Application of vernoniamycin or derivative thereof in preparation of medicine for treating gastric cancer

Abstract

The invention belongs to the field of biological medicine, and particularly relates to application of vernoniamycin or a derivative thereof in preparation of a medicine for treating gastric cancer. The invention finds the new application of the ivernonamycin in treating the gastric cancer, the action effect of the ivernonamycin in human primary gastric cancer organs is obviously reduced by more than 4 times compared with that of cis-platinum, and the ivernonamycin has obvious advantages compared with the common chemotherapeutic drug cis-platinum. Besides, in pharmacokinetic experiments of rats and mice, the ivernoniamycin has high plasma exposure and good oral bioavailability, and is suitable for oral administration. In a whole blood environment, the vernoniamycin is basically not metabolized within 120 minutes, and has very high stability. In various types of liver microsomes, the amount of the turtledoamycin can be maintained to be 80% within 60 min, only the turtledoamycin can be seen, the turtledoamycin has a good inhibiting and killing effect on gastric cancer, the pharmacokinetics is excellent, the stability in organisms is high, and the effect can be continuously achieved through oral administration.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically relates to the application of cantharicin or its derivatives in the preparation of drugs for treating gastric cancer. Background Art

[0002] Gastric cancer is one of the most common cancers and one of the most common causes of cancer-related death. It is characterized by high heterogeneity and poor prognosis. In the past decade, the development and marketing of new drugs such as targeted drugs, immunotherapy and antibody-drug conjugates (ADCs), as well as the standardization and maturity of laparoscopic gastric cancer surgery, have greatly enriched the treatment strategies for gastric cancer.

[0003] Fluorouracil, platinum and taxane are the main chemotherapy drugs for gastric cancer. First-line chemotherapy is based on fluorouracil drugs, combined with platinum and (or) taxane drugs to form a two-drug or three-drug chemotherapy regimen, and second-line chemotherapy is usually taxane drugs. In order to achieve different treatment strategies, chemotherapy is often combined with anti-human epidermal growth factor receptor 2 (HER2) antibodies, anti-vascular endothelial growth factor (VEGF) antibodies and immune checkpoint inhibitors to improve efficacy.

[0004] Currently, programmed death receptor 1 (PD-1) inhibitors combined with chemotherapy have become the new standard for first-line treatment of advanced gastric cancer. Although single-target immune checkpoint inhibitors combined with chemotherapy have significantly improved the overall response rate (ORR), PFS, and OS, the beneficiaries are patients with high PD-L1 expression, high-frequency microsatellite instability (MSI-H), or high tumor mutation burden (TMB). This accounts for a small proportion of gastric cancer patients. Therefore, the introduction of combination therapy with other immune checkpoint inhibitors has become a hot topic in clinical trials, such as monoclonal antibodies such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3).

[0005] Although the innovation of therapies such as chemotherapy, anti-HER2, anti-VEGF, immune checkpoint inhibitors and ADC drugs has changed the landscape of gastric cancer treatment, there are still a large number of unmet clinical needs. In addition, chemotherapy, immunotherapy, etc. have many adverse reactions, such as gastrointestinal toxicity, endocrine toxicity, skin toxicity, etc. In addition, for patients who are resistant to traditional chemotherapy and first-line immunotherapy, their treatment options are more limited and the prognosis is often poor. Therefore, the development of new small molecule compounds with anti-gastric cancer activity is an urgent need to improve efficacy and safety. Summary of the invention

[0006] The purpose of the first aspect of the present invention is to provide the use of cantharicin and its derivatives in the preparation of products for treating gastric cancer.

[0007] The second aspect of the present invention aims to provide a method.

[0008] In order to achieve the above-mentioned purpose of the present invention, the technical solution adopted by the present invention is:

[0009] The first aspect of the present invention provides the use of cantharicin and its derivatives in the preparation of products for treating gastric cancer.

[0010] Preferably, the Ikarugamycin (Ika) or its derivatives include at least one of a pharmaceutically acceptable salt and a pharmaceutically acceptable modification.

[0011] Preferably, the pharmaceutically acceptable salt includes at least one of a metal salt, an ammonium salt, a salt formed with an inorganic acid, a salt formed with an organic base, a salt formed with an organic acid, a salt formed with a basic amino acid, and a salt formed with an acidic amino acid.

[0012] Preferably, the metal salt comprises an alkali metal salt or an alkaline earth metal salt.

[0013] Preferably, the alkali metal salt includes at least one of a sodium salt and a potassium salt.

[0014] Preferably, the alkaline earth metal salt includes at least one of calcium salt, magnesium salt, barium salt and aluminum salt.

[0015] Preferably, the salt formed with the organic base includes a salt formed with the following organic bases: at least one of trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.

[0016] Preferably, the salt formed with an inorganic acid includes a salt formed with the following inorganic acids: at least one of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.

[0017] Preferably, the salt formed with the organic acid includes a salt formed with the following organic acids: at least one of formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0018] Preferably, the salt formed with a basic amino acid comprises a salt formed with the following basic amino acids: at least one of arginine, lysine and ornithine.

[0019] Preferably, the salt formed with the acidic amino acid includes a salt formed with the following acidic amino acids: at least one of aspartic acid and glutamic acid.

[0020] Preferably, the pharmaceutically acceptable modification comprises at least one of phosphorylation, sulfonation, acylation, glycosylation, ubiquitination, acetylation, methylation, sulfation, phospholipidation, and halogenation.

[0021] Preferably, the product comprises a medicine.

[0022] Preferably, the drug comprises pharmaceutically acceptable excipients, and / or any one or more other active ingredients.

[0023] Preferably, the pharmaceutically acceptable excipients include at least one of solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, and carriers.

[0024] Furthermore, in order to facilitate medication, the active ingredient cantharicin or its derivatives can be processed into a specific dosage form with any one or more pharmaceutically acceptable excipients. These excipients can be diluents (such as starch, pregelatinized starch, dextrin, sucrose, lactose, mannitol and microcrystalline cellulose, etc.), absorbents (such as calcium sulfate, calcium hydrogen phosphate, light magnesium oxide and calcium carbonate, etc.), wetting agents (such as water and ethanol, etc.), binders (such as hydroxypropyl methylcellulose, povidone, starch slurry and syrup, etc.), disintegrants (such as dry starch, sodium hydroxymethyl starch, low-substituted hydroxypropyl cellulose, effervescent disintegrants and cross-linked polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycol and micropowder, etc.), and other additives. silica gel, etc.), colorants (such as titanium dioxide, sunset yellow, methylene blue and medicinal iron oxide, etc.), coating materials (such as acrylic resin, hydroxypropyl methylcellulose and povidone, etc.), solvents (such as water for injection, ethanol, propylene glycol and glycerol, etc.), acid-base regulators (such as hydrochloric acid, lactic acid, sodium hydroxide, tartaric acid and sodium tartrate, etc.), antioxidants (such as sodium sulfite, sodium pyrosulfite and sodium thiosulfate, etc.), antibacterial agents (such as phenol, benzyl alcohol and thimerosal, etc.), and isotonic regulators (such as sodium chloride and glucose, etc.).

[0025] Preferably, the dosage form of the product includes a dosage form for enteral administration or a dosage form for parenteral administration.

[0026] Preferably, the dosage form for administration via the gastrointestinal tract includes at least one of powders, tablets, granules, capsules, sustained-release agents, solutions, dry suspensions, effervescent tablets, emulsions, suspensions, syrups, drops, and chewable tablets.

[0027] Furthermore, the dosage forms for administration through the gastrointestinal tract include but are not limited to enteric-coated tablets, coated tablets, film-coated tablets, sugar-coated tablets, dispersible tablets, sucking tablets, chewable tablets, effervescent tablets, scratched tablets, sustained-release and controlled-release dosage forms such as sustained-release tablets, sustained-release coated tablets, controlled-release tablets, orally disintegrating tablets, lozenges, oral patches, etc.

[0028] Preferably, the non-intestinal administration dosage form includes at least one of an injection dosage form, a respiratory tract administration dosage form, a skin administration dosage form, a mucosal administration dosage form, and a cavity administration dosage form.

[0029] Furthermore, the injectable dosage forms include but are not limited to injection solutions, injection solutions, intravenous injection solutions, injection suspensions, sterile powders for injection, intravenous injections, water injections, injection emulsions, powder injections, injections, sterile powder injections, freeze-dried powder injections, etc.

[0030] In some embodiments of the present invention, the dosage form administered through the gastrointestinal tract has better effects; preferably, it is an oral dosage form.

[0031] Preferably, the product is administered to a mammal.

[0032] Preferably, the mammal comprises a human.

[0033] The second aspect of the present invention provides an in vitro method for inhibiting the proliferation and growth of gastric cancer cells for non-therapeutic purposes, comprising the following steps: treating cells with cantharicin or its derivatives.

[0034] The beneficial effects of the present invention are:

[0035] The present invention finds a new use of cantharicin for treating gastric cancer. In human primary gastric cancer organoids, the effect of cantharicin is more than 4 times less sensitive than cisplatin, and has obvious advantages over the commonly used chemotherapy drug cisplatin. In addition, cantharicin has a high plasma exposure and good oral bioavailability in the pharmacokinetic experiments of rats and mice, and is suitable for oral administration. In the whole blood environment, cantharicin is basically not metabolized within 120 minutes and has high stability. In liver microsomes of various genera, cantharicin can also be maintained at 80% of the amount within 60 minutes, indicating that cantharicin is a slowly metabolized compound, which will not be rapidly decomposed and metabolized in the body and has a certain stability. It can be seen that cantharicin has a good inhibitory and killing effect on gastric cancer, and has excellent pharmacokinetics, high stability in the body, and can be continuously effective through oral administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 , 2 , 3 are the inhibitory data results of cantharicin on three different primary gastric cancer cell organoid models.

[0037] Figure 4 This is a diagram of the cell state of YSTAD240029 affected by canthamicin, where the concentrations of canthamicin in 1, 2, 3, and 4 are 25, 6.25, 0.78, and 0 μM, respectively.

[0038] Figure 5 , 6 , 7 are the inhibitory data results of cisplatin on three different primary gastric cancer cell organoid models.

[0039] Figure 8 The pharmacokinetic data of cantharicin injection in rat model.

[0040] Fig. 9 The oral pharmacokinetic data of cantharicin in rat model.

[0041] Fig.10 The pharmacokinetic data of cantharicin injection in mouse model.

[0042] Fig.11 The oral pharmacokinetic data of cantharicin in a mouse model. DETAILED DESCRIPTION

[0043] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0044] The drugs used in the present invention are as follows:

[0045] Canthamicin, a method for producing canthamicin, using Xiamen Streptomyces (Streptomyces xiamenensis) CGMCC No.5675 to ferment and culture to obtain canthamicin; the culture medium used for the fermentation culture is prepared by adding 4g of yeast extract and 10g of malt extract to every 1000ml of deionized water; the pH value of the culture medium is 7.0-7.2; after the Xiamen Streptomyces is fermented and cultured, the fermentation liquid is extracted with ethyl acetate, and after column chromatography separation, canthamicin is obtained (the specific method has been disclosed in patent: ZL201510542281.8).

[0046] Cisplatin: from MCE, product number 15663-27-1.

[0047] Example 1 Effect of Cantharicin on Human Gastric Cancer Organoids

[0048] 1. Experimental Materials

[0049] In this example, three gastric cancer primary cells were collected, numbered YSTAD240029, YSTAD240031, and YSTAD240032. The above cells were collected from the Zhongke Puruisheng Renewable Cancer Primary Cell Biobank, and the relevant experiments have been approved by the Nanfang Hospital of Southern Medical University (Ethics Approval No.: NFEC-2024-398).

[0050] The original sample library numbers of YSTAD240029, YSTAD240031 and YSTAD240032 in the Sino-Science Renewable Cancer Primary Cell Biobank are LPCBA1009, LPCBA1482 and LPCBA1483 respectively.

[0051] 2. Organoid Culture

[0052] Since tumor cells have a complex microenvironment system in the real environment and interact with surrounding tissues in a three-dimensional form, it is difficult for a two-dimensional cell model to simulate the state of tumor cells in the real environment. In this regard, this example uses a tumor organoid model with a 3D morphology for experiments.

[0053] YSTAD240029, YSTAD240031, and YSTAD240032 were cultured to the organoid state.

[0054] Model building method:

[0055] (1) Wash and digest fresh gastric cancer specimens to a single-cell state;

[0056] (2) After lysis of the red blood cells, the cells were filtered, counted, and centrifuged. The supernatant was discarded and the precipitate was mixed with the matrix gel;

[0057] (3) 50 μL / well of gel droplets were seeded into each well of a 24-well plate. After solidification in an incubator for 30 min, culture medium was added to cover the gel droplets.

[0058] (4) Continue to observe the growth status of organoids. When the organoid diameter reaches 50 μM or more and no longer expands, it can be dissociated and subcultured for use in experiments.

[0059] 3. In vitro anti-proliferative effect test

[0060] The tumor organoid model cultured in step 2 was treated with different concentrations (0.78, 1.56, 3.125, 6.25, 12.5, 25, 50 μM), and the cell viability was detected using Cell Counting-Lite (CTG) after 144 hours. The in vitro antiproliferative activity of each compound was processed using GraphPad software to calculate the IC 50 .

[0061] 4. Experimental results

[0062] The experimental results are as follows Figures 1 to 3 As shown, the IC of cantharicin was measured after 144 hours of treatment in the gastric cancer organoid model. 50 Both were lower than 10 μM, indicating that cantharicin had a strong inhibitory effect on the proliferation of primary gastric cancer tumor cells in vitro.

[0063] Among them, in YSTAD240029 cells, the IC 50 is 9.647 μM. YSTAD240031 and YSTAD240032 cells are more sensitive to cantharicin. 50 Less than or close to 0.78μM.

[0064] Furthermore, IC 50Taking YSTAD240029 cells as an example, after forming organoids for 72 hours, the cells were treated with 0, 0.78, 12.5, and 25 μM cantharicin for 144 hours. Figure 4 As shown, when the concentration of cantharicin was greater than 12.5 μM, most of the cells died, and when the concentration was 0.78 μM, the growth of organoids was significantly inhibited compared with the cell control, and the cell control was in good condition.

[0065] Example 2 Effects of cantharicin on human gastric cancer organoids compared with commonly used chemotherapy drugs

[0066] With reference to the method steps of Example 1, the present invention takes cisplatin, a commonly used chemotherapy drug in the art, as an example to further compare the effects of cantharicin and cisplatin.

[0067] The results are as follows Figures 5 to 7 As shown, the IC of cisplatin in three primary gastric cancer organoid models, YSTAD240029, YSTAD240031, and YSTAD240032 50 The results are 37.98, 7.139, and 47.15 μM, respectively. It can be seen that for the same gastric cancer cells, the effect of cantharicin is more than 4 times less sensitive than cisplatin, which proves that cantharicin has obvious advantages over the commonly used chemotherapy drug cisplatin.

[0068] Tables 1 to 4 are the layout diagrams of cantharicin and cisplatin in 96-well plates and the original drug sensitivity data. It can be seen from the data that at the same concentration, cantharicin has a significantly stronger inhibitory effect on the same gastric cancer sample than cisplatin, proving that cantharicin has a significant advantage in inhibiting the growth of gastric cancer compared to cisplatin.

[0069] Table 1 Layout of cantharicin and cisplatin in 96-well plate

[0070]

[0071] Table 2 Original data of drug sensitivity of cytomycin and cisplatin on YSTAD240029

[0072]

[0073] Table 3 Original data of drug sensitivity of cytomycin and cisplatin on YSTAD240031

[0074]

[0075] Table 4 Original data of drug sensitivity of cytomycin and cisplatin on YSTAD240032

[0076]

[0077] Example 3: Pharmacokinetics and Stability of Veromucin

[0078] 1. Experimental methods

[0079] Animal model: SPF male SD rats and SPF male ICR mice.

[0080] 1.1 Pharmacokinetic experiments:

[0081] 1) Animals and breeding environment

[0082] 9 SPF male SD rats, 6-8 weeks old, weighing 180-220g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., animal license number: SCXK (Beijing) 2021-0011; the experimental animals were adaptively fed for one week after receipt, and then pharmacokinetic studies were performed. The temperature of the animal room was 20-26°C; the humidity was 40-70%; the light and dark were alternated for 12 hours; free access to water and food; the animals were fasted for 12 hours before the start of the experiment.

[0083] 9 SPF male ICR mice, 4-6 weeks old, weighing 18-22g, were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., animal license number: SCXK (Beijing) 2021-0011; the experimental animals were adaptively fed for one week after receipt, and then pharmacokinetic studies were performed. The temperature of the animal room was 20-26℃; the humidity was 40-70%; the light and dark were alternated for 12 hours; free access to water and food; the animals were fasted for 12 hours before the start of the experiment.

[0084] 2) Dosage regimen

[0085] This study adopted a single-dose single-cycle administration scheme, and selected 9 healthy and suitable animals, divided into 3 groups, recorded as Group 1, 2, and 3. The administration scheme is shown in Table 5 (same for mice and rats).

[0086] Table 5 Dosage regimen

[0087]

[0088] 3) Blood sample collection

[0089] After administration to SD rats, blood was collected from the jugular vein. The specific collection time points are shown in the following Table 6.

[0090] Table 6 Blood sample collection design

[0091]

[0092]

[0093] For ICR mice, blood was collected from the cheek after administration. The sampling time was the same as that for rats, and the sampling volume was 0.05 mL / time.

[0094] 4) Plasma separation and storage

[0095] Sampling requirements and processing: Blood was collected using K2EDTA anticoagulant tubes and placed in a wet ice environment for more than 15 minutes, centrifuged at 6000r / min for 3 minutes, the plasma was separated, and stored in a -20℃ refrigerator for testing.

[0096] 5) Biological sample analysis

[0097] The concentration of samples from each animal at each time point was determined by LC-MS / MS. Samples with high concentrations exceeding the detection limit were diluted to the quantitative range with blank plasma and then measured.

[0098] 6) Data processing and statistical analysis

[0099] Microsoft Excel 2010 spreadsheet software was used for data management, and WinNolin 8.2 software was used to calculate pharmacokinetic parameters.

[0100] Absolute bioavailability calculation formula:

[0101] F(%)=(Dose iv ×AUC oral(0-∞)) / (Dose oral ×AUC iv(0-∞) )×100%.

[0102] Calculation of pharmacokinetic parameters: According to the blood drug concentration-time data of each test animal measured in the experiment, the main pharmacokinetic parameters of the test substance are obtained. Including T max (peak time), C max (peak concentration), t 1 / 2 (elimination half-life), AUC (area under the plasma concentration-time curve) and other parameter values.

[0103] 1.2 Whole blood stability test:

[0104] 1) Add blank whole blood to each culture plate. Add control compound or test compound solution to the culture plate. The final concentration of the test compound is 1 μM, and the final concentration of the control compound is 1 μM.

[0105] 2) All reaction plates containing the compound and whole blood mixture were incubated in a 37°C water bath.

[0106] 3) Take 50 μL aliquots from the reaction solution at 0, 5, 15, 30, 60 and 120 minutes. Stop the reaction by adding 300 μL of cold acetonitrile / methanol (v:v=10:90) solution containing IS (50 ng / mL labetalol, 50 ng / mL tolbutamide). Centrifuge the sample at 4000 rpm for 10 minutes. Mix 100 μL aliquots of the supernatant with 100 μL ultrapure H2O and use for LC-MS / MS analysis.

[0107] 4) Data analysis:

[0108] The percentage of test compound remaining after incubation in whole blood was calculated using the following equation:

[0109] %Remaining=100×(PAR at appointed incubation time / PAR at T0 time)

[0110] where PRP is the peak area ratio of the analyte to the internal standard (IS).

[0111] The designated incubation time points are T0 (0 min), T n (n=0, 5, 15, 30, 60, 120 minutes)

[0112] All calculations were performed using Microsoft Excel.

[0113] The slope value, k, was determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus the incubation time curve.

[0114] The in vitro half-life (in vitro t 1 / 2 ):

[0115] in vitro 1 / 2 =-(0.693 / k).

[0116] 1.3 Liver microsome experiment:

[0117] 1) Prepare solutions according to Table 7.

[0118] Table 7. Solution preparation recipe

[0119]

[0120] 2) Add the main solution to the culture plate. Diclofenac was used as a positive control in this study, and the final concentration of the test drug and diclofenac was 1 μM. Preheat the mixture at 37°C for 5 minutes.

[0121] 3) The reaction was started with NADPH regeneration solution. The test compound samples without NADPH (named NCF60, NCF0) were used as negative controls. The incubation solution was incubated in a water bath at 37°C.

[0122] 4) At 0, 5, 15, 30, and 60 minutes, the reaction was stopped by adding 200 μL of IS (50 ng / mL labetalol, 50 ng / mL toluamide) in a cold methanol:acetonitrile = 1:1 solution. The sample was centrifuged at 4000 rpm for 10 minutes. An aliquot of 50 μL of the supernatant was mixed with 150 μL of H2O and then used for LC-MS / MS analysis.

[0123] 5) Data analysis

[0124] All calculations were performed using Microsoft Excel.

[0125] The peak areas were determined from the ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the percentage of parent drug remaining versus the incubation time curve.

[0126] Determine the in vitro half-life (in vitro t1 / 2) based on the slope value:

[0127] in vitro 1 / 2 =-(0.693 / k).

[0128] The in vitro t 1 / 2 (min) converted to in vitro intrinsic clearance (in vitro C Lint , in μL / min / mg protein):

[0129]

[0130] CLint (mL / min / kg) = (0.693 / T 1 / 2 )×(1 / (microsomal protein concentration (0.5 mg / mL))×scaling factor.

[0131] a Scaling factor = (microsomal protein per gram of liver) x (liver weight per kilogram of body weight).

[0132] 2. Experimental results

[0133] 1) SD rats

[0134] The results of the pharmacokinetic study of cantharicin in SD rats showed that ( Figure 8 , 9 ; Table 8), when the oral dose was 10 mg / kg, veromycin had a higher plasma exposure (AUC 0-∞=2643±328h*ng / mL) and good oral bioavailability (F=11.20±0.01%). In addition, veromucin showed a moderate clearance rate (Cl=426±32mL / h / kg), a half-life of 7.54±5.67h, and a maximum plasma concentration of 129±12.7ng / mL. These data indicate that veromucin has good pharmacokinetic properties and is suitable for oral administration.

[0135] Table 8 Pharmacokinetic results of cantharicin in SD rats

[0136]

[0137]

[0138] 2) Mice

[0139] In comparison, cantharicin has better pharmacokinetic performance in ICR mice ( Fig.10 , 11 ; Table 9). When the oral dose was 10 mg / kg, veromycin had a higher plasma exposure (AUC 0-∞ =8819±4671h*ng / mL) and oral bioavailability (F=24.40±0.13%). The half-life reached 6.73±1.96h, and the maximum plasma concentration was 581±228ng / mL. This further indicated that veromycin was suitable for oral administration.

[0140] Table 9 Pharmacokinetic results of cantharicin in ICR mice

[0141]

[0142] 3) Whole blood stability

[0143] The metabolic stability results of cantharicin in whole blood and liver microsomes are shown in Tables 10 and 11.

[0144] Table 10 Whole blood stability data of cantharicin in five species

[0145]

[0146]

[0147] Table 11 Metabolic stability data of cantharicin in liver microsomes in five species

[0148]

[0149] In the whole blood environment, cantharicin is basically not metabolized within 120 minutes, and has high stability. In liver microsomes of various species, cantharicin can also maintain 80% of the amount within 60 minutes, indicating that cantharicin is a slowly metabolized compound and will not be rapidly decomposed and metabolized in the body, and has a certain stability.

[0150] In summary, cantharicin has a good inhibitory and killing effect on gastric cancer, and has excellent pharmacokinetics, high stability in the body, and can exert its effects continuously through oral administration.

Claims

1. Application of cantharicin or its derivatives in the preparation of products for treating gastric cancer.

2. The use according to claim 1, characterized in that: The canthamicin or its derivatives include at least one of pharmaceutically acceptable salts and pharmaceutically acceptable modifications.

3. The use according to claim 2, characterized in that: The pharmaceutically acceptable salt includes at least one of a metal salt, an ammonium salt, a salt formed with an inorganic acid, a salt formed with an organic base, a salt formed with an organic acid, a salt formed with a basic amino acid, and a salt formed with an acidic amino acid.

4. The use according to claim 2, characterized in that: The pharmaceutically acceptable modification includes at least one of phosphorylation, sulfonation, acylation, glycosylation, ubiquitination, acetylation, methylation, sulfation, phospholipidation, and halogenation.

5. The use according to claim 1, characterized in that: The products include pharmaceuticals.

6. The use according to claim 5, characterized in that: The drug includes pharmaceutically acceptable excipients, and / or any one or more other active ingredients.

7. The use according to claim 6, characterized in that: The pharmaceutically acceptable excipients include at least one of solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, and carriers.

8. The use according to claim 5, characterized in that: The dosage form of the product includes a dosage form for gastrointestinal administration or a dosage form for parenteral administration; Preferably, the dosage form for administration via the gastrointestinal tract includes at least one of powder, tablet, granule, capsule, sustained-release agent, solution, dry suspension, effervescent tablet, emulsion, suspension, syrup, drops, and chewable tablet; Preferably, the non-intestinal administration dosage form includes at least one of an injection dosage form, a respiratory tract administration dosage form, a skin administration dosage form, a mucosal administration dosage form, and a cavity administration dosage form.

9. The use according to claim 8, characterized in that: The product is administered to a mammal; Preferably, the mammal comprises a human.

10. A method for inhibiting the proliferation and growth of gastric cancer cells in vitro for non-therapeutic purposes, comprising the following steps: Treat cells with cantharicin or its derivatives.

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