CN108324707B - Application of fenofibrate single drug and combined chemotherapeutic drug in preparation of antitumor drugs - Google Patents
Application of fenofibrate single drug and combined chemotherapeutic drug in preparation of antitumor drugs Download PDFInfo
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- CN108324707B CN108324707B CN201810350759.0A CN201810350759A CN108324707B CN 108324707 B CN108324707 B CN 108324707B CN 201810350759 A CN201810350759 A CN 201810350759A CN 108324707 B CN108324707 B CN 108324707B
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Abstract
The invention provides application of fenofibrate in preparation of an anti-tumor drug, and particularly relates to application of fenofibrate in preparation of a chemotherapeutic drug sensitizing drug. The fenofibrate is used singly to obviously inhibit the growth of the tumor, the tumor volume is reduced, the tumor weight is reduced, and the fenofibrate does not have obvious hepatorenal toxicity and systemic toxic or side effect; the fenofibrate and the chemotherapeutic drug have obvious synergistic effect in combination, and can increase the sensitivity of the tumor to the chemotherapeutic drug; the combination of fenofibrate and the chemotherapeutic drug does not increase the toxicity of chemotherapy, and the toxic and side effects of chemotherapy can be reduced by reducing the dosage of the chemotherapeutic drug under the condition of achieving the same tumor inhibition effect.
Description
Technical Field
The invention relates to the technical field of antitumor drugs, and particularly discloses application of fenofibrate single drug and combined chemotherapeutic drug in preparation of antitumor drugs.
Background
Gastric cancer is one of common tumors, and the number of the disease people and the number of the death people are the second in China. The tumor therapy applied in clinic is mainly through surgery, physical therapy, chemotherapy and biological therapy. Chemotherapy is one of the main means for treating gastric cancer, and especially plays a major role in the systemic treatment of advanced gastric cancer. The chemotherapy drug resistance phenomenon is an important reason for the failure of the treatment of the advanced gastric cancer, so that the discovery of a new drug treatment method, the improvement of the sensitivity of the chemotherapy drugs and the reversal or reduction of the occurrence of the chemotherapy drug resistance have important significance for the treatment of the gastric cancer. The search for safe, low-toxicity and small-side-effect drugs and chemotherapy sensitization are important means for treating tumors and solving chemotherapy drug resistance.
In recent years, the abnormal energy metabolism of tumor cells is one of ten characteristics of new tumors, and the metabolic abnormality of the tumors has become a hotspot of oncology research. From the earliest discovery of the existence of aerobic glycolysis in tumor cells to the discovery of analysis and complex metabolic regulation networks of various aspects (sugar, fat, amino acid and the like) of tumor metabolic activities, abnormal metabolic pathways in the tumor cells and complex metabolic regulation networks formed among regulatory factors, metabolic enzymes and metabolic products abnormally expressed in the tumor cells, the research and analysis of metabolic reprogramming of the tumor cells are of great significance for discovering potential targets of anti-tumor and developing anti-cancer drugs. Except for the single-drug anti-tumor effect of the metabolism regulating drug, the combined use of the metabolism regulating drug and the chemotherapeutic drug can also effectively inhibit the tumor chemotherapy drug resistance condition aiming at the common chemotherapeutic drug resistance condition.
Fenofibrate (fenofibrate), an alias of which is benzoyl lipid-lowering propyl ester; a source of pullulan; standing and flattening fat; isopropyl 2-methyl-2- (4- (4-chlorobenzoyl) phenoxy) propionate, CAS number 49562-28-9, as a white or off-white crystalline powder, odorless, tasteless, melting point 80-81 ℃. Highly soluble in chloroform, readily soluble in acetone or diethyl ether, sparingly soluble in ethanol, practically insoluble in water, molecular formula C20H21ClO4, molecular weight: 360.83100. fenofibrate has been used since 1975, is mainly used for reducing cholesterol and triglyceride levels, is one of the most commonly used fibrate drugs, has good effect and tolerance, has low toxicity after long-term application, does not have accumulation effect, is not combined with DNA, and does not have gene mutation-causing effect. Besides the lipid regulating effect, fenofibrate has the effects of anti-inflammation, anti-angiogenesis and the like. Based on a large number of experimental studies, the inventor finds that fenofibrate has a certain inhibition effect on tumors.
Disclosure of Invention
The invention aims to solve the technical problems of the prior art that the single fenofibrate or the fenofibrate and the chemotherapeutic drug are combined for use in preparing the antitumor drug in order to overcome the defects of antitumor drug treatment and chemotherapy drug resistance.
The technical scheme of the invention can be realized by the following technical measures:
the invention provides application of fenofibrate in preparation of anti-tumor drugs.
The invention also provides the application of fenofibrate in the preparation of chemotherapeutic drug sensitizing drugs.
Preferably, the chemotherapeutic agent is cisplatin or docetaxel.
When the fenofibrate is used for any one of the applications, the dosage range of the fenofibrate is 1-200 mg/kg of the drug-receiving object per 1-4 days according to the weight of the drug-receiving object, the preferred dosage range is 5-150 mg/kg of the drug-receiving object per day, and the more preferred dosage range is 100mg/kg of the drug-receiving object per day.
The invention also provides a pharmaceutical composition for treating tumors, which comprises a chemotherapeutic drug and fenofibrate used in combination with the chemotherapeutic drug.
The fenofibrate has a structure shown in a formula (I):
the fenofibrate is tablet, granule or powder, the conventional dosage form of the chemotherapeutic drug is powder, injection and the like, and the fenofibrate and the chemotherapeutic drug are prepared from pharmaceutically acceptable carriers. The fenofibrate can be orally administered, and the cisplatin and docetaxel chemotherapeutic drugs can be intraperitoneally injected or intravenously injected. The fenofibrate and the chemotherapeutic drug are simultaneously, respectively or sequentially administered, and the combination of the two drugs has obvious synergistic effect on tumors.
When fenofibrate is used alone, tumors affected include: breast cancer, ovarian cancer, pancreatic cancer, lung cancer, liver cancer, melanoma, retinoblastoma, esophageal cancer, colorectal cancer, colon cancer, leukemia, lymphoma, brain tumor, cervical cancer, sarcoma, prostate cancer, bladder cancer, reticuloendothelioma, Wilm's tumor, astrocytoma, glioblastoma, neuroblastoma, osteosarcoma, renal cancer, or head and neck cancer.
Tumors in which fenofibrate acts in combination with cisplatin include: ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophageal cancer, malignant lymphoma, head and neck squamous cell carcinoma, thyroid cancer, and osteogenic sarcoma.
Tumors in which fenofibrate in combination with docetaxel may act include: breast cancer, ovarian cancer, non-small cell lung cancer, head and neck tumor, small cell lung cancer, gastric cancer, pancreatic cancer, and melanoma.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention discovers that fenofibrate is used alone to have obvious inhibition effect on tumor growth, the tumor volume is reduced, and the fenofibrate has no obvious hepatotoxicity and systemic toxic and side effects;
(2) the fenofibrate and the chemotherapeutic drug have obvious synergistic effect in combination, and can increase the sensitivity of the tumor to the chemotherapeutic drug;
(3) the combination of fenofibrate and chemotherapeutic drugs does not increase the toxicity of chemotherapy, and the use of the chemotherapeutic drugs in combination with fenofibrate can reduce the dosage of the chemotherapeutic drugs to relieve the toxic and side effects of chemotherapy under the condition of achieving the same tumor inhibition effect.
Drawings
The invention is further illustrated by means of the attached drawings, the examples of which are not to be construed as limiting the invention in any way.
FIG. 1 shows the tumor body of tumor inhibition experiment; wherein A is the tumor body weight of mice in six experimental groups; b is the weight of the tumor body reduced by combining the chemotherapeutic drug combination of fenofibrate and the tumor body reduced weight of the chemotherapeutic drug and fenofibrate single drug combination which are simply added compared with the control group; and (2) Fen: fenofibrate, Doc: docetaxel, DDP: cisplatin; (p is p <0.05 compared with a control group, # is p <0.05 compared with a docetaxel combination fenofibrate group and a docetaxel monotherapy group, & is p <0.05 compared with a cisplatin combination fenofibrate group and a cisplatin monotherapy group, p is the probability of appearance of a sample observation result or more extreme result obtained when an original hypothesis is true, if the p value is small, the probability of occurrence of the original hypothesis is small, and according to a small probability principle, the original hypothesis is rejected by the aid of the p value, the smaller the p value is, the more sufficient the reason for rejecting the original hypothesis is, and the limit is usually 0.05;
FIG. 2 is a graph of tumor growth curves for six experimental groups of mice in a tumor suppression experiment, in which: a is a comparison curve of the fenofibrate single medicine group and a control group; b is a comparison curve of a docetaxel monotherapy group, a docetaxel combined fenofibrate group and a control group; c is a comparison curve of the cisplatin monocase group, the cisplatin combined fenofibrate group and the control group;
FIG. 3 shows the body weight change of mice during administration in different experimental groups (ns means p > 0.05);
FIG. 4 shows the effect of the combination of fenofibrate and chemotherapeutic drugs on the liver and kidney function of mice; in the figure, A represents AST (aspartate aminotransferase) content; b represents ALT (glutamic-pyruvic transaminase) content, C represents Cr (creatinine) content;
FIG. 5 shows the effect of fenofibrate as a single drug and in combination with chemotherapeutic drugs on the liver tissue structure of mice, which is stained by Hematoxylin Eosin (HE) staining method for mouse liver tissue sections at 200X;
fig. 6 shows the effect of fenofibrate as a single drug and in combination with chemotherapeutic drugs on the mouse kidney tissue structure, and the staining of mouse kidney tissue sections by Hematoxylin Eosin (HE) staining method is 200X.
Detailed Description
In order that the invention may be more readily understood, specific embodiments thereof will be described further below.
(1) Experimental animals and breeding
Male 6-8 week old BALB/C inbred mice (body weight 16-20g) were purchased from the center of the Beijing Huafukang laboratory animals. In the experimental process, the mice were raised in the ABSL-3 animal experiment center of Wuhan university medical department.
(2) Construction of mouse gastric cancer transplantation tumor model
1) Taking MGC803 cells growing in logarithmic phase, digesting the cells with 0.25% pancreatin, adding 10% FBS complete culture medium to stop digestion, then preparing cell suspension with PBS solution, adjusting cell concentration to 3 × 107one/mL.
2) Taking 18 healthy BALB/C nude mice, male, 6-8 weeks old, body weight about 20g, mixing 3X 106MGC803 gastric cancer cells (0.1mL) are inoculated to the thigh outer part of each mouse by subcutaneous injection, tumor cells are inoculated in the experiment to serve as subcutaneous nodules of all mice on 1 day and 3-5 days, and tumors grow to 100mm in about 1 week3The site model was successful and tumor suppression experiments started from day 7.
(3) Mice were randomly grouped and tumor suppression experiments were performed
18 mice were randomly divided into six groups of 3 mice each, and the following tumor suppression experiments were performed, respectively:
1) control group: gavage with 0.1 ml/day of 5% sodium carboxymethylcellulose solution; normal saline 0.1mL/4 day intraperitoneal injection
2) Fenofibrate single drug group: fenofibrate 100 mg/kg/day (0.1ml of 5% sodium carboxymethyl cellulose solution is added to prepare a suspension) and the stomach is filled;
3) docetaxel monotherapy: docetaxel 2mg/kg/4 days is added with 0.1ml physiological saline for intraperitoneal injection;
4) docetaxel in combination with fenofibrate: docetaxel 2mg/kg/4 days is added with 0.1ml normal saline for intraperitoneal injection, fenofibrate 100 mg/kg/day (0.1ml 5% sodium carboxymethyl cellulose solution is added to prepare suspension) is used for gastric lavage;
5) cisplatin monotherapy group: cisplatin 4mg/kg/4 days, adding 0.1ml physiological saline for intraperitoneal injection;
6) cisplatin combined fenofibrate group: cisplatin 4mg/kg/4 days, adding 0.1ml physiological saline for intraperitoneal injection, and fenofibrate 100 mg/kg/day (adding 0.1ml 5% sodium carboxymethylcellulose solution to make into suspension) for intragastric administration.
At the beginning of the tumor inhibition experiment, all animals were fed and drunk freely except for experimental intervention factors, and animal activities, hair, body weight, other general conditions and tumor body size were observed and recorded daily.
(4) End point detection index of experiment
1) After 30 days of observation, the experimental mice are killed by using excess pentobarbital (100mg/kg) for anesthesia, tumor bodies are completely stripped, and the tumor weight is measured;
2) a blood sample of the mouse is reserved for detecting the liver and kidney function indexes;
3) mouse liver and kidney tissues are reserved and fixed by 4% paraformaldehyde solution, and after tissue sections are prepared, HE staining is carried out to observe the change of tissue structure.
(5) Results of the experiment
With the progress of tumor inhibition experiments, the activity state of the mice is basically unchanged, the tumors are mostly circular or elliptical and have uniform size, the tumors start to be irregular gradually after the later-stage drug intervention and have different sizes, wherein the tumor volume of a control group is increased most rapidly, and the tumor inhibition result is shown in fig. 1. As shown in FIG. 1A, the tumor weight of fenofibrate group alone (0.8145 + -0.03833 g) was smaller than that of control group (1.015 + -0.05668 g) (difference was statistical, p <0.05), and the tumor weight of chemotherapeutic drug combined with fenofibrate was smaller than that of chemotherapeutic drug alone (Doc group 0.7308 + -0.02996 g vs Doc + Fen group 0.3045 + -0.03860 g; DDP group 0.5132 + -0.03696 g vs DDP + Fen group 0.1322 + -0.01678 g) (difference was statistical, p < 0.05). As shown in FIG. 1B, compared with the control group, the tumor body weight reduction of the chemotherapeutic drug combined with fenofibrate is greater than the simple addition of the tumor body weight reduction of the chemotherapeutic drug and fenofibrate single drug (0.7110 + -0.03860 g of Doc + Fen combined with 0.4856 + -0.06215 g of vs Doc + Fen added, and 0.7032 + -0.05104 g of DDP + Fen combined with 0.8832 + -0.01678 g of vs DDP + Fen added) (the difference is statistical, and p is less than 0.05), so that the remarkable synergistic treatment effect is presented.
As shown in fig. 2, the growth rate of the transplanted tumor is lower in the fenofibrate group alone than in the control group (the difference is statistically significant, p is less than 0.05), the growth rate of the transplanted tumor is lower in the chemotherapeutic drug combination than in the chemotherapeutic drug group alone (the difference is statistically significant, p is less than 0.05), and the growth rate of the transplanted tumor can be significantly inhibited by adding fenofibrate.
As can be seen from FIG. 3, there was no significant difference in mouse body weight between the experimental groups (p >0.05), and the influence of the individual differences of the mice between the groups on the experimental results was reduced.
As can be seen from fig. 4, fenofibrate single drug has no significant negative effect on liver and kidney functions of mice, AST, ALT and CREA are increased compared with a control group (difference has statistical significance, p is less than 0.05), which indicates that the liver and kidney toxicity can be caused by using the chemotherapeutic drug alone, while the toxic and side effects of the chemotherapeutic drug are not increased by combining the fenofibrate chemotherapeutic drug (p is more than 0.05), and the phenomenon of toxic and side effects reduction is observed at part of data points. By observing the HE staining result of liver and kidney tissues, compared with a control group, the fenofibrate single drug has no obvious influence on the liver and kidney tissue structure of the mouse (figures 5 and 6), the liver and kidney tissues of the mouse with the single drug group of docetaxel and cisplatin have liver and kidney injury change compared with the control group, and the combined use of the docetaxel and the cisplatin and the fenofibrate respectively does not increase the injury of the liver and kidney tissues compared with the use of the docetaxel or the cisplatin alone (figures 5 and 6).
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (2)
1. The application of fenofibrate and chemotherapeutic drugs in preparing drugs for resisting gastric cancer tumors is characterized in that the fenofibrate is used for preparing chemotherapeutic sensitizers, the chemotherapeutic drugs are docetaxel, and the dosage of fenofibrate and docetaxel is as follows: docetaxel 2mg/kg/4 days, fenofibrate 100 mg/kg/day.
2. A pharmaceutical combination for the treatment of gastric carcinoma tumors comprising the chemotherapeutic drug docetaxel and fenofibrate for use in combination with said chemotherapeutic drug docetaxel, said fenofibrate and docetaxel being used in doses: docetaxel 2mg/kg/4 days, fenofibrate 100 mg/kg/day.
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