阅读说明：本技术 一种治疗肝癌的联合用药物 (Combined medicine for treating liver cancer ) 是由 毕锋 任美玲 唐秋琳 徐焕基 夏洪伟 于 2021-09-10 设计创作，主要内容包括：本发明提供了一种治疗肝癌的联合用药物,它含有用于同时或者分别给药的索拉非尼和阿伐麦布,以及药学上可接受的载体。本发明的索拉非尼和阿伐麦布联合用药物可以明显增强抗肝癌疗效,增加患者的用药依从性,为临床提供了一种新的选择。(The invention provides a combined medicament for treating liver cancer, which contains sorafenib and avasimibe for simultaneous or separate administration and a pharmaceutically acceptable carrier. The combined medicament of sorafenib and avasimibe can obviously enhance the anti-liver cancer curative effect, increase the medication compliance of patients and provide a new choice for clinic.)

1. A combined medicine for treating liver cancer is characterized in that: it contains sorafenib and avasimibe for simultaneous or separate administration, and a pharmaceutically acceptable carrier.

2. The combination as set forth in claim 1, wherein: the mass ratio of the sorafenib to the avasimibe is 5-15: 10-20.

3. The combination as set forth in claim 2, wherein: the mass ratio of the sorafenib to the avasimibe is 10: 15.

4. use of sorafenib and avasimibe in the preparation of a combined medicament for treating liver cancer.

5. Use according to claim 4, characterized in that: the mass ratio of the sorafenib to the avasimibe is 5-15: 10-20.

6. Use according to claim 5, characterized in that: the mass ratio of the sorafenib to the avasimibe is 10: 15.

7. use according to claim 4, characterized in that: the liver cancer is primary liver cancer or secondary liver cancer.

8. Use according to claim 7, characterized in that: the liver cancer is primary liver cancer.

9. Use according to claim 5, characterized in that: the medicine is a medicine for inhibiting the proliferation of liver cancer cells.

Technical Field

The invention relates to the field of anti-cancer drugs, in particular to a combined drug for treating liver cancer.

Background

Liver cancer is a common malignant tumor in the digestive system, and is generally classified into primary liver cancer and secondary liver cancer. Primary liver cancer is classified into diffuse, lump, nodular and small cancer types, and clinical diseases often include liver pain, abdominal distension, asthenia, liver palms, spider nevus, jaundice and ascites. The secondary liver cancer is also called metastatic liver cancer, and malignant tumors generated in various parts of the whole body of a human body are accumulated to the liver to form the secondary liver cancer.

Sorafenib (chemical name: 4- (4-3- [ 4-chloro-3- (trifluoromethyl) phenyl ] ureidophenoxy) -N2-methylpyridine-2-carboxamide-4-tosylate), an oral multi-target kinase inhibitor, is a first-line treatment drug for advanced liver cancer, but sorafenib is only effective on 30% of patients with advanced liver cancer and only prolongs the median survival time for 3 months. Most patients are sensitive to sorafenib early, but after a period of treatment with sorafenib, the liver cancer recurs again and even progresses, the main reason for this being the development of sorafenib resistance. Although the curative effect of the sorafenib is limited by the drug resistance, the safety tolerance and the controllability of side effects of the sorafenib drug cause the sorafenib drug to be a first-line targeted drug for treating the liver cancer. In order to overcome the drug resistance of sorafenib, a combined drug scheme is urgently needed to be researched to enhance the curative effect of sorafenib.

Avasimibe (chemical name: N- (2, 6-diisopropylphenoxy) sulfonyl-2- (2,4, 6-triisopropylphenyl) acetamide) is an inhibitor of SOAT, and inhibits liver cancer by inhibiting synthesis of structural lipid and reducing fluidity of cell membrane, but unfortunately, avasimibe has very limited benefit on liver cancer patients.

At present, the combination of sorafenib and avasimibe for treating liver cancer does not exist.

Disclosure of Invention

In order to solve the problems, the invention provides a combined medicament for treating liver cancer, which comprises sorafenib and avasimibe for simultaneous or separate administration and a pharmaceutically acceptable carrier.

Further, the mass ratio of the sorafenib to the avasimibe is 5-15: 10-20.

Further, the mass ratio of sorafenib to avasimibe is 10: 15.

The invention also provides application of sorafenib and avasimibe in preparing a combined medicament for treating liver cancer.

Further, the mass ratio of the sorafenib to the avasimibe is 5-15: 10-20.

Further, the mass ratio of sorafenib to avasimibe is 10: 15.

Further, the liver cancer is primary liver cancer or secondary liver cancer.

Further, the liver cancer is a primary liver cancer.

Further, the drug is a drug that inhibits proliferation of liver cancer cells.

When the medicine is used for treating liver cancer, the combined medicine of sorafenib and avasimibe can obviously enhance the anti-liver cancer effect and increase the medication compliance of patients, thereby providing a new choice for clinic.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is a statistical table of the change in the number of liver cancer cells (Control for Control group; Sora for sorafenib; Ava for avasimibe; FA for inhibition; CI for synergy index, where CI <1 for synergy, CI ═ 1 for simple additive effect, and CI >1 for antagonism; for significant difference p < 0.05; for very significant difference p < 0.01; for very significant difference p < 0.0001).

FIG. 2 is a graph showing the result of crystal violet staining (Control for Control; Sora for sorafenib; Ava for avasimibe)

FIG. 3 is a graph showing the effect of tumor inhibition (Control for Control group; Sora for sorafenib; Ava for avasimibe)

FIG. 4 tumor weight statistics (Control for Control; Sora for sorafenib; Ava for avasimibe; for very significant differences p < 0.01; for very significant differences p <0.001)

FIG. 5 tumor volume statistics (Control for Control; Sora for sorafenib; Ava for avasimibe; significant differences p < 0.05; very significant differences p <0.001)

Detailed Description

Experimental example 1 Sorafenib in combination with avasimibe inhibits hepatoma cells in vitro.

1. Experimental methods

1.1 cells for experiments

Liver cancer cell line: HepG2 liver cancer cell, HUH7 liver cancer cell

1.2 Experimental treatment: the hepatoma cell lines were treated with Control (Control), sorafenib (10 μ M), avasimibe (20 μ M), sorafenib (10 μ M) + avasimibe (20 μ M), respectively.

1.3, detection:

(1) CCK8 detection of cell number changes

After 3 days of experimental treatment, CCK8 is adopted to detect the proliferation condition of the liver cancer cells, and the result uses compusyn to calculate the synergy index.

(2) Observation of cell clone formation

After 7 days of experimental treatment, the number of clones was observed using crystal violet staining.

2. Results of the experiment

The results of the CCK8 testing the cell number change after different drug treatments are shown in FIG. 1, and can be seen from FIG. 1: the relative cell proliferation ratio of the sorafenib and avasimibe group is significantly lower than that of other groups. From fig. 1 it can be seen that: sorafenib and avasimibe in a molar ratio of 1: 2, the synergy indexes aiming at HepG2 liver cancer cells and HUH7 liver cancer cells are both less than 1, so that the sorafenib and the avasimibe can synergistically inhibit the proliferation of the liver cancer cells.

The crystal violet staining result is shown in figure 2, and it can be seen from figure 2 that the relative cell clone number of the sorafenib and avasimibe group is obviously less than that of other groups, so that the sorafenib and avasimibe group can be judged to be capable of effectively inhibiting the proliferation of liver cancer cells, and the anticancer effect of the sorafenib and avasimibe group is obviously better than that of sorafenib or avasimibe used alone.

3. Conclusion

Compared with the independent use of sorafenib or avasimibe, the combined use of sorafenib and avasimibe has better capability of inhibiting the proliferation of liver cancer cells in-vitro experiments, and the sorafenib and the avasimibe have synergistic effect.

Experimental example 2 Sorafenib and avasimibe in vivo inhibition of hepatoma cell proliferation

1. Experimental methods

1.1 constructing an animal model: mice were injected subcutaneously with HepG2 liver cancer cells (5.0X 10)⁶Individual cells).

1.2 drug configuration: sorafenib and avasimibe were dissolved with 20% PEG300, 5% Tween80, 5% DMSO and saline.

1.3 Experimental treatment: one week after injection, tumors were approximately 180mm in size³The mice are randomly divided into a control group, a sorafenib group, an avasimibe group and a sorafenib combined avasimian group, and each group comprises 8 mice. Control group (20% PEG300, 5% Tween80, 5% DMSO and normal saline, intraperitoneal injection, once a day), sorafenib group (10mg/kg, intraperitoneal injection, once a day); avasimibe group (15mg/kg, intraperitoneal injection, once a day); sorafenib (10mg/kg i.p., once daily) + avasimibe (15mg/kg i.p., once daily). Tumor diameter was measured every three days for 14 days. When the maximum diameter of the tumor reaches 1.5-2.0cm, the nude mice are killed by removing the neck, the tumor is stripped, the weight is measured, the tumor size is measured, and the volume is calculated: v ═ W (L ═ W)²) And/2, wherein L and W represent length and width.

2. Results

The tumor inhibition effect of each experimental group is shown in FIG. 3, the tumor weight statistics of each group are shown in Table 1 and FIG. 4, and the tumor volume statistics of each group are shown in Table 2 and FIG. 5.

TABLE 1 tumor weight changes

TABLE 2 tumor volume changes

As can be seen from tables 1-2 and FIGS. 3-5: in a nude mouse tumorigenesis experiment, compared with the sorafenib group or the avasimibe group which is used alone, the combination of the sorafenib and the avasimibe group can remarkably reduce the weight of the liver tumor and remarkably reduce the volume of the liver tumor.

3. Conclusion

In vivo experiments, sorafenib and avasimibe were mixed in a mass ratio of 10:15 compared with the single drug sorafenib or the single drug avasimibe, the combination can effectively inhibit the growth of liver cancer cells, reduce the weight and volume of tumors and has the synergistic effect.

In conclusion, the invention adopts the following steps that the molar ratio is 1: 2 (mass ratio 10: 22) is combined with avasimibe to be used for in vitro inhibition experiments of liver cancer cells, and the combination has obvious coordination and synergism effects, and because the in vivo experiments have more influence factors including drug absorption, drug metabolism, drug half-life period and the like, the in vivo and in vitro drug ratio can be different, and the invention adopts the following components in mass ratio of 10: the sorafenib and the avasimibe used for animal in-vivo inhibition experiments of liver tumors also show that the combination of the sorafenib and the avasimibe can remarkably inhibit the proliferation of liver cancer cells, and has good clinical application prospect.