(WHO)报告2010年全世界共有840万人死于恶性肿瘤，预计到2020年可能增至1000万。我国恶性肿瘤每年新发病人数约180万，约有130万人死于恶性肿瘤，恶性肿瘤已成为我国人口死亡的首要因素。
肿瘤的药物治疗在近代肿瘤内科治疗的历史很短，迄今不足70年，但不足一个世纪的药物治疗已取得很多重大成果，使得药物治疗已成为肿瘤综合治疗中不可缺少的部分。而目前临床上使用的大多数抗肿瘤药物在杀伤肿瘤细胞的同时又杀伤机体正常的细胞，在免疫系统和造血系统中体现最明显。最终导致患者中远期的药物不耐受和肿瘤的复发转移以及肿瘤的耐药。因此，近年来人们一直致力于开发新型抗肿瘤药物，其中大多数药物靶点明确且对于免疫和造血系统伤害少甚至无伤害。
甘氨胆酸是一种结合胆酸，是胆固醇在肝内的代谢产物胆酸与甘氨酸结合生成的。其生理作用主要是在肠道内促进脂肪的消化吸收，但作为药物，尤其是应用在抗肿瘤药物中尚未见报道。
发明内容
针对现有技术存在的缺陷，充分利用甘氨胆酸的活性成分，本发明的目的在于提供甘氨胆酸在制备抗肿瘤药物中的应用。
为了实现上述发明目的，本发明提供了甘氨胆酸在抗肿瘤药物中的应用，其中，所述甘氨胆酸的分子结构式为：
Figure PCTCN2019078305-appb-000001
甘氨胆酸在制备抗肿瘤药物的应用中，抗肿瘤药物为人用抗肿瘤药物。
甘氨胆酸在制备抗肿瘤药物的应用中，抗肿瘤药物为动物用抗肿瘤药物。
甘氨胆酸在制备抗肿瘤药物的应用中，所述抗肿瘤药物应用的动物为灵长目动物和啮齿目动物。
甘氨胆酸在制备抗肿瘤药物的应用中，所涉及的肿瘤为乳腺癌、卵巢癌、子宫内膜癌等恶性肿瘤。
甘氨胆酸在制备抗肿瘤药物的应用中，抗肿瘤药物的应用包括在肿瘤细胞生长抑制剂中的应用。
本发明还提供了一种含甘氨胆酸及其衍生物的抗肿瘤药物。
上述含甘氨胆酸及其衍生物的抗肿瘤药物，所述抗肿瘤药物包含有效治疗量的甘氨胆酸和余量的药学上可接受的载体。
上述含甘氨胆酸及其衍生物的抗肿瘤药物，所述有效治疗量为4T1(小鼠乳腺癌细胞)0.4～1.6nmol/L，MCF-7(人乳腺癌细胞)为0.16～1.28μmol/L，MDA-MB-468(人乳腺癌细胞)为0.08～1.32μmol/L。
上述含甘氨胆酸及其衍生物的抗肿瘤药物，所述药物是口服制剂、栓剂、注射剂或透皮剂。
本发明提供了甘氨胆酸的新的应用领域，甘氨胆酸可应用在制备抗肿瘤药物中，主要适用的肿瘤有乳腺癌(如4T1、MCF-7、MDA-MB-468)、卵巢癌(如NIH:OVCAR-3)、子宫内膜癌(如RL95-2)或它们的组合，甘氨胆酸作为抗肿瘤药物的有效活性成分，其有效治疗量为4T10.4～1.6nmol/L，MCF-7为0.16～1.28μmol/L，MDA-MB-468为0.08～1.32μmol/L；本发明有助于开发出新型 的抗肿瘤药物。
附图说明
图1：4T1小鼠乳腺癌细胞甘氨胆酸0.8nmol/L组，各时间段的抑制率(与阴性对照组进行比较， *P＜0.05)。
图2：4T1小鼠乳腺癌细胞各组在12小时的抑制率(与阴性对照组进行比较， *P＜0.05)。
图3：MCF-7人乳腺癌细胞1.28μmol/L组，各时间段的抑制率(与阴性对照组进行比较， *P＜0.05)。
图4：MCF-7人乳腺癌细胞各组在36小时的抑制率(与阴性对照组进行比较， *P＜0.05)。
图5：MDA-MB-468人乳腺癌细胞1.32μmol/L组，各时间段的抑制率(与阴性对照组进行比较， *P＜0.05)。
图6：MDA-MB-468人乳腺癌细胞各组在36小时的抑制率(与阴性对照组进行比较， *P＜0.05)。
图7：NIH:OVCAR-3人卵巢癌细胞1.28μmol/L组，各时间段的抑制率(与阴性对照组进行比较， *P＜0.05)。
图8：NIH:OVCAR-3人卵巢癌细胞各组在48小时的抑制率(与阴性对照组进行比较， *P＜0.05)。
图9：RL95-2人子宫内膜癌细胞1.28μmol/L组，各时间段的抑制率(与阴性对照组进行比较， *P＜0.05)。
图10：RL95-2人子宫内膜癌细胞各组在36小时的抑制率(与阴性对照组进行比较， *P＜0.05)。
图11：4T1小鼠乳腺癌细胞甘氨胆酸钠0.7nmol/L组，各时间段的抑制率(与阴性对照组进行比较， *P＜0.05)。
图12：4T1小鼠乳腺癌细胞各组在12小时的抑制率(与阴性对照组进行比较， *P＜0.05)。
图13：4T1小鼠乳腺癌细胞0.8nmol/L组在12h时FXR基因表达量曲线
图14：4T1小鼠乳腺癌细胞0.8nmol/L组在12h时FXR基因表达量柱状图(与阴性对照组进行比较， *P＜0.05)。
图15：4T1小鼠乳腺癌细胞0.8nmol/L组在12h时FXR蛋白表达量印迹条带
图16：4T1小鼠乳腺癌细胞0.8nmol/L组在12h时FXR蛋白表达量柱状图(与阴性对照组进行比较， *P＜0.05)。
具体实施方式
以下结合具体实施例对本发明做进一步说明。
实施例中所用甘氨胆酸均购自阿拉丁试剂，产品编号G131002。
实施例1 甘氨胆酸的体外抗肿瘤实验
1.细胞株：4T1(小鼠乳腺癌细胞)、MCF-7(人乳腺癌细胞)、MDA-MB-468(人乳腺癌细胞)、NIH:OVCAR-3(人卵巢癌细胞)、RL95-2(人子宫内膜癌细胞)(以上均购自中科院上海细胞库)
2.培养基：RPMI-1640(Gibco货号31800022)；高糖DMEM培养基(Gibco货号11965092)
3.方法
3.1 收集对数生长期细胞，分别用1640培养基和DMEM培养基调整细胞浓度为5×10 4个/ml，在96孔板内加入100μl的细胞悬液。
3.2 5％的CO 2，37℃培养24小时后，4T1小鼠乳腺癌细胞加入浓度梯度分别为(0.1nmol/L，0.2nmol/L，0.4nmol/L，0.8nmol/L，1.6nmol/L，3.2nmol/L，6.4nmol/L)、MCF-7细胞加入浓度梯度为(0.02μmol/L，0.04μmol/L，0.08μmol/L，0.16μmol/L，0.32μmol/L，0.64μmol/L，1.28μmol/L)、MDA-MB-468细胞加入浓度梯度为(0.02μmol/L，0.04μmol/L，0.08μmol/L，0.16μmol/L，0.33μmol/L，0.66μmol/L，1.32μmol/L)、NIH:OVCAR-3细胞加入浓度梯度为(0.02μmol/L，0.04μmol/L，0.08μmol/L，0.16μmol/L，0.32μmol/L，0.64μmol/L，1.28μmol/L)、RL95-2细胞加入浓度梯度为(0.02μmol/L，0.04μmol/L，0.08μmol/L，0.16μmol/L，0.32μmol/L，0.64μmol/L，1.28μmol/L)的甘氨胆酸，设5个复孔，同时设置空白组和对照组。
3.3 分别在12h，24h，36h，48h，60h小时后加入CCK-8试剂，继续孵育3h，孵育完成后在酶标仪OD450nm处测量各孔吸光值。
3.4 利用公式：抑制率＝(对照孔OD-加药孔OD)/(对照孔OD-空白孔OD)×100％，求出各个浓度的甘氨胆酸对于肿瘤细胞的抑制率。
4.结果：4T1小鼠乳腺癌细胞在12小时达到的抑制最高点为甘氨胆酸浓度0.8nmol/L，见图1、图2，其IC50在0.01nmol/L-0.1nmol/L之间，MCF-7细胞在36小时达到抑制率的最高点为1.28μmol/L，见图3、图4，其IC50分别在0.64μmol/L-1.00μmol/L之间，MDA-MB-468细胞在36小时达到抑制率的最高点为1.32μmol/L，见图5、图6，其IC50分别在0.33μmol/L-0.66μmol/L之间，NIH:OVCAR-3细胞在48小时达到抑制率的最高点为1.28μmol/L，见图7、图8，其IC50分别在0.16μmol/L-0.32μmol/L之间，RL95-2细胞在36小时达到抑制率的最高点为1.28μmol/L，见图9、图10，其IC50分别在0.32μmol/L-0.64μmol/L之间。
实施例2 甘氨胆酸钠体外抗肿瘤实验
1.细胞株：4T1(小鼠乳腺癌细胞)(以上均购自中科院上海细胞库)
2.培养基：RPMI-1640(Gibco货号31800022)
3.方法
3.1 收集对数生长期细胞，用1640培养基调整细胞浓度为5×10 4个/ml，在96孔板内加入100μl的细胞悬液。
3.2 5％的CO 2，37℃培养24小时后，4T1小鼠乳腺癌细胞加入浓度梯度分别为(0.1nmol/L，0.25nmol/L，0.35nmol/L，0.7nmol/L，1.4nmol/L，2.8nmol/L，5.6nmol/L)的甘氨胆酸钠，设5个复孔，同时设置空白组和对照组。
3.3 分别在12h，24h，36h，48h，60h小时后加入CCK-8试剂，继续孵育3h，孵育完成后在酶标仪OD450nm处测量各孔吸光值。
3.4 利用公式：抑制率＝(对照孔OD-加药孔OD)/(对照孔OD-空白孔OD)×100％，求出各个浓度的甘氨胆酸钠对于肿瘤细胞的抑制率。
4.结果：4T1小鼠乳腺癌细胞在12小时达到的抑制最高点为甘氨胆酸钠浓度0.7nmol/L，见图11、图12，其IC50在0.01nmol/L-0.1nmol/L之间。
实施例3 动物模型测定甘氨胆酸抑瘤率
1.材料：雌性BABL/c小鼠10周龄30只，购自大连医科大学SPF实验动物中心。4T1肿瘤细胞购自中科院上海细胞库。
2.方法：
2.1 造模：收集对数生长期4T1小鼠乳腺癌细胞，用PBS调整细胞浓度为 2×10 6/ml。用无菌注射器在小鼠右侧腋下注射0.1ml细胞悬液。
2.2 给药：于造模后的第二天开始灌胃给药甘氨胆酸15mg/kg(2次/天)，每次0.2mL，对照组给等量蒸馏水，连续给药两周。末次给药当晚给小鼠禁食，于第15日采用脱颈法处死小鼠，无菌剥离小鼠腋下肿瘤组织，称重并按
Figure PCTCN2019078305-appb-000002
Figure PCTCN2019078305-appb-000003
3.结果：实验组小鼠肿瘤平均质量：0.247±0.08g，对照组小鼠平均肿瘤质量：0.431±0.167g，实验组小鼠肿瘤较对照组明显缩小，抑瘤率达到42.83％。
实施例4 Real-time PCR测定肿瘤细胞中甘氨胆酸特异性靶点RNA表达量
1.材料：4T1小鼠乳腺癌细胞购自中科院上海细胞库。
2.方法：提取甘氨胆酸干预后4T1细胞的RNA，逆转录后进行Real-time PCR测定甘氨胆酸特异性靶点RNA表达量变化。
3.结果：甘氨胆酸干预后，相关RNA量表达提高1.5倍，见图13、图14。从RNA水平证实了甘氨胆酸对于肿瘤细胞的干预结果，揭示了甘氨胆酸抑制肿瘤细胞的生长机制。
实施例5 Western blot实验测定甘氨胆酸干预后肿瘤细胞的甘氨胆酸特异性靶点蛋白的表达量变化
1.材料：4T1小鼠乳腺癌细胞购自中科院上海细胞库。
2.提取甘氨胆酸干预后4T1细胞的蛋白后，经过变性处理，按照Western blot流程测定相关蛋白的表达量变化。
结果：Western blot实验显示肿瘤细胞的甘氨胆酸特异性靶点蛋白表达增高，见图15、图16。从蛋白水平证实了甘氨胆酸对于肿瘤细胞的干预结果，揭示了甘氨胆酸抑制肿瘤细胞的生长机制。

Claims (8)

  1. 甘氨胆酸在制备抗肿瘤药物中的应用，其特征在于，所述抗肿瘤药物为人用抗肿瘤药物或动物用抗肿瘤药物，所述的肿瘤为乳腺癌、卵巢癌、子宫内膜癌中一种或一种以上。
  2. 根据权利要求1所述的应用，其特征在于，所述动物为灵长目动物和啮齿目动物。
  3. 根据权利要求1所述的应用，其特征在于，所述的抗肿瘤药物为肿瘤细胞生长抑制剂。
  4. 一种含甘氨胆酸或其衍生物在体内转化为甘氨胆酸的抗肿瘤药物，其特征在于，所述抗肿瘤药物包含有效治疗量的甘氨胆酸和余量的药学上可接受的载体。
  5. 根据权利要求4所述的含甘氨胆酸及其衍生物的抗肿瘤药物，其特征在于，所述小鼠乳腺癌细胞4T1有效治疗量为0.4～1.6nmol/L。
  6. 根据权利要求4所述的含甘氨胆酸及其衍生物的抗肿瘤药物，其特征在于，所述人乳腺癌细胞MCF-7有效治疗量为0.16～1.28μmol/L。
  7. 根据权利要求4所述的含甘氨胆酸及其衍生物的抗肿瘤药物，其特征在于，所述人乳腺癌细胞MDA-MB-468有效治疗量为0.08～1.32μmol/L。
  8. 根据权利要求4所述的含甘氨胆酸及其衍生物的抗肿瘤药物，其特征在于，所述药物是口服制剂、栓剂、注射剂或透皮剂。
PCT/CN2019/078305 2019-03-15 2019-03-15 甘氨胆酸在制备抗肿瘤药物中的应用 WO2020186392A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
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CN108938607A (zh) * 2017-05-18 2018-12-07 中国人民解放军军事医学科学院毒物药物研究所 一种维生素k组合物及其制备方法、制剂和用途
CN109575100A (zh) * 2018-10-25 2019-04-05 大连大学 甘氨胆酸在制备抗肿瘤药物中的应用
CN109771430A (zh) * 2019-03-15 2019-05-21 大连大学 甘氨胆酸在制备抗肿瘤药物中的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108938607A (zh) * 2017-05-18 2018-12-07 中国人民解放军军事医学科学院毒物药物研究所 一种维生素k组合物及其制备方法、制剂和用途
CN109575100A (zh) * 2018-10-25 2019-04-05 大连大学 甘氨胆酸在制备抗肿瘤药物中的应用
CN109771430A (zh) * 2019-03-15 2019-05-21 大连大学 甘氨胆酸在制备抗肿瘤药物中的应用

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