CN113616649B - Combined medicine for treating liver cancer - Google Patents
Combined medicine for treating liver cancer Download PDFInfo
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- CN113616649B CN113616649B CN202111063025.2A CN202111063025A CN113616649B CN 113616649 B CN113616649 B CN 113616649B CN 202111063025 A CN202111063025 A CN 202111063025A CN 113616649 B CN113616649 B CN 113616649B
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- sorafenib
- liver cancer
- avasimibe
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
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.
Description
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 all parts of the 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 drug is limited, the safety tolerance and the controllability of side effects of the sorafenib drug still enable 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.
Further, the mass ratio of sorafenib and avasimibe is 10.
The invention also provides application of the sorafenib and the avasimibe in preparing a combined medicament for treating liver cancer.
Further, the mass ratio of the sorafenib to the avasimibe is 5-15.
Further, the mass ratio of sorafenib and avasimibe is 10.
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.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
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 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 indicates synergy, CI =1 indicates only additive effect alone, and CI >1 indicates antagonism; indicates a significant difference p <0.05; indicates a very significant difference p <0.01; and indicates a 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 statistical plots (Control for Control; sora for sorafenib; ava for avasimibu;. Indicates a significant difference p < 0.05;. Indicates a very significant difference 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 assay for the change in cell number after treatment with different drugs are shown in FIG. 1, and it can be seen from FIG. 1 that: 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 index aiming at HepG2 liver cancer cells and HUH7 liver cancer cells is 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 the sorafenib or the avasimibe, the combined use of the sorafenib and the avasimibe has better capability of inhibiting the proliferation of the liver cancer cells in an in-vitro experiment, and the sorafenib or the avasimibe has a synergistic effect.
Experimental example 2 Sorafenib and avasimibe in vivo inhibition of hepatoma cell proliferation
1. Experimental method
1.1 constructing an animal model: mice were injected with HepG2 hepatoma cells (5.0X 10) 6 One cell).
1.2 drug configuration: sorafenib and avamprobbe were dissolved in 20% PEG300, 5% Tbeen80, 5% DMSO and physiological saline.
1.3 Experimental treatment: one week after injection, tumors were approximately 180mm in size 3 The 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-Tween 80, 5-DMSO and physiological saline, i.p., once daily), sorafenib group (10 mg/kg, i.p., once daily); avasimibe group (15 mg/kg, intraperitoneal injection, once a day); sorafenib (10 mg/kg i.p., once daily) + avasimibe (15 mg/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 = (L x W) 2 ) And/2, wherein L and W represent length and width.
2. As a result, the
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: 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.
Claims (8)
1. A combined medicine for treating liver cancer is characterized in that: the drug combination is characterized by comprising sorafenib and avasimibe for simultaneous administration and a pharmaceutically acceptable carrier; the mass ratio of the sorafenib to the avasimibe is 5-15.
2. The combination as set forth in claim 1, wherein: the mass ratio of the sorafenib to the avasimibe is 10:15.
3. use of sorafenib and avasimibe in the preparation of a combined medicament for treating liver cancer.
4. Use according to claim 3, characterized in that: the mass ratio of the sorafenib to the avasimibe is 5-15.
5. Use according to claim 4, characterized in that: the mass ratio of the sorafenib to the avasimibe is 10:15.
6. use according to claim 3, characterized in that: the liver cancer is primary liver cancer or secondary liver cancer.
7. Use according to claim 6, characterized in that: the liver cancer is primary liver cancer.
8. Use according to claim 3, characterized in that: the medicine is a medicine for inhibiting the proliferation of liver cancer cells.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125324A (en) * | 2017-06-15 | 2019-01-04 | 北京蛋白质组研究中心 | Acyl-CoA: the new application of Cholesteryl acyltransferase 1 inhibitor |
| CN112494471A (en) * | 2020-12-14 | 2021-03-16 | 江南大学 | Application of cholesterol ester synthetase ACAT1 inhibitor in preparing medicine for preventing/treating non-alcoholic fatty liver disease |
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| BR112013011874A2 (en) * | 2010-11-11 | 2019-09-24 | Akron Molecules Gmbh | compounds and methods for treating pain |
| US20140357676A1 (en) * | 2013-05-28 | 2014-12-04 | National Defense Medical Center | Pharmaceutical compositions and methods for treating cancer and biomarkers for drug screening |
| CN107320472A (en) * | 2017-08-09 | 2017-11-07 | 上海市第五人民医院 | A kind of pharmaceutical composition and its application for being used to treat liver cancer |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109125324A (en) * | 2017-06-15 | 2019-01-04 | 北京蛋白质组研究中心 | Acyl-CoA: the new application of Cholesteryl acyltransferase 1 inhibitor |
| CN112494471A (en) * | 2020-12-14 | 2021-03-16 | 江南大学 | Application of cholesterol ester synthetase ACAT1 inhibitor in preparing medicine for preventing/treating non-alcoholic fatty liver disease |
Non-Patent Citations (1)
| Title |
|---|
| Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis;Li Gu1等;《Oncogene》;20200123;1-13 * |
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