CN112674028B - Method for establishing cancer model of animal induced by cancer inducer - Google Patents
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Abstract
The application belongs to the technical field of biological medicines, and particularly discloses a method for inducing the establishment of an animal cancer model, which comprises the following steps: s1: cancer induction stage: selecting an animal, and administering the animal cancer-inducing agent to induce the formation of cancer in the animal; s2: and (3) promoting cancer stage: administering the animal cancer promotion drug of step S1 to promote the development of cancer in the animal. The application has at least one of the following beneficial effects: on the basis of inducing the formation of animal cancers by the cancer inducer, the application of the cancer-promoting drug further improves the formation of the animal cancers, shortens the time for constructing animal cancer models, improves the cancer-inducing efficiency, increases the stability of animal models, and provides good animal models for the research of the occurrence and development of the cancers and the prevention, early diagnosis and treatment of the cancers.
Description
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to a method for establishing an animal model for promoting methylbenzyl nitrosamine to induce rat esophageal cancer.
Background
Cancer, i.e., malignant tumor, is a general term for more than 100 related diseases. When a cell in the body mutates, it constantly divides and is not controlled by the body, and finally forms cancer. Cancer has become a predator endangering human health and life, especially esophageal cancer. Esophageal cancer is a common malignant tumor that occurs in the esophagus and is derived from esophageal epithelial cells, and about 30 million people die of esophageal cancer each year worldwide. Its morbidity and mortality vary widely from country to country. China is one of the world areas with high incidence of esophageal cancer, and the average death rate of the people is about 15 ten thousand every year. More men than women, the onset age is usually over 40 years. Esophageal cancer typically has progressive dysphagia, which is characterized by difficulty swallowing dry food, followed by semifluid food, and finally, water and saliva.
In recent years, research on diagnosis and treatment and pathogenesis of esophageal cancer has been advanced to a certain extent, but at present, the treatment of esophageal cancer patients at early stage is mainly performed by combining operations with chemoradiotherapy, and the treatment of esophageal cancer patients who cannot be operated at late stage is mainly performed by conventional chemotherapeutics such as platinum, and specific targeted treatment and accurate medical treatment methods are lacked. Therefore, the method further researches the occurrence and development process and canceration mechanism of the esophageal cancer, masters the characteristics of the esophageal cancer at the initial stage, the promotion stage, the evolution stage, the development stage, the heterogeneity stage, the metastasis stage and the like, searches for specific early diagnosis and accurate medical targets, can provide better diagnosis and treatment for esophageal cancer patients, improves the survival rate of the esophageal cancer patients and improves the prognosis.
The tumor animal model can provide good experimental materials for basic and clinical tumor research, and has important significance for the research of the occurrence and development mechanism of tumors. At present, the most common method is to use methylbenzyl nitrosamine (NMBzA) carcinogen to induce rat esophageal cancer to establish a model, but the cancer induction success rate is only 10%, the success rate is still low, the experimental period is long (>35 weeks), and the method is not beneficial to further expanding the research of the model on the esophageal cancer occurrence and development molecular mechanism and the esophageal cancer treatment drug research and development. Therefore, it is important to find a method for improving cancer induction efficiency and shortening cancer induction period in an animal model of rat esophageal cancer.
Disclosure of Invention
Based on the method, the animal cancer model established by the method has the advantages of short period, high success rate and strong stability.
The application is realized by the following scheme:
in one aspect, the present application provides a method for modeling cancer in an animal induced by a carcinogen, comprising the steps of: s1: cancer induction stage: selecting animals, and administering the animal carcinogen to induce the formation of cancer in the animals; s2: and (3) promoting cancer stage: administering the animal cancer promotion drug of step S1 to promote the development of cancer in the animal.
On the basis of taking a cancer inducing agent as an initiator (Initiating agent) to administer the drug for inducing the cancer in the first stage, the application increases the use of cancer Promoting drugs (Promoting agents), shortens the cancer inducing period, improves the cancer inducing efficiency, and establishes a rat esophageal cancer animal model with short period, high success rate and strong stability.
In a specific embodiment of the invention, the cancer-promoting drug is one or more of BRAF inhibitors.
In a specific embodiment of the invention, the BRAF inhibitor is Vemurafenib (Vemurafenib), sorafenib (Sabrafenib) or Encorafenib (LGX 818). Preferably, the BRAF inhibitor is sorafenib, vemurafenib or the like.
Although BRAF inhibitors have a targeted inhibitory effect on BRAF-mutated tumor cells, in BRAF wild-type cells, they rather exert a BRAF-activating effect by inhibiting autophosphorylation of BRAF. Based on the characteristic of the BRAF inhibitor, the cancer inducing agent is applied as an initiator to administer the cancer inducing agent, the use of the cancer promoting agent BRAF inhibitor is increased, the cancer inducing period is shortened, the cancer inducing efficiency is improved, and a good animal model is provided for researching the occurrence and development of the esophageal cancer.
In one embodiment of the invention, the sorafenib is administered by gavage or intraperitoneal injection.
In one embodiment of the invention, the sorafenib is administered in a dose ranging from 10 to 50 mg/kg. For example, the dose is 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 40mg/kg, or 50mg/kg, etc. Preferably, the administration dose of the sorafenib is 20mg/kg or 50 mg/kg.
In one embodiment of the invention, the cancer-inducing agent includes, but is not limited to, methylbenzylnitrosamine, 4-nitroquinoline-1-oxide (4-nitroquinoline-1-oxide, 4 NQO).
In one embodiment of the invention, the cancer inducing agent is methylbenzyl nitrosamine.
In one embodiment of the invention, the cancer-inducing agent is 4-nitroquinoline-1-oxide (4-nitroquinoline-1-oxide, 4 NQO).
In one embodiment of the invention, the treatment time of the methylbenzylnitrosamine is 1 to 6 weeks, for example 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks. Preferably, the treatment time of the methylbenzyl nitrosamine is 5 weeks.
In one embodiment of the invention, the methylbenzylnitrosamine is administered in a dose of 0.2 to 0.5 mg/kg. For example, the dose is 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, or 0.5mg/kg, etc. Preferably, the dosage of the methylbenzyl nitrosamine is 0.3 mg/kg.
In one embodiment of the invention, the methylbenzylnitrosamine is administered by subcutaneous injection.
In one embodiment of the invention, the 4-nitroquinoline-1-oxide is administered in a dose of 50 to 100 μ g/ml; for example, the 4-nitroquinoline-1-oxide is administered in a dose of 60. mu.g/ml, 70. mu.g/ml, 75. mu.g/ml, 80. mu.g/ml, 85. mu.g/ml, 90. mu.g/ml, 100. mu.g/ml, or the like. Preferably, the 4-nitroquinoline-1-oxide is administered in a dose of 100. mu.g/ml.
In one embodiment of the invention, the 4-nitroquinoline-1-oxide is administered by orally administering a solution of 4-nitroquinoline-1-oxide in drinking water, the concentration of the 4-nitroquinoline-1-oxide solution being 100. mu.g/ml and the solvent being water.
In one embodiment of the present invention, the cancer treatment promoting method in step S2 is every other day for 8-20 weeks. For example for 8, 10, 12, 13, 15, 18 or 20 weeks, etc. Preferably, for 8-15 weeks.
In a particular embodiment of the invention, the animal is a rat and/or a mouse.
In a specific embodiment of the invention, the rat is a 7-week-old F344 male rat.
In a specific embodiment of the invention, the mouse is a 7-week-old C57BL/6 male mouse.
In a specific embodiment of the present invention, the cancer includes, but is not limited to, esophageal cancer, head and neck squamous cancer, breast cancer, cervical cancer, skin cancer, colon cancer, stomach cancer, lung cancer and liver cancer.
In a specific embodiment of the invention, the method for establishing the model of the sorafenib methyl benzyl nitrosamine-induced rat esophageal cancer specifically comprises the following steps:
s1: cancer induction stage: selecting a rat, injecting methylbenzyl nitrosamine subcutaneously at a dose of 0.3mg/kg, 3 times per week for 5 weeks, and inducing the formation of esophageal cancer of the rat;
s2: and (3) promoting cancer stage: beginning at week 6, the rat cancer promoting drug sorafenib of step S1 was administered every other day for 15 weeks to promote the formation of esophageal cancer in rats.
In a specific embodiment of the invention, the method for establishing the sorafenib 4-nitroquinoline-1-oxide-induced mouse esophageal cancer model specifically comprises the following steps:
s1: cancer induction stage: selecting a mouse, and treating the mouse with a 4-nitroquinoline-1-oxide aqueous solution with the concentration of 100 mu g/ml for 1-10 weeks to induce the formation of esophageal cancer of the mouse;
s2: and (3) promoting cancer stage: and (5) after cancer induction is finished, the mouse cancer promotion medicament Sorafenib in the step S1 is administered every other day for 15 weeks to promote the formation of mouse esophageal cancer.
Another aspect of the present application provides the use of a BRAF inhibitor in promoting an animal cancer model.
In a specific embodiment of the invention, the BRAF inhibitor is Vemurafenib (Vemurafenib), sorafenib (Sabrafenib) or Encorafenib (LGX 818). Preferably, the BRAF inhibitor is sorafenib.
The establishment method of the cancer model of the animal induced by the cancer inducer provided by the application has at least one of the following beneficial effects:
on the basis of inducing the formation of animal cancers by the cancer inducer, the application of the cancer-promoting drug further improves the formation of the animal cancers, shortens the time for constructing animal cancer models, improves the cancer-inducing efficiency, increases the stability of animal models, and provides good animal models for the research of the occurrence and development of the cancers and the prevention, early diagnosis and treatment of the cancers.
Drawings
FIG. 1 is a graph of esophageal cancer at week 15 and week 20 in the control, Th and So groups of rat esophageal cancer models.
FIG. 2 is the statistics of the number of esophageal papilloma at week 15 in the rat esophageal cancer models of the control group, the Th group and the So group.
FIG. 3 is the statistics of the number of esophageal papilloma at 20 weeks in the rat esophageal cancer models of the control group, the Th group and the So group.
Fig. 4 is a representative picture of esophagus at week 30 for the rat esophageal cancer models of the control group and So group.
Fig. 5 is a representative picture of esophagus at 25 weeks in the control group and So group mouse esophageal cancer models.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The animal esophageal cancer model is taken as an example for illustration in the application.
Example 1 rat esophageal carcinoma animal model establishment
1 materials
F344 rats, 7 weeks old, male, purchased from beijing vintonia limited.
NMBzA (purity 98% or more): dissolved in PBS containing 20% DMSO to a final concentration of 0.3 mg/ml.
Thalidomide (thalidomide): as a negative control, purchased from Nanjing Kanmaining chemical industry Co., Ltd., a suspension was prepared using a 1% carboxymethylcellulose solution to a final concentration of 4 mg/ml.
Sorafenib (Sorafenib): purchased from Shanghai ceramic Biochemical technology Ltd, was made into a suspension using a 1% carboxymethyl cellulose solution to a final concentration of 4 mg/ml.
2 method
(1) After purchasing, F344 male rats at 7 weeks of age were divided into 3 groups of 10 animals, namely a control group, a thalidomide-treated group (designated as a Th group) and a Sorafenib-treated group (designated as a So group). Rats were acclimated in an SPF-rated animal room for 1 week and fed with normal drinking water and maintenance feed.
(2) The experiment was started after 1 week of acclimation of the rats, and 3 groups of rats were injected subcutaneously with NMBzA (0.3mg/kg) 3 times a week for 5 weeks.
(3) Beginning at week 6, control rats received a 1% carboxymethylcellulose solution fed (5ml/kg) on alternate days for 25 weeks; th group rats received thalidoside administration (20mg/kg) on alternate days for 25 weeks; group So received sorafenib gavage (20mg/kg) for 25 weeks every other day.
(4) The whole experimental process was observed and recorded. The experimental results are shown in FIGS. 1-4 and Table 1.
As shown in fig. 1, from the beginning of the experiment, rats treated with the carcinogen NMBzA alone in the control group had smooth esophagus at week 15, with rough esophagus portion at week 20 but no apparent papilloma; the results of the Th experimental group are not obviously different from those of the control group, no obvious papilloma is still seen at the 20 Th week, and the cancer promotion effect is poor; the rats in the So experimental group can observe the roughness of the esophagus at the 15 th week and show obvious papilloma at the 20 th week, which indicates that the rats have obvious cancer promotion effect.
FIGS. 2 and 3 are statistics of the numbers of esophageal papillomas at 15 and 20 weeks of cancer induction in rats in the control group, Th group and So group, respectively. As can be seen from FIGS. 2 and 3, the Th group rats had no significant difference in esophageal lesion status between weeks 15 and 20 from the control group; while the So group had individual papilloma in rats at week 15, an average of about 6 papillomas per rat at week 20 was significantly higher than the control group (average number of papillomas per rat < 1). The result shows that the immunosuppressant thalidomide can not achieve the effective cancer promotion effect, the BRAF inhibitor sorafenib can obviously promote the development of the esophageal cancer of a rat, shorten the cancer induction period, and can be used as an effective cancer promoter to construct an esophageal cancer animal model of the rat.
TABLE 1 incidence of papilloma and esophageal squamous carcinoma in rats at 30 weeks of cancer induction
Table 1 shows the incidence of papilloma and esophageal squamous carcinoma at 30 weeks of induction in the control and So rats. FIG. 4 is a representative photograph of esophagus at 30 weeks of cancer induction in rats in the control group and the So group. As can be seen from FIG. 4, papilloma was observed mostly at week 30 in the control group rats, but the difference between individuals was large, and even no papilloma appeared in individual rats; the esophagus of rats in the So group all have a large number of papilloma, the number of the papilloma is obviously higher than that of the esophagus of a control group, and a part of the esophagus of rats has squamous cell carcinoma (the circle marks in the figure). As can be seen from the table 1, the incidence rate of papilloma of the control group rat is only 70%, and esophageal squamous cell carcinoma is not generated, which indicates that the cancer induction effect is unstable; so group rats had a papilloma incidence of 100% and a squamous cell carcinoma incidence of 40%, and showed higher cancer induction efficiency and model stability compared to the control group.
The inventor of the application finds that by using the cancerogen NMBzA and the cancerogen Sorafenib together, a large amount of papilloma and epithelial hyperplasia of various degrees can be induced in a rat within about 20 weeks, and ESCC can be induced within about 25-30 weeks. Therefore, the method for inducing the rat to establish the esophageal cancer animal model by utilizing the carcinogen and the carcinogen in cooperation with the carcinogen obviously shortens the cancer induction period, improves the cancer induction efficiency, and simultaneously improves the stability of the ESCC animal model, thereby laying a theoretical basis for researching the multi-stage carcinogenic mechanism of initiation, promotion, evolution, development, heterogeneity, transfer and the like of the ESCC, discovering potential targets related to the ESCC generation and development and realizing the prevention, early diagnosis and accurate medical treatment of the ESCC.
Example 2 establishment of animal model of mouse esophageal carcinoma
1 Material
C57BL/6 mice, 7 weeks old, male, purchased from Weitongli, Inc., Beijing.
4-nitroquinoline-1-oxide (4 NQO): from Sigma-Aldrich, 100. mu.g/ml of working solution was prepared using mouse drinking water.
Sorafenib (Sorafenib): prepared from Shanghai ceramic Biotechnology Ltd using Cottonseed oil cottonsed oil (available from Glpbio) containing 5% DMSO to a final concentration of 10 mg/ml.
2 method
(1) The 7-week-old C57BL/6 male mice were purchased and divided into 2 groups of 10 mice each, a control group and a Sorafenib-treated group (designated as So group). Mice were acclimated in SPF-grade animal rooms for 1 week and fed with normal drinking water and maintenance feed.
(2) The experiment was started after 1 week of acclimation of the mice, and 2 groups of mice were replaced with drinking water containing 4NQO at 100 μ g/ml for 10 weeks.
(3) Control mice received 5% DMSO cotton seed oil intraperitoneal injections (5ml/kg) beginning at week 11, administered every other day for 15 weeks; group So received sorafenib intraperitoneal injections (50mg/kg) administered every other day for 15 weeks.
(4) The whole experimental process was observed and recorded. The experimental results are shown in fig. 5.
During the whole experiment, the mice in So group appeared papilloma earlier than the control group, and some mice appeared papilloma at about 15 weeks; at week 20, mice in So group all developed papilloma, while only very individual mice in control group developed papilloma; at week 25, as shown in fig. 5, the control mice exhibited papillomas in the esophagus or the forestomach, but did not progress to squamous cell carcinoma; the tongue, esophagus or forestomach of So mice all developed a large number of papillomas, and most of the mice had developed squamous cell carcinoma of the esophagus or forestomach (circled marks in the figure). Therefore, compared with the single use of the cancer inducer 4NQO, the combined use of sorafenib and 4NQO can promote the occurrence of mouse cancer, shorten the cancer induction time, improve the cancer induction efficiency and increase the stability of a mouse cancer model.
After attempting to use a variety of cancer-promoting drugs such as phorbol ester TPA (activated protein kinase C), Telocidin (activated protein kinase C), Benzoyl peroxide (oxidative stress), immunosuppressant thalidomide (thalidomide), Vemurafenib (Vemurafenib), Sorafenib (Sorafenib), Encoraafenib (LGX818) BRAF inhibitor (some of the drug data are not shown), the inventors finally determined that Sorafenib (Sorafenib) has the best effect as a cancer-promoting drug, and can be used in combination with a variety of cancer-inducing agents to promote the formation of cancer in animals, for example, in the examples of the present application, Sorafenib and methylbenzylnitrosamine promote the formation of esophageal cancer in rats, and 4-nitroquinoline-1-oxide promotes the formation of squamous cell carcinoma in mouse esophagus or anterior stomach. Sorafenib can also be used in combination with inducers for skin cancer, head and neck squamous cell carcinoma, breast cancer, cervical cancer, colon cancer, lung cancer, liver cancer, etc., to promote the formation of various cancers.
In conclusion, the method for establishing the cancer inducing agent induced animal cancer model adopts the common chemical carcinogenic agent to induce the animal to induce cancer in the cancer inducing stage; after a period of time, in the cancer promotion stage, the animal cancer promotion medicine is given, so that the formation of animal papilloma or cancer can be promoted, the cancer induction efficiency is improved, the cancer induction time is shortened, the stability of an animal cancer model is increased, and a foundation is laid for the research of the occurrence and development of the cancer.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (9)
1. The method for establishing the cancer model of the animal induced by the cancer inducer is characterized by comprising the following steps:
s1: cancer induction stage: selecting an animal, and administering the animal cancer-inducing agent to induce the formation of cancer in the animal;
s2: and (3) promoting cancer stage: administering to the animal a cancer-promoting drug of step S1 to promote the development of cancer in the animal;
the cancer promotion drug is one or more of BRAF inhibitors;
the cancer inducer is methyl benzyl nitrosamine or 4-nitroquinoline-1-oxide.
2. The method of claim 1, wherein the BRAF inhibitor is sorafenib (Sabrafenib) or Vemurafenib (Vemurafenib).
3. The method according to claim 2, characterized in that the sorafenib is administered in a dose ranging from 10 to 50 mg/kg.
4. The method of claim 1, wherein said methylbenzylnitrosamine is administered at a dose of from 0.2 to 0.5 mg/kg.
5. The method of claim 1, wherein said injected dose of methylbenzylnitrosamine is 0.3 mg/kg.
6. The method of claim 1, wherein the 4-nitroquinoline-1-oxide is administered in a dose of 50 to 100 μ g/ml.
7. The method of claim 1, wherein the 4-nitroquinoline-1-oxide is administered in a dose of 100 μ g/ml.
8. The method according to any one of claims 1 to 7, wherein the cancer promotion treatment regimen of step S2 is every other day for 8 to 20 weeks.
9. The method of any one of claims 1-7, wherein the cancer is selected from esophageal cancer, head and neck squamous cancer, breast cancer, cervical cancer, skin cancer, colon cancer, gastric cancer, lung cancer and liver cancer.
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