CN106119367B - Novel use of acetaldehyde dehydrogenase 2 gene - Google Patents
Novel use of acetaldehyde dehydrogenase 2 gene Download PDFInfo
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- CN106119367B CN106119367B CN201610519115.0A CN201610519115A CN106119367B CN 106119367 B CN106119367 B CN 106119367B CN 201610519115 A CN201610519115 A CN 201610519115A CN 106119367 B CN106119367 B CN 106119367B
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Abstract
The invention belongs to the field of medical detection, and particularly relates to a new application of an acetaldehyde dehydrogenase 2 gene. The invention discloses application of an acetaldehyde dehydrogenase 2 gene as a detection index of gastric cancer molecular typing and application of an anthracycline medicament in preparation of an acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer treatment medicament, discovers that the ALDH2 gene deletion or mutation causes different sensitivities of gastric cancer cells to tumor chemotherapy medicaments for the first time, and is verified by in vivo experiments, thereby providing a new detection index of gastric cancer molecular typing, and simultaneously discloses application of the anthracycline medicament in preparation of the acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer treatment medicament, and providing a new choice for individualized treatment of gastric cancer.
Description
Technical Field
The invention belongs to the field of medical detection, and particularly relates to a new application of an acetaldehyde dehydrogenase 2 gene.
Background
Gastric cancer is the fourth most fatal cancer worldwide, with more than half of the total cases in east asia and a chinese incidence of 43% worldwide; mortality accounts for 45% worldwide. Moreover, Chinese gastric cancer patients are discovered to have late clinical stages, and the proportion of the advanced gastric cancer accounts for about 70 percent, so that the Chinese gastric cancer patients are the people with the highest attention. Because of the strong heterogeneity of gastric cancer, the prognosis and treatment outcome are different depending on the gastric cancer location, type of case, age, sex, etc.
Typing of gastric cancer has undergone gross morphological typing, histological typing, environmental, genetic, molecular typing.
Molecular classification (molecular classification) was first proposed by the national cancer institute, and tumor classification was carried out by molecular analysis techniques, which shifted the classification of tumors from traditional morphology to molecular classification based on molecular characteristics. In 2003, Kim B et al used 14K cDNA chips to classify gastric cancer into a high-grade inflammatory infiltrative type and a low-grade inflammatory infiltrative type, and the latter is classified into 3 subtypes, namely, a diffuse type and 2 intestinal types with different malignant characteristics. Simultaneously, Tay ST and the like are combined to apply technologies such as microsatellite instability analysis and the like to treat 3 subtypes of gastric cancer atmosphere according to gene expression difference: tumorigenic (tumourigenic), reactive (reactive) and gastroid (gastic-like), where patients with gastroid have better overall survival. In 2011, Tan et al analyzed the differences in gene expression profiles of 37 gastric cancer cell lines by gene core technology, and classified gastric cancer into intestinal (G-INT) and diffuse (G-DIF) subtypes. In 2013, Lei et al study the gene expression profile of gastric adenocarcinoma by gene chip to classify gastric cancer into mesenchymal type, increment type and metabolic type.
A paper published online in Nature by The Cancer Genome Atlas (TCGA) at 23.7.2014, proposed a molecular typing of gastric Cancer, which divided it into four subtypes: EBV (Epstein-Barr, EBV) positive virus, characterized by frequent mutation of PIK3CA, DNA hypermethylation and amplification of JAK2, CD274 and PDCD1LG 2; 2. microsatellite instability (MSI) type, characterized by high mutation rates, including activating gene mutations encoding oncogene signaling pathway proteins; 3. genome-stable (GS) type, which mostly occurs in histologically diffuse type, by RHOA mutation or THO family gtpase activation protein gene fusion phenomenon; 4.a Chromosome Instability (CIN) type with marked heterochromosome and receptor tyrosine kinase amplification in situ.
With the continuous improvement of gastric cancer molecular typing systems, from the genotypic type of Tan (genome intestinal type and diffuse type), the molecular typing of Lei (proliferation type, metabolic type and mesenchymal type), to the TCGA genetic typing in 2014 (EB virus infection type, microsatellite instability type, gene stability type and chromosome instability type).
At present, the treatment of the advanced gastric cancer is mainly comprehensive treatment mainly based on chemotherapy and targeted therapy, and the commonly used medicines and schemes are as follows: platinum (DDP, OXA, etc.) in combination with fluorouracil (F-FU, XELODA, S-1, etc.), paclitaxel in combination with capecitabine; chemotherapy in combination with trastuzumab is commonly applied to HER2 positive patients; other targeted drugs in research, such as VEGF2, PD-1/PD-L1 and the like.
From the current situation, few chemotherapy drugs (only three major classes), delayed targeted therapy (trastuzumab is only suitable for about 15% of patients), and high heterogeneity of gastric cancer are the main treatment bottlenecks of advanced gastric cancer. Therefore, individual chemotherapy based on clinical features, pathological typing, and molecular typing is very important for advanced gastric cancer. The change of tumor treatment mode is created from molecular biology, the disease is recognized from molecular level, and the future tumor treatment mode is individualized treatment guided by molecular typing.
Disclosure of Invention
The invention aims to provide a new detection index for gastric cancer molecular typing so as to provide guidance for individualized treatment of gastric cancer in the future.
Therefore, the invention discloses the application of the acetaldehyde dehydrogenase 2 gene as a detection index of gastric cancer molecular typing. More preferably the application of the acetaldehyde dehydrogenase 2 gene as the molecular typing index of the anthracycline sensitive gastric cancer.
On the other hand, the invention also discloses the application of the anthracycline medicament in preparing a medicament for treating the acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer;
further, the anthracycline is adriamycin, epirubicin, pirarubicin, daunorubicin, or mitoxantrone.
On the other hand, the invention also discloses application of the anthracycline medicament and the acetaldehyde dehydrogenase 2 inhibitor in preparing a medicament for treating gastric cancer.
On the other hand, the invention also discloses a method for treating acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer by using the anthracycline, which comprises the step of administering an effective dose of the anthracycline to a patient with acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer;
in another aspect, the invention also discloses a method for treating gastric cancer with acetaldehyde dehydrogenase 2 gene mutation or deletion type by using the anthracycline and the acetaldehyde dehydrogenase 2 inhibitor, which comprises the step of administering effective doses of the anthracycline and the acetaldehyde dehydrogenase 2 inhibitor or a compound preparation thereof to a gastric cancer patient.
The invention discovers that ALDH2 gene deletion or mutation causes gastric cancer cells to show different sensitivities to tumor chemotherapy drugs for the first time, and the experiments in vivo prove that the invention provides a new detection index for gastric cancer molecular typing, and also discloses the application of anthracyclines in preparing acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer treatment drugs, and provides a new choice for individualized treatment of gastric cancer.
Drawings
FIG. 1 is the effect of small interfering RNA on the knock-down of ALDH2 gene in SGC-7901 cells.
Figure 2 effect of ALDH2 on the sensitivity of SGC-7901 cells to chemotherapeutic drugs knockdown.
FIG. 3LDH2 knockdown clonogenic effects of SGC-7901 cells.
Figure 4 apoptosis flow cytometry analysis after knockdown of ALDH2 expressing gastric cancer cell DOX treatment.
FIG. 5 ALDH2 knockdown of SGC-7901 cell chemotherapy sensitivity assay of nude mouse transplantable tumors.
Detailed Description
Acetaldehyde dehydrogenase 2(ALDH2) is one of NAD + -dependent acetaldehyde dehydrogenase superfamily members, and 19 acetaldehyde dehydrogenase family members have been found, and acetaldehyde dehydrogenase 2 is an important aldehyde oxidase localized in mitochondria and can oxidize acetaldehyde, which is an ethanol metabolism intermediate, to acetic acid. Meanwhile, the acetaldehyde dehydrogenase 2 can decompose acetaldehyde metabolite 4-hydroxynonenal, so that the oxidative damage of acetaldehyde and acetaldehyde metabolite to cells is reduced. It is a tetrameric enzyme, and is expressed in a large amount in tissues such as liver, kidney and lung, and also in heart and brain tissues with active mitochondrial function. Recent studies have shown that activation of this enzyme has a significant protective effect on myocardial cell death caused by myocardial ischemia-reperfusion. Since the acetaldehyde dehydrogenase 2 gene has a polymorphism and the 487 amino acid residue of the expression product thereof may be glutamic acid (Glu487) or lysine (Lys487), several alleles such as a Glu487 homozygote (acetaldehyde dehydrogenase 2 x 1/1), a Glu487/Lys487 heterozygote (acetaldehyde dehydrogenase 2 x 1/2), and a Lys504 homozygote (acetaldehyde dehydrogenase 2 x 2/2) can be included in the gene. Wherein, the activity of the acetaldehyde dehydrogenase 2 × 1/2 is 10% -45% of the normal activity, and the activity of the acetaldehyde dehydrogenase 2 × 2/2 is 1% -5% of the normal activity. The mutation rate of the gene in the oriental Asian population is more than 40 percent. At present, few researches on the relation between acetaldehyde dehydrogenase 2 and cancers are carried out, the researches are basically focused on statistics, and a plurality of statistical data show that a person carrying ALDH2 mutant genotype is obviously increased in risk of suffering from various cancers, including liver cancer, esophagus cancer and the like, when drinking a large amount of alcohol.
The main detection method of the polymorphism of the acetaldehyde dehydrogenase 2 gene comprises the following steps: restriction Fragment Length Polymorphism (Restriction Fragment Length Polymorphism), single-strand conformation Polymorphism, PCR-ASO probe method, PCR-SSO method, PCR-SSP method, PCR-fluorescence method, PCR fingerprinting method, gene chip method, AFLP (amplification Fragment Length Polymorphism) method: DGGE (denaturing gradient electrophoresis) method, RAPD (random amplified polymorphic DNA) method, including but not limited to methods and detection kits as shown in CN105177159A, CN102758008A, CN103184268A, CN 104120180A.
The anthracycline is an anti-tumor medicament with wide anti-tumor spectrum and high efficiency, and has strong anti-cancer activity on breast cancer, malignant lymphoma, lung cancer, ovarian cancer, soft tissue tumor and liver cancer. The anthracycline drugs comprise adriamycin, epirubicin, pirarubicin, demethoxydaunorubicin, mitoxantrone and the like, belong to periodic nonspecific drugs, and have main toxic and side effects of bone marrow suppression and cardiac toxicity.
The anthracycline sensitive gastric cancer is gastric cancer with therapeutic effect of anthracycline, preferably gastric cancer with deletion or mutation of ALDH2 gene, such as acetaldehyde dehydrogenase 2X 1/2 genotype gastric cancer and acetaldehyde dehydrogenase 2X 2/2 genotype gastric cancer.
Acetaldehyde dehydrogenase 2 inhibitors refer to agents that specifically inhibit acetaldehyde dehydrogenase 2 activity or down-regulate acetaldehyde dehydrogenase 2 expression, including but not limited to, e.g., daidzin.
Medicament or pharmaceutical composition
The pharmaceutical composition used in the invention or containing the anthracycline medicament is disclosed. Generally, when the pharmaceutical composition of the present invention is used for the above-mentioned purpose, the anthracycline can be mixed with one or more pharmaceutically acceptable carriers or excipients to prepare pharmaceutical dosage forms of different administration routes, such as tablet, capsule, powder, granule, syrup, solution, oral liquid, spirit, tincture, aerosol, powder, injection, sterile powder for injection, suppository, etc.
A "pharmaceutically acceptable" component is one that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable carrier" is a pharmaceutically or comestibly acceptable solvent, suspending agent or excipient for delivery of the fusion protein of the invention to an animal or human. The carrier may be a liquid or a solid.
The anthracyclines of the invention may be administered by oral, intravenous, intramuscular or subcutaneous routes.
The dosage form which can be orally administrated comprises the following dosage forms: tablet, capsule, powder, granule, syrup, solution, spirit. The solid support comprises: starch, lactose, calcium hydrogen phosphate, microcrystalline cellulose, sucrose, kaolin, superfine silica gel powder, talcum powder, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch and polyvinylpyrrolidone. And the liquid carrier includes: sterile water, ethanol, polyethylene glycol, nonionic surfactant, and edible oil (such as corn oil, peanut oil, and sesame oil). Adjuvants commonly used in the preparation of pharmaceutical compositions include: flavoring agents, coloring agents, preservatives (e.g. butyl paraben, sodium benzoate, sorbic acid) and antioxidants (e.g. vitamin E, vitamin C, sodium metabisulphite and dibutylhydroxytoluene).
Among the above dosage forms, those useful for administration by injection route include: injections and sterile powders for injection, which are prepared by mixing the drug with one or more pharmaceutically acceptable excipients and are prepared into a form for injection administration. The solvent comprises: sterile water, ethanol, glycerol, propylene glycol, and polyethylene glycol. In addition, bacteriostatic agent (such as benzyl alcohol, oxybenzone butyl ester, and thimerosal), isotonic regulator (such as sodium chloride and glucose), suspending agent (such as sodium carboxymethylcellulose and methylcellulose), solubilizer (Tween-80 and lecithin), antioxidant (such as vitamin E, vitamin C and sodium pyrosulfite), and filler (such as lactose and mannitol) can be added.
From the standpoint of ease of preparation and administration, the preferred pharmaceutical composition is a liquid composition.
The pharmaceutical compositions of the present invention may be prepared according to well known and accepted procedures required for pharmaceutical manufacturing. The pharmaceutical compositions suitably comprise an anthracycline of the invention in a pharmaceutically acceptable carrier, and are suitably in unit dosage form.
Use of
The anthracycline medicine or the anthracycline medicine and the acetaldehyde dehydrogenase 2 inhibitor can be used for treating gastric cancer, and preferably treating gastric cancer with acetaldehyde dehydrogenase 2 gene mutation or deletion type.
The effective dose of the active ingredient used may vary with the mode of administration and the severity of the disease to be treated. For most large mammals, the total dose of active ingredient administered is about 0.01-1000mg per day. Generally, the amount to be clinically administered to an adult is in the range of 0.01 to 200 mg/day, preferably 0.05 to 100 mg/day.
Generally, when the compositions of the present invention are used for the above-mentioned purpose, they can be mixed with one or more pharmaceutically acceptable carriers or excipients to prepare pharmaceutical dosage forms of various administration routes, such as tablets, capsules, powders, granules, syrups, solutions, oral liquids, spirits, tinctures, aerosols, dusts, injections, sterile powders for injections, suppositories, and the like.
A "pharmaceutically acceptable" ingredient is one that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. A "pharmaceutically acceptable carrier" is a pharmaceutically or comestibly acceptable solvent, suspending agent or excipient for use in delivering the anthracycline and acetaldehyde dehydrogenase 2 inhibitor of the present invention to an animal or human. The carrier may be a liquid or a solid.
The compounds of the invention may be administered by oral, intravenous, intramuscular or subcutaneous routes.
The disclosures of all publications, including patents and patent application publications, referred to herein are incorporated by reference to the extent that they are fully set forth in the specification.
The present invention is described in more detail below by way of the following examples, which, however, do not limit the scope of the present invention.
Materials and methods
1 test reagent
RPMI 1640 medium, DMEM medium (Thermo Fisher Co., USA); calf serum (Gibco, usa);
taq DNA Polymerase High Fidelity (Invitrogen, USA); 5 × Lane Marker Reducing Sample Buffer (Pierce, USA); RIPA Buffer (Beyotime, china); pancreatin digest (Beyotime, china); BamH I restriction endonuclease (Takara, Japan); EcoR I restriction endonucleases (Takara, Japan); agarose (Sigma, usa); QIAGENPasmid Mini Kit (QIAGEN, Germany); EndoFree plasma Maxi Kit (QIAGEN, Germany); dako REALTMEnVisionTMDetection System, Peroxidase/DAB +, Rabbit/Mous (Dako, Germany); t4DNA ligase (TaKaRa, japan); DH-5. alpha. competent bacteria (Shanghai Bo-Biotech, Inc., China); ACS grade absolute ethanol (alatin reagent ltd, china); methanol (shanghai zhenxing chemical industry, china); isopropanol (shanghai zhenxing chemical industry, china); bovine serum albumin (dingguo, china); puromycin (Sigma, usa); DOX (Sigma, usa); 5-Fu (Sigma, USA); cisplatin (Sigma, usa); 4-HNE (Cayman, usa); PBS powder (shanghai bo photobio-technology limited, china); crystal violet staining solution (Beyotime, china); DAPI staining solution (Vector, japan); centrifugal column type bulk DNA gel recovery kit (TIANGEN, china); in Situ Cell Death Detection Kit (Roche, Switzerland); CCK-8 cell activity assay kit (Dojindo, Japan); PageRulerTMPrestained Protein Ladder (Fermentas, usa); alexa Fluor-555Donkey anti-mouse Ab fluorescent secondary antibody (Invitrogen, USA); a murine anti-human ALDH2 monoclonal antibody (ABGENT, usa); a murine anti-human p53 monoclonal antibody (Santa Cruz Biotechnology, USA); murine anti-human PARP monoclonal antibodies (Santa Cruz Biotechnology, usa);
the following examples further illustrate specific embodiments of the present invention.
Example 1: establishment of ALDH2 knockdown expression gastric cancer cell strain
Human gastric carcinoma cell SGC-7901 was purchased from cell bank of Shanghai cell biology institute of Chinese academy of sciences, and embryonic kidney cell 293T was originally stored. Cell culture conditions: SGC-7901 cells in logarithmic growth phase were used for experiments in RPMI-l640 cell culture medium containing 10% calf serum, cultured at 37 ℃ and 5% CO 2.
Constructing an ALDH2 knockdown expression retrovirus vector, wherein the steps of a retrovirus packaging method are as described above, infecting SGC-7901 cells for 48h by using a retrovirus, screening by using puromycin with the final concentration of 1 mu g/ml to obtain a stable knockdown expression cell strain, and verifying the knockdown effect by using qRT-PCR, Western Blot and immunofluorescence respectively. The results show that the small interfering RNA can obviously reduce the expression of ALDH2 in SGC-7901 cells, and qRT-PCR results show that the ALDH2mRNA expression of ALDH2-shRNA1 and ALDH2-shRNA2 groups is obviously lower than that of a control group (2.47 +/-1.36 vs75.00 +/-6.10, P is less than 0.001; 5.95 +/-2.71 vs75.00 +/-6.10, P is less than 0.001)) (FIG. 1).
FIG. 1.A. Western Blot method for detecting ALDH2-shRNA1 and ALDH2-shRNA2 cell ALDH2 expression is lower than that of a control group; detecting ALDH2-shRNA1 and ALDH2-shRNA2 cells by a qRT-PCR method, wherein the expression of ALDH2 is lower than that of a control group (P < 0.001); C. the small interfering RNA of ALDH2-shRNA1 and ALDH2-shRNA2 detected by an immunofluorescence method can obviously knock down the expression of ALDH2 in cells.
Example 2: drug sensitivity test of ALDH 2-knocked-down expressed gastric cancer cells
The sensitivity difference of the gastric cancer cell knock-down ALDH2 gene to the chemotherapeutic drug 5-Fu, cisplatin and DOX is compared. We treated ALDH2 from example 1 to knock down gastric cancer cell SGC-7901(ALDH2shRNA1 and shRNA2 cells) and control gastric cancer cell SGC-7901(shRNA empty vector) separately with several chemotherapeutic drugs at graded concentrations (0 μ M, 0.01 μ M, 0.1 μ M, 1 μ M, 10 μ M and 100 μ M concentrations) and compared the relative survival of each group of cells.
Studies have shown that the relative survival rate of ALDH2shRNA1 and shRNA2 cells decreased significantly below that of the shRNA empty vector group (P0.0014, P0.0082) with DOX treatment of gastric cancer cells for 24h, suggesting that ALDH 2-knockdown cells are more sensitive to DOX treatment. The gastric cancer cells treated with cisplatin for 24h, ALDH2-shRNA1 and ALDH2-shRNA2 cells had no significant difference in sensitivity to drug treatment compared with shRNA empty vector group (P-0.9593, P-0.8200). Stomach cancer cells treated with 5-Fu for 24h, ALDH2-shRNA1 and ALDH2-shRNA2 cells showed no significant difference in sensitivity to drug treatment compared to the shRNA empty vector group (P-0.9940, P-0.9907) (fig. 2). Then, we detected that the DOX drug-treated IC50 of cells of the experimental group of DOX-treated ALDH2-shRNA1, ALDH2-shRNA2 and shRNA empty vector group IC50, ALDH2-shRNA1 and ALDH2-shRNA2 is obviously lower than that of the shRNA empty vector group (2.17 +/-0.40 vs.3.97 +/-0.45, P < 0.01; 2.70 +/-0.36 vs.3.97 +/-0.45, P <0.05), which indicates that the sensitivity of the stomach cancer cells with ALDH2 gene expression deletion to the DOX drug is increased.
FIG. 2 shows that the sensitivity of each group of cells to the drug is not obviously different after A.5-Fu treatment; B. the sensitivity of each group of cells treated by the cisplatin to the medicine has no obvious difference; knock-down ALDH2 group was seen to be significantly more sensitive to DOX drugs than the empty vector group after DOX treatment (. P < 0.01).
In addition, for SGC-7901 cells with reduced ALDH2 expression, we performed clonality assays of gastric cancer cells after DOX treatment. As shown in FIG. 3, the gastric cancer cells were treated with DOX at a final concentration of 1 μ M for 48 hours, and the gastric cancer cells were cultured continuously for 14 days, and then photographed and observed, the clonogenic capacities of the ALDH2-shRNA1 and ALDH2-shRNA2 were both significantly lower than that of the shRNA empty vector group (4.47 + -1.29% vs.16.23 + -1.53%, P < 0.01; 7.87 + -0.75% vs.16.23 + -1.53%, P < 0.01). When gastric cancer cells are treated for 48 hours when the DOX final concentration is 2 mu M, the cloning forming capability of the ALDH2-shRNA1 and ALDH2-shRNA2 gastric cancer cells is obviously lower than that of shRNA empty vector group (1.10 +/-0.26% vs.5.37 +/-1.00%, P < 0.01; 3.60 +/-0.46% vs.5.37 +/-1.00%, P <0.05) by photographing and observing after continuously culturing for 14 days.
FIG. 3. A.1. mu.M, 2. mu.M DOX treatment of ALDH2-shRNA1, ALDH2-shRNA2 and shRNA empty vector group for 48h, continuous culture for 14 days, observation of clone formation; B. statistical results for clone formation (. < 0.05;. P < 0.01).
Meanwhile, the ALDH2-shRNA1, the ALDH2-shRNA2 and shRNA empty vector group are treated by DOX with the final concentration of 2 mu M for 24h, cells in a control group are treated by DMSO solvent with the same volume for 24h, and the cells are collected for flow cytometry detection. The gastric cancer cells are treated by DMSO for 24h, and the apoptosis between the ALDH2-shRNA1, the ALDH2-shRNA2 and the shRNA empty vector group has no obvious difference (5.22 +/-0.69%, 5.44 +/-0.94% vs.5.19 +/-0.67%); the apoptosis rate of ALDH2-shRNA1 and ALDH2-shRNA2 treated by DOX for 24h by gastric cancer cells is obviously higher than that of shRNA empty vector group (18.01 +/-1.52% vs.8.31 +/-1.09%, P < 0.01; 14.79 +/-1.32% vs.8.31 +/-1.09%, P <0.01) (figure 4).
FIG. 4 is a representative picture of flow cytometry detection results of ALDH2-shRNA1, ALDH2-shRNA2 and shRNA empty vector cells treated with DOX at 2. mu.M for 24 h; B. statistical results of flow assay ({ dot over) <0.01)
Example 3: research on drug sensitivity of transplanted tumor inoculated in nude mouse by knocking down ALDH2 gene gastric cancer cell
To evaluate the difference in drug sensitivity of ALDH2 gene-deleted gastric cancer cells in vivo, we performed transplantation tumor inoculation and experimental treatment studies using immunodeficient nude mice. In total, 14 BALB/C nude mice with 4 weeks of age are adopted, 3 x 106ALDH2-shRNA1 cells and shRNA empty vector SGC-7901 cells are respectively inoculated under the subcutaneous tissues of the left thigh and the right thigh of the nude mice, and the transplanted tumor grows to 150mm3The experimental group and the control group are 7 respectively administered with 2mg/Kg body weight of DOX and DMSO by intraperitoneal injection, 2 times are injected every week, the tumor size is measured before each drug injection, the treatment is continuously carried out for 3 weeks, the tumor size is measured 3 days after the last drug injection, and the mice are killed, and the research shows that the tumor weight of the subcutaneous transplantation tumor after the ALDH2-shRNA1 treatment group is smaller than that of the control group after DOX administration (0.82g +/-0.56 vs.1.38g +/-0.35, P<0.05), the proliferation speed of the transplanted tumor of ALDH2-shRNA1 group is obviously lower than that of the control group (P)<0.05); in the DMSO solvent treatment group, the weight of the transplanted tumor of the ALDH2-shRNA1 group is obviously higher than that of the control group (2.72g +/-0.63 vs.1.74g +/-0.17, P)<0.01), and the proliferation rate of the transplanted tumor is obviously higher than that of the control group (P)<0.001). Meanwhile, 10 BALB/C nude mice with the age of 4 weeks are inoculated with 3 x 106ALDH2-shRNA1 and shRNA empty vector SGC-7901 cells subcutaneously on the left thigh and the right thigh respectively, and the transplanted tumor grows to 150mm 3. The experimental group and the control group are respectively given 40mg/Kg to 5 of the miceTumor growth status after intraperitoneal injection of 5-Fu and PBS dissolving agent. Tumor size was measured 2 times per week before each injection of drug, treated for 3 consecutive weeks, measured 3 days after the last injection of drug and mice were sacrificed.
As a result, the weight of transplanted tumor in the PBS treatment group and ALDH2-shRNA1 group was significantly higher than that in the control group (3.43 g. + -. 0.53vs. 1.88g. + -. 0.64, P < 0.01). In contrast, in the 5-Fu treated group, the weight of transplanted tumor in ALDH2-shRNA1 group was significantly lower than that in the control group (2.08 g. + -. 0.53vs. 0.0.65g. + -. 0.40, P <0.01) (FIG. 5). The findings show that the growth rates of the DMSO and PBS dissolving agent treatment groups in the ALDH2-shRNA1 group are obviously higher than those of the control group, and the effect of the ALDH2 gene on the cancer suppressor gene in the growth of gastric cancer is suggested. In the shRNA empty vector group without ALDH2 gene intervention, after DOX and 5-Fu drug treatment, the tumor weight of the 5-Fu treated group is obviously lower than that of the DOX treated group (0.65g +/-0.40 vs.1.38g +/-0.35, P <0.01), and the result indicates that: when the ALDH2 gene is wild type, the sensitivity of gastric cancer cells to 5-Fu drugs is superior to that of DOX drugs. After the intervention group (ALDH2-shRNA1SGC-7901 cells) of the ALDH2 gene is respectively treated with DOX and 5-Fu drugs, the tumor weight of the DOX drug group is obviously lower than that of the 5-Fu treatment group (0.82g +/-0.56 vs.2.08g +/-0.53, P is less than 0.01). The above results suggest: the sensitivity of the gastric cancer cells with ALDH2 gene function loss to DOX drugs is better than that of chemotherapy effect to 5-Fu (figure 5).
FIG. 5 shows that in A, B.2mg/kg DOX is intraperitoneally injected into nude mice, and the weight of SGC-7901 subcutaneous cell tumor of ALDH2-shRNA1 group is lower than that of shRNA empty vector group; c.2mg/kg DOX is injected into a nude mouse in an abdominal cavity, and the proliferation speed of subcutaneous tumor of SGC-7901 cell group of ALDH2-shRNA1 group is lower than that of shRNA empty vector group; d, E.40mg/kg 5-Fu is injected into the abdominal cavity of a nude mouse, and the weight of SGC-7901 subcutaneous cell tumor of the ALDH2-shRNA1 group is higher than that of shRNA empty vector group. As can be seen from the tumor volume changes of the nude mice shown in the graphs A and D, when the ALDH2 gene is in the wild type, the effect of the 5-Fu treatment is obviously better than that of the DOX treatment. However, when ALDH2 gene is deficient, DOX has better tumor inhibition effect than 5-Fu.
Chemotherapy is one of the main therapeutic approaches taken against middle and late gastric cancer, 5-Fu, cisplatin and DOX all belong to traditional tumor chemotherapeutics, and 5-Fu and cisplatin are recommended as first-line chemotherapeutics for patients with advanced gastric cancer.
We find for the first time that the apoptosis of gastric cancer cells with the knocked-down ALDH2 gene is obviously increased after DOX drug treatment, and the biological effect is induced by the increase of DNA damage. Compared with a control group, the parallel 5-Fu and cisplatin drug-treated ALDH2 knock down gastric cancer cells, and apoptosis and DNA damage are not significantly changed.
Another important finding of this study is that when we treated nude mice with DOX and 5-Fu respectively, it was shown that nude mice subcutaneous transplanted tumors responded well to 5-Fu drug when ALDH2 was in wild type, and both volume and weight of nude mice subcutaneous transplanted tumors were significantly reduced compared to DOX treated group; however, when the ALDH2 gene is interfered to lose function, the tumor cell inhibition effect of the 5-Fu drug is far inferior to that of the ALDH1 wild-type group. And the sensitivity of the gastric cancer cells of the ALDH2 gene deletion group to DOX drug treatment is increased.
Through the research, the inventor proposes that when an individual has the ALDH2 gene function defect (such as 'oriental variation', gene mutation or epigenetic inactivation), the resistance of the cell to endogenous and exogenous DNA damage is obviously reduced, for example, the resistance to DNA damage caused by an environmental mutagen MNU and a bacterial carcinogen helicobacter pylori is obviously reduced. As a result, the risk of gastric cancer of the individual carrying ALDH2 gene defect is obviously higher than that of the wild individual. Further analysis shows that an individual with ALDH2 genotype defects is required to pay attention to the selection of chemotherapeutic drugs, and the individual carrying ALDH2 gene variation is insensitive to the traditional first-line chemotherapeutic drugs but is more sensitive to anthracycline DOX, so the finding combines the phenomenon that east Asian population has higher ALDH2 gene variation, and has a certain reference value for guiding the individualized accurate treatment of gastric cancer patients in the future.
Claims (3)
1. The application of the anthracycline medicine in preparing the medicine for treating the acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer is that the acetaldehyde dehydrogenase 2 gene mutation or deletion type gastric cancer is acetaldehyde dehydrogenase 2 x 1/2 genotype gastric cancer or acetaldehyde dehydrogenase 2 x 2/2 genotype gastric cancer.
2. Use according to claim 1, characterized in that the anthracycline is doxorubicin, epirubicin, pirarubicin, idarubicin or mitoxantrone.
3. Use according to claim 1, characterized in that the anthracycline is doxorubicin.
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