Application of preparation with mTOR (mammalian target of rapamycin) inhibition capability in preparation of anti-tumor combined pharmaceutical composition

Abstract

The invention provides application of an mTOR inhibitor in preparation of an anti-tumor combined pharmaceutical composition, the pharmaceutical composition comprises a preparation with mTOR inhibition capability, and the pharmaceutical composition is applied to preparation of drugs for preventing or treating side effects caused by an anti-tumor process. The invention also discloses application of the compound in preparation of drugs for preventing or inhibiting pyroptosis caused by the anti-tumor process and application of the compound in preparation of drugs for preventing or treating intestinal inflammation caused by the anti-tumor process. The invention provides an anti-tumor combined pharmaceutical composition. The anti-tumor combined pharmaceutical composition comprises a compound (B) which is used in combination with an anti-tumor agent (A), wherein (A) is at least one chemotherapeutic drug which is selected from cis-platinum, etoposide, 5-fluorouracil and paclitaxel and plays an anti-tumor role by activating GSDME-dependent pyroptosis; (B) is selected from the group consisting of preparations having an ability to inhibit mTOR. The pharmaceutical composition is used for synergistically resisting tumors and relieving toxic and side effects on normal tissues.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to an anti-tumor combined drug composition and application thereof. Background Art

[0002] Pyroptosis, also known as programmed cell necrosis, is a type of inflammatory cell death. Pyroptosis is caused by gasdermin (GSDMs) family proteins, which lead to cell swelling and rupture, accompanied by the release of inflammatory mediators such as IL-1β, LDH and HMGB1. GSDME-mediated tumor cell pyroptosis is considered to be a new molecular mechanism for the treatment of tumors with chemotherapy drugs.

[0003] As a newly discovered pyroptosis executioner protein, GSDME is expressed in many normal cells. In some cancers, the expression level of the GSDME promoter region may be reduced due to hypermethylation. Therefore, GSDME is considered to be a gene that inhibits tumor growth, and this view has been confirmed in clinical samples of breast cancer, gastric cancer and colorectal cancer. Traditional chemotherapy drugs such as cisplatin, etoposide, 5-fluorouracil and paclitaxel can induce cell pyroptosis through the caspase-3 / GSDME pathway. However, it should be noted that after the administration of chemotherapy drugs or radiotherapy, normal cells (which often highly express GSDME) may also undergo pyroptosis, causing the body to produce an inflammatory response and damage the body. Therefore, targeted therapy for GSDME may help to effectively reduce the risk of damage to normal tissues caused by pyroptosis.

[0004] mTOR (mammalian target of rapamycin) is a highly conserved serine / threonine protein kinase with a molecular weight of 289 kDa, belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. mTOR can recruit other proteins and active factors to assemble into two types of mTOR complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is composed of mTOR, RAPTOR, mLST8 and two negative regulators PRAS40 and Deptor, and mTORC2 is composed of mTOR, Protor, Rictor, Deptor, mSlN1, and mLST8. mTORC1 and mTORC2 have different signal transduction roles in cells. mTORC1 integrates information about nutrient abundance and environmental status to regulate the balance of anabolism and catabolism in cells, which is related to cell growth, while mTORC2 controls cytoskeleton reorganization, regulates glucose metabolism, and is related to cell survival and proliferation.

[0005] mTOR is mainly involved in four signaling pathways, including PI3K / AKT / mTOR, Ras / MAPK / mTORC1, Ras / MAPK / mTORC1 and ULK-ATG13-FIP200 pathways. The occurrence and development of many diseases are related to abnormal mTOR signaling, most of which are manifested as overactivation or expression of mTOR. Continuous overactivation of mTOR signals will lead to increased cell metabolism, continuous growth and proliferation, prolonged cell lifespan and even cell immortalization, which can directly or indirectly induce cancer, metabolic and aging-related diseases. Inhibiting this state can effectively delay or treat diseases such as cancer and cardiovascular damage caused by overactivation of mTOR.

[0006] mTOR is at a key position in the tumor signaling pathway, and inhibitors targeting mTOR are widely used in targeted tumor therapy. Some scholars have analyzed a variety of human cancers and found that these cancers have abnormal PI3K / Akt / mTOR pathways. mTOR inhibitors have been shown to have considerable therapeutic prospects in a series of clinical studies targeting neuroendocrine tumors, renal cancer, breast cancer, etc. Summary of the invention

[0007] The purpose of the present invention is to provide a new application of mTOR inhibitors in drug preparation. By preparing a pharmaceutical composition containing an mTOR inhibitor, a novel pharmaceutical composition with synergistic effects is obtained, wherein the mTOR inhibitor in the pharmaceutical composition reduces the strong toxic effects of chemotherapy drugs on the body through the synergistic effect between drugs, and reduces the activation of pyroptosis of normal tissues by the chemical drugs, thereby reducing side effects.

[0008] In order to achieve the above object, the present invention provides the use of an mTOR inhibitor in the preparation of a combined anti-tumor pharmaceutical composition.

[0009] The present invention provides the use of an mTOR inhibitor in preparing a drug for preventing or treating side effects caused by an anti-tumor process.

[0010] The present invention provides the use of an mTOR inhibitor in preparing a drug for preventing or inhibiting cell pyroptosis caused by an anti-tumor process.

[0011] The present invention provides the use of an mTOR inhibitor in preparing a medicine for preventing or treating intestinal inflammation caused by an anti-tumor process.

[0012] In the present invention, the mTOR inhibitor refers to a preparation having mTOR inhibitory ability.

[0013] Preferably, the mTOR inhibitor comprises at least one of AZD-8055, rapamycin or rhamnosine.

[0014] Preferably, any of the above items has an effective concentration of AZD8055 of 0.5 μM to 5 μM; more preferably, it is 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 μM and ranges therebetween.

[0015] Preferably, in any of the above items, the effective concentration of rapamycin is 0.2 μM to 5 μM; more preferably, it is 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 μM and ranges therebetween.

[0016] Preferably, any of the above items has an effective concentration of emodin of 0.5 μM to 10 μM; more preferably, it is 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0 μM and ranges therebetween.

[0017] Preferably, any of the above items is that the side effect caused by the anti-tumor process is a side effect caused by cell pyroptosis caused by the anti-tumor process.

[0018] Preferably, any of the above items is that the side effect caused by the anti-tumor process is a side effect caused by normal cell pyroptosis caused by the anti-tumor process.

[0019] Preferably, any of the above items is that the pharmaceutical composition comprises an anti-tumor chemotherapy drug.

[0020] Preferably, any of the above items is that the anti-tumor chemotherapy drug comprises etoposide and / or cisplatin.

[0021] Preferably, in any of the above items, the effective concentration of Etoposide is preferably 30 μM to 100 μM; more preferably 30, 40, 50, 60, 70, 80, 90, 100 μM and ranges therebetween.

[0022] Preferably, in any of the above items, the effective concentration of Cisplatin is preferably 50 μM to 200 μM; more preferably 50, 70, 90, 100, 120, 140, 160, 180, 200 μM and ranges therebetween.

[0023] Preferably, any of the above items is that the administration route of the anti-tumor combination pharmaceutical composition includes at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration or transdermal administration.

[0024] Preferably, in any of the above items, the anti-tumor combination pharmaceutical composition is two separate preparations of the mTOR inhibitor and the anti-tumor chemotherapy drug; the two separate preparations are used for simultaneous, separate or sequential administration.

[0025] Preferably, in any of the above items, the tumor is a solid tumor.

[0026] Preferably, in any of the above items, the dosage form of the anti-tumor combination pharmaceutical composition includes any pharmaceutically acceptable dosage form.

[0027] The pharmaceutical composition for treating tumors obtained by the pharmaceutical use of the present invention combines the mTOR inhibitor with the chemotherapy drug, thereby reducing the toxic side effects of the chemotherapy drug alone on the body.

[0028] The present invention also provides an anti-tumor combined pharmaceutical composition prepared by any of the above applications.

[0029] The present invention is achieved on the basis of the following research findings:

[0030] 1. It was found that inhibiting mTOR function in normal colon epithelial cells (NCM460) reduced the killing of normal colon epithelial cells by chemotherapy drugs etoposide or cisplatin, the release of reactive oxygen species (ROS), and the inhibition of cell proliferation by reducing the level of pyroptosis in normal cells; inhibiting mTOR function in colon cancer cells (MC38) did not affect the inhibition of colon cancer cell proliferation by chemotherapy drugs etoposide or cisplatin.

[0031] 1) After treating normal colon epithelial cells with the small molecule inhibitor of mTOR AZD8055, rapamycin or emodin, they were treated with chemical drugs and the killing of colon epithelial cells, the production of reactive oxygen species (ROS) by colon epithelial cells, the proliferation of colon epithelial cells and the release of LDH were observed under a microscope. It was found that the proportion of pyroptotic cells was significantly reduced, the release of ROS was reduced, the inhibition of cell proliferation was reversed, and the release of LDH was significantly reduced.

[0032] 2) After treating colon cancer cells with the small molecule mTOR inhibitor AZD8055, rapamycin or emodin, they were treated with chemical drugs and the proliferation of colon cancer cells was observed under a microscope. It was found that AZD8055 treatment did not affect the inhibition of colon cancer cell proliferation by chemical drugs.

[0033] According to the above research on molecular mechanisms, the combined use of mTOR inhibitors and chemical treatment can negatively regulate the occurrence of cell pyroptosis and help reduce side effects such as intestinal damage caused by chemical drugs. The above molecular mechanism was verified by preclinical experiments using mouse models.

[0034] 2. It was found that in animal tumor-bearing models, compared with the use of etoposide or cisplatin alone, the combination of AZD8055 can significantly reduce the intestinal tissue damage induced by etoposide or cisplatin, but does not reverse the tumor damage induced by etoposide or cisplatin.

[0035] 1) AZD8055 was given to C57BL / 6 mice one hour before chemotherapy drugs were given, and the intestinal damage of the mice was observed. It was found that compared with chemotherapy drugs alone, the combination of AZD8055 and chemotherapy drugs could significantly reduce the intestinal tissue damage induced by chemotherapy drugs.

[0036] 2) In the C57BL / 6 mouse transplant tumor model, AZD8055 was given one hour before chemotherapy drugs, and the tumor growth of the mice was observed. It was found that compared with chemotherapy drugs alone, the combination of AZD8055 did not reverse the tumor killing effect of chemotherapy drugs.

[0037] The present invention has the following advantages:

[0038] 1) For the first time, it was discovered that inhibiting mTOR function through small molecule inhibitors can control inflammatory damage by reducing normal cell pyroptosis induced by chemotherapy drugs, while reducing damage to normal tissues of the body.

[0039] 2) For the first time, it was found that when mTOR inhibitors were used in combination with chemotherapy drugs, they did not reverse the chemotherapy-induced pyroptosis of tumor cells, nor did they reverse the damage of chemotherapy drugs to tumor tissues. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 In the preferred embodiment 1 of the present invention, in a normal colon epithelial cell line (NCM460 cells), mTOR function was inhibited by using an mTOR inhibitor and then treated with chemical drugs, and the release of LDH caused by the chemotherapeutic drugs was significantly reduced.

[0041] Figure 2 In the preferred embodiment 1 of the present invention, in a normal colon epithelial cell line (NCM460 cells), mTOR function was inhibited by using an mTOR inhibitor and then treated with chemical drugs, and the proportion of pyroptotic cells caused by chemotherapeutic drugs was significantly reduced.

[0042] Figure 3 In the preferred embodiment 1 of the present invention, in a normal colon epithelial cell line (NCM460 cells), mTOR function is inhibited by using an mTOR inhibitor and then treated with chemical drugs, and the release of reactive oxygen species caused by the chemotherapeutic drugs is reduced.

[0043] Figure 4In the preferred embodiment 1 of the present invention, in a normal colon epithelial cell line (NCM460 cells), mTOR function is inhibited by using an mTOR inhibitor and then treated with chemical drugs, and the cell proliferation inhibition caused by the chemotherapeutic drugs is reversed.

[0044] Figure 5 In the preferred embodiment 2 of the present invention, in the colon cancer cell line (MC38 cells), after the mTOR function is inhibited by using an mTOR inhibitor and then treated with chemical drugs, the cell proliferation inhibition caused by the chemotherapeutic drugs is not affected.

[0045] Figure 6 In the preferred embodiment 3 of the present invention, in the C57BL / 6 mouse model, when AZD8055 and chemical drugs were used in combination, reversal of small intestinal villus damage was observed in paraffin sections.

[0046] Figure 7 In the preferred embodiment 3 of the present invention, in the C57BL / 6 mouse transplant tumor model, the combination of AZD8055 and chemical drugs did not reverse the inhibitory effect of the chemical drugs on tumor growth. DETAILED DESCRIPTION

[0047] The present invention is further described in detail below through the accompanying drawings and specific embodiments. The test methods in the following examples are all conventional methods unless otherwise specified, and the experimental materials used are all commercially available products.

[0048] Test Materials:

[0049] Human normal colon epithelial cells NCM460; mouse colon cancer cells MC38; mouse melanoma cells B16; 8-week-old male C57BL / 6 mice were purchased from Liaoning Changsheng Experimental Animal Co., Ltd.

[0050] AZD8055, emodin, etoposide (ETO), cisplatin (CDDP), propidium iodide (PI), and cell proliferation (EdU) detection kit were purchased from Meilun Company, reactive oxygen species (ROS) detection kit and lactate dehydrogenase (LDH) detection kit were purchased from Beyotime Biotechnology Co., Ltd., and rapamycin (Rapamycin) was purchased from MCE.

[0051] Example 1

[0052] Example 1 Inhibition of mTOR using mTOR inhibitor AZD8055, rapamycin or emodin can significantly inhibit chemical-induced cell pyroptosis.

[0053] By pre-treating normal human colon epithelial cells (NCM460) with mTOR and then treating them with chemical drugs, it was found that the release of LDH in normal colon epithelial cells was reduced, the proportion of pyroptosis decreased, the release of reactive oxygen species was reduced, and the inhibition of cell proliferation was reversed.

[0054] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, AZD8055 (preferably at a concentration of 0.5μM to 5μM, more preferably 1μM) was added to the culture medium for pretreatment for 6 hours, and then treated with chemical drugs (preferably at a concentration of Etoposide 30μM to 100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, the supernatant was aspirated to detect the release of LDH. Compared with the treatment with chemical drugs alone, the release of LDH in the supernatant after the combination with AZD8055 was reduced ( Figure 1 ); Propidium iodide dye was added to statistically analyze the proportion of cells undergoing pyroptosis. Compared with the treatment with chemical drugs alone, the proportion of cells undergoing pyroptosis decreased after combined treatment with AZD8055 ( Figure 2 ).

[0055] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, rapamycin (preferably at a concentration of 0.2μM to 5μM, more preferably 0.2μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM to 100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, the supernatant was aspirated to detect the release of LDH. Compared with the treatment with chemical drugs alone, the release of LDH in the supernatant after the combination with rapamycin was reduced ( Figure 1 ); Propidium iodide dye was added, and the proportion of cells undergoing pyroptosis was statistically analyzed. Compared with the treatment with chemical drugs alone, the proportion of cells undergoing pyroptosis decreased after combined with rapamycin ( Figure 2 ).

[0056] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, emodin (preferably at a concentration of 0.5μM to 10μM, more preferably 1μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM to 100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, the supernatant was aspirated to detect the release of LDH. Compared with the treatment with chemical drugs alone, the release of LDH in the supernatant after the combination with emodin was reduced ( Figure 1). Propidium iodide dye was added to statistically analyze the proportion of cells that underwent pyroptosis. Compared with the treatment with chemical drugs alone, the combined use of emodin and chemical drugs also had the technical effect of reducing the proportion of cells that underwent pyroptosis ( Figure 2 ).

[0057] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, AZD8055 (preferably at a concentration of 0.5μM to 5μM, more preferably 1μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM-100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, ROS dye was added, and the proportion of cells producing reactive oxygen was statistically analyzed. Compared with the treatment with chemical drugs alone, the release of reactive oxygen species in cells after the combination with AZD8055 was reduced ( Figure 3 ).

[0058] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, Rapamycin (preferably at a concentration of 0.2μM to 5μM, more preferably 0.2μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM-100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, ROS dye was added, and the proportion of cells producing reactive oxygen was statistically analyzed. Compared with the treatment with chemical drugs alone, the release of reactive oxygen species in cells after the combination with Rapamycin was reduced ( Figure 3 ).

[0059] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, emodin (preferably at a concentration of 0.5μM-10μM, more preferably 1μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM-100μM; or Cisplatin 50μM-200μM) for 16 hours. After the drug treatment, ROS dye was added, and the proportion of cells producing reactive oxygen was statistically analyzed. Compared with the treatment with chemical drugs alone, the release of reactive oxygen species in cells after the combination with emodin was reduced ( Figure 3 ).

[0060] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, AZD8055 (preferably at a concentration of 0.5μM to 5μM, more preferably 1μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM to 100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, EdU dye was added, and the proportion of cell proliferation was statistically analyzed after incubation at 37°C for 2 hours. Compared with the treatment with chemical drugs alone, the inhibitory effect of cell proliferation after the combination with AZD8055 was reversed ( Figure 4 ).

[0061] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, Rapamycin (preferably at a concentration of 0.2μM to 5μM, more preferably 0.2μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM to 100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, EdU dye was added, and the proportion of cell proliferation was statistically analyzed after incubation at 37°C for 2 hours. Compared with the treatment with chemical drugs alone, the inhibitory effect of cell proliferation after the combination with Rapamycin was reversed ( Figure 4 ).

[0062] NCM460 cells were seeded in a 6-well plate. When the cell density was about 70-80%, emodin (preferably at a concentration of 0.5μM to 10μM, more preferably 1μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of Etoposide 30μM to 100μM; or Cisplatin 50μM to 200μM) for 16 hours. After the drug treatment, EdU dye was added, and the proportion of cell proliferation was statistically analyzed after incubation at 37°C for 2 hours. Compared with the treatment with chemical drugs alone, the inhibitory effect of cell proliferation after the combination with emodin was reversed ( Figure 4 ).

[0063] Example 2

[0064] In Example 2, by pre-treating mouse colon cancer cells (MC38) with mTOR and then treating with chemical drugs, it was found that cell proliferation inhibition and DNA damage of colon cancer cells were not affected.

[0065] MC38 cells were seeded in a 6-well plate. When the cell density was about 70-80%, AZD8055 (preferred concentration was 0.5μM-5μM, and further preferred concentration was 1μM) was added to the culture medium for pretreatment for 6 hours, and then treated with chemical drugs (preferred concentration of Etoposide was 30μM-100μM; or preferred concentration of Cisplatin was 50μM-200μM) for 16 hours. After the drug treatment, EdU dye was added, and the proportion of cell proliferation was statistically analyzed after incubation at 37°C for 2 hours. The effect of inhibiting cell proliferation was not affected ( Figure 5 ).

[0066] MC38 cells were seeded in a 6-well plate. When the cell density was about 70-80%, Rapamycin (preferably at a concentration of 0.2μM to 5μM, more preferably 0.2μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of 30μM to 100μM for Etoposide or 50μM to 200μM for Cisplatin) for 16 hours. After the drug treatment, EdU dye was added, and the proportion of cell proliferation was statistically analyzed after incubation at 37°C for 2 hours. The effect of inhibiting cell proliferation was not affected ( Figure 5 ).

[0067] MC38 cells were seeded in a 6-well plate. When the cell density was about 70-80%, etoposide (preferably at a concentration of 0.5 μM to 10 μM, more preferably 1 μM) was added to the culture medium for pretreatment for 6 hours, and then the cells were treated with chemical drugs (preferably at a concentration of 30 μM to 100 μM for Etoposide; or 50 μM to 200 μM for Cisplatin) for 16 hours. After the drug treatment, EdU dye was added, and the proportion of cell proliferation was statistically analyzed after incubation at 37°C for 2 hours. The effect of inhibiting cell proliferation was not affected ( Figure 5 ).

[0068] Example 3

[0069] Example 3 In animal models, when AZD8055 was used in combination with chemotherapy drugs, the combined drug therapy could significantly reduce the intestinal tissue damage induced by etoposide or cisplatin without reversing the killing effect of chemotherapy drugs on tumors.

[0070] AZD8055 was given to C57BL / 6 mice one hour before chemotherapy drugs were given, and the intestinal damage of the mice was observed. It was found that compared with chemotherapy drugs alone, the combination of AZD8055 and chemotherapy drugs could significantly reduce the intestinal tissue damage induced by chemotherapy drugs.

[0071] Eight-week-old male C57BL / 6 mice were randomly and evenly divided into 4 groups, with 8 mice in each group. The four groups were: 1) control treatment group; 2) AZD8055 alone group; 3) chemical drug alone group; 4) AZD8055 and chemical drug combination group. According to the grouping, AZD8055 was pretreated by intraperitoneal injection for one hour, and then the chemical drug was injected intraperitoneally. The dosage of AZD8055 was 10 mg / kg, the dosage of etoposide was 5 mg / kg, and the dosage of cisplatin was 10 mg / kg. The mice were given drugs every day, and the mice were killed after the physical condition of the mice showed a difference. The intestinal tissue of the mice was taken to make paraffin sections. Observation of the paraffin sections revealed that the damage to the intestinal villi in the small intestine was reduced in the combination group compared with the group using chemical drugs alone ( Figure 6 ).

[0072] In the C57BL / 6 mouse transplant tumor model, AZD8055 was given one hour before chemotherapy drugs, and the tumor growth of the mice was observed. It was found that compared with chemotherapy drugs alone, the combination of AZD8055 did not reverse the tumor killing effect of chemotherapy drugs.

[0073] Eight-week-old male C57BL / 6 mice were randomly and evenly divided into 4 groups, with 5 mice in each group. The four groups were: 1) control treatment group; 2) AZD8055 alone group; 3) chemical drug alone group; 4) AZD8055 and chemical drug combination group. Four days after tumor implantation, the mice were pretreated with AZD8055 by intraperitoneal injection for one hour, and then the chemical drug was injected intraperitoneally. The dosage of AZD8055 was 10 mg / kg, the dosage of etoposide was 5 mg / kg, and the dosage of cisplatin was 10 mg / kg, and they were given daily. According to the requirements of animal experiment ethics and experimental animal welfare, the volume of mouse tumors was greater than 2000mm 3 Or when the diameter of the tumor ulcer approaches 1 cm, the observation is terminated, that is, the mice are killed and assumed to be dead. From the experimental results, it can be seen that the combination therapy does not reverse tumor growth compared with the chemotherapy drug alone ( Figure 7 ).

[0074] The above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. Application of mTOR inhibitors in the preparation of anti-tumor combined pharmaceutical compositions.

2. The use according to claim 1, characterized in that: Use of mTOR inhibitors in the preparation of drugs for preventing or treating side effects caused by anti-tumor processes.

3. The use according to claim 2, characterized in that: The mTOR inhibitor includes at least one of AZD-8055, rapamycin or rhamnosine.

4. The use according to claim 3, characterized in that: The side effects caused by the anti-tumor process are side effects caused by normal cell pyroptosis caused by the anti-tumor process.

5. The use according to claim 4, characterized in that: The side effect is intestinal inflammation caused by the anti-tumor process.

6. The use according to claim 5, characterized in that: The pharmaceutical composition comprises an anti-tumor chemotherapy drug.

7. The use according to claim 6, characterized in that: The anti-tumor chemotherapy drugs include etoposide and / or cisplatin.

8. The use according to claim 7, characterized in that: The administration route of the anti-tumor combination pharmaceutical composition includes at least one of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, sublingual administration, nasal administration or transdermal administration.

9. The use according to claim 8, characterized in that: The anti-tumor combined pharmaceutical composition is two separate preparations of the mTOR inhibitor and the anti-tumor chemotherapy drug; the two separate preparations are used for simultaneous, separate or sequential administration.

10. An anti-tumor combined pharmaceutical composition prepared according to any one of claims 1 to 9.

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