CN116262137A - Anti-tumor combined drug capable of killing tumor and improving immune microenvironment simultaneously - Google Patents
Anti-tumor combined drug capable of killing tumor and improving immune microenvironment simultaneously Download PDFInfo
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Abstract
The invention discloses an anti-tumor combined medicament for simultaneously killing tumors and improving immune microenvironment for the first time, which comprises the following components in percentage by weight: the oncolytic medicine and glucocorticoid medicine as active ingredients are at least one of oncolytic peptides LTX-315, LTX-302, LTX-401 and DTT-304. The glucocorticoid medicine is at least one of dexamethasone, betamethasone, prednisone and prednisolone which are clinically used. Compared with single use of oncolytic drugs, the combined use of the oncolytic drugs and glucocorticoid anti-inflammatory drugs can effectively improve the tumor microenvironment, increase the number of cytotoxic CD8 positive T cells, exert better anti-tumor effect and reduce the recurrence rate after tumor resection, and the combined use of the oncolytic drugs has a significantly better curative effect than a single drug treatment group. The combined application anti-tumor strategy provided by the invention has a good application prospect for treating tumors.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a combined medicine capable of killing tumor cells and improving immunosuppressive microenvironment to enhance anti-tumor effect and application thereof, and in particular relates to an oncolytic medicine and a glucocorticoid medicine and application thereof.
Background
Cancer has become the second leading cause of death in humans, with tens of millions of cancer deaths worldwide each year, on average tens of thousands of people each day diagnosed with cancer, severely threatening human health. One of the main methods for treating malignant tumors is surgical excision, but incomplete tumor excision and circulation tumor cells in a patient can cause quite high postoperative recurrence rate, so that the survival period of the patient is greatly reduced. Therefore, effective cancer treatment methods and inhibition of postoperative tumor recurrence are current research hotspots.
Compared with the traditional treatment means of tumors, such as operation treatment, chemotherapy, radiotherapy and the like, the oncolytic therapy is a novel cancer treatment strategy with prospect, and the oncolytic therapy can exert stronger tumor inhibition and killing effects under the condition of not affecting normal cells, and simultaneously promote organisms to generate anti-tumor immune response through immune induction, so that the killing effect on tumor cells is further improved. As a novel tumor cell biological therapy, the oncolytic therapy has the characteristics of high efficiency, good killing effect, targeted therapy and the like. However, its single use is not limited by the safety issues of this therapy.
Relieving local inflammatory reaction of tumor, and improving immunity, and has inhibiting effect on tumor generation and growth. Many studies have shown that inflammation exists at various stages of the tumor, and chronic inflammation is beneficial to the occurrence of gene mutation, thus increasing the incidence of the tumor; inflammatory factors released by immune cells and inflammatory cells can reduce apoptosis of tumor cells and promote angiogenesis, thereby facilitating mass growth and propagation of the tumor cells, and even promoting metastasis of the tumor to a systemic target organ in the later stage. Therefore, the anti-inflammatory drug can enlarge the light in the aspects of inhibiting the occurrence, growth and metastasis of tumors, reducing the drug resistance of chemotherapy and improving the survival rate of cancer patients. For example, dexamethasone has been reported to greatly improve the efficacy of platinum and gemcitabine-based chemotherapeutics in the treatment of colon, lung and breast cancers, and the like.
Currently, oncolytic drugs are not ideal for their final tumor treatment effect due to their inherent immunogenicity and limited therapeutic capabilities alone. Therefore, the combined medicine of the oncolytic medicine and the glucocorticoid medicine is developed to directly kill tumor cells, promote the organism to generate anti-tumor immune response, improve local inflammation and immune microenvironment, play high-efficiency anti-tumor activity, reduce treatment risk and have wide application and development prospect.
Disclosure of Invention
In order to solve the problems of low safety and limited treatment capacity of the existing oncolytic therapy, the invention provides a combined treatment strategy, and the combined glucocorticoid medicaments can improve the microenvironment of the tumor growth part, inhibit the growth and metastasis of the tumor, increase the curative effect of the oncolytic medicament and reduce the adverse reaction of the oncolytic medicament.
One of the purposes of the invention is to overcome the defects and shortcomings of the existing oncolytic drugs, and combine oncolytic treatment with anti-inflammatory treatment, and provide a strategy for combining oncolytic drugs with glucocorticoid drugs for anti-tumor use.
Another object of the invention is to provide the use of oncolytic and glucocorticoid-like drugs in the manufacture of an antitumor combination. The combined use of the oncolytic medicine and the glucocorticoid medicine can directly kill tumor cells to cause organism immune response, and the combined use of the glucocorticoid anti-inflammatory medicine can improve tumor immune inhibition microenvironment, thereby obviously improving the anti-tumor effect of the medicine.
The aim of the invention is achieved by the following technical scheme: a combined medicine for killing tumor cells and improving the immunosuppression microenvironment to increase the anti-tumor effect contains oncolytic medicine and glucocorticoid medicine as active components.
The combined medicament capable of killing tumor cells and improving immunosuppressive microenvironment to enhance anti-tumor effect can also contain one or at least two pharmaceutically acceptable carriers.
The glucocorticoid anti-inflammatory drug is at least one selected from dexamethasone, betamethasone, prednisone and prednisolone, and is preferably dexamethasone.
The oncolytic medicine is at least one of oncolytic peptides LTX-315, LTX-302, LTX-401 and DTT-304, preferably LTX-315 peptide, and the chemical structure of the LTX-315 peptide is as follows:
the tumor comprises breast cancer, liver cancer, lung cancer, colon cancer, nasopharyngeal carcinoma, bladder cancer, cervical cancer, esophageal cancer, gastric cancer and prostatic cancer; breast cancer is preferred. Including failed and/or recurrent tumors treated by chemotherapeutic drugs, failed and/or recurrent tumors treated by radiotherapy, failed and/or recurrent tumors treated by targeted drugs.
The effective concentration of the oncolytic medicine is 10-500 uM, and the content of the active ingredients of the anti-inflammatory medicine is 0.1-100 mg/kg.
The invention adds the oncolytic medicine and the glucocorticoid anti-inflammatory medicine into the tumor at the same time, or treats the tumor with the oncolytic medicine before adding the glucocorticoid anti-inflammatory medicine, or treats the tumor with the glucocorticoid anti-inflammatory medicine before adding the oncolytic medicine.
The combined use of the oncolytic medicine and the glucocorticoid anti-inflammatory medicine can improve tumor inflammation and immune microenvironment, and effectively kill tumor cells, thereby inhibiting the progress of tumors.
The combined administration of the oncolytic medicine and the glucocorticoid anti-inflammatory medicine can obviously cause infiltration of CD8 positive T cells at tumor parts, reduce adverse reactions while improving inflammation and immunosuppression microenvironment, improve anti-tumor effect and realize combination of oncolytic and anti-inflammatory treatment.
Compared with the prior art, the invention has the following advantages and effects:
(1) The invention provides a combined medicament capable of killing tumor cells and improving immunosuppressive microenvironment to enhance anti-tumor effect, on one hand, the oncolytic medicament can directly and effectively kill the tumor cells in vivo, and on the other hand, the combined glucocorticoid anti-inflammatory medicament can inhibit the release of inflammatory factors and improve tumor microenvironment. Starting from the two aspects, the anti-tumor drug has good tumor inhibition effect, and compared with the single use of the anti-tumor drug, the anti-tumor drug has better anti-tumor effect;
(2) Compared with the oncolytic therapy currently in clinical trials, the combined treatment scheme of the invention can effectively reduce adverse reactions and reduce treatment risks;
the combined medicament capable of killing tumor cells and improving immunosuppressive microenvironment to enhance anti-tumor effect simultaneously has good inhibition effect on common tumors, and can play a good inhibition effect on failed and/or recurrent tumors treated by chemotherapy medicaments, failed and/or recurrent tumors treated by radiotherapy and/or recurrent tumors treated by targeted medicaments after tumor surgical excision.
Drawings
FIG. 1 shows a ratio diagram of the case where flow cytometry detects that the oncolytic peptide LTX-315 peptide causes the expression of calreticulin by 4T1 cells;
FIG. 2 shows a ratio map of flow cytometry detection of oncolytic peptide LTX-315 peptides to induce apoptosis of 4T1 cells;
FIG. 3 shows a ratio graph of flow cytometry detection of relapsed intratumoral T lymphocytes following surgery in mice;
FIG. 4 shows a graph of the ratio of bone marrow-derived suppressor cells in a flow cytometry detection post-operative recurrence in mice;
FIG. 5 shows a graph of the ratio of the intracellular cyclooxygenase 2 content of recurrent tumor cells after flow cytometry detection in mice;
FIG. 6 shows a graph of prostaglandin E2 content ratio in a recurrent tumor after flow cytometry detection in mice;
FIG. 7 shows a graph of the ratio of tumor-associated macrophages in tumor cells of a flow cytometric test mouse post-operatively recurrent tumor;
figure 8 shows a graph of the volume increase of recurrent tumors after tumor resection in mice of different treatment groups.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. The present invention is further illustrated in detail below with reference to examples, which are provided only to illustrate the present invention and are not intended to limit the scope of the present invention. Moreover, it will be understood by those skilled in the art that various changes and modifications in detail and form of the present invention may be made without departing from the spirit and scope of the invention, but such changes and modifications are to be included within the scope of the invention.
EXAMPLE 1 flow cytometry detection of LTX-315 peptide causing expression of calreticulin by 4T1 cells
4T1 cells were seeded at 8000 cells/well in 12-well plates, placed in a cell incubator to adhere and grown for 24h. Experiments were performed in a control group and LTX-315 peptide group:
control group: 2ml of RPM 1640 medium (containing 10% FBS) was added;
LTX-315 peptide group: 2ml of RPMI1640 medium containing LTX-315 peptide (containing 10% FBS) at a concentration of 50uM was added, and after co-incubation for 4 hours, the above-mentioned medicated medium was aspirated, and after washing gently twice with phosphate buffer (pH 7.4), normal RPMI1640 medium (containing 10% FBS) was added.
After 24h incubation, the cells were washed 2 times with phosphate buffer (pH 7.4), blocked with 5% blocking serum, and incubated with anti-calreticulin goat anti-rabbit primary antibody for 1h at room temperature. After that, the cells were washed 2 times with phosphate buffer (pH 7.4), and incubated with the corresponding AF647 fluorescent-labeled goat anti-rabbit antibody for 40min, followed by washing 2 times with phosphate buffer (pH 7.4). Finally, the cells positive for calreticulin on the surface of the cell membrane are measured by flow cytometry in a phosphate buffer (pH 7.4) and the results are shown in figure 1 of the accompanying drawings.
As can be seen from FIG. 1, the control group had a low expression rate of calreticulin cells, whereas administration of LTX-315 peptide induced strong calreticulin expression, up to about 80%.
Example 2 flow cytometry to examine the ability of LTX-315 peptides to cause apoptosis of 4T1 cells
4T1 cells were seeded at 8000 cells/well in 12-well plates, placed in a cell incubator to adhere and grown for 24h. Experiments were performed in a control group and LTX-315 peptide group:
control group: 2ml of RPM 1640 medium (containing 10% FBS) was added;
LTX-315 peptide group: 2ml of RPMI1640 medium containing LTX-315 peptide (containing 10% FBS) at a concentration of 50uM was added, and after co-incubation for 4 hours, the above-mentioned medicated medium was aspirated, and after washing gently twice with phosphate buffer (pH 7.4), normal RPMI1640 medium (containing 10% FBS) was added.
After 24h incubation, cells from the supernatant were collected, digested with 0.25% pancreatin and the adherent 4T1 cells were collected, the two parts of cells were pooled, after which the cells were stained according to the method of Annexin V-FITC/PI apoptosis detection kit, after which the apoptosis results were detected with a flow cytometer. The results are shown in figure 2 of the drawings.
FIG. 2 shows that the oncolytic peptide LTX-315 peptide can induce a large number of apoptosis, with an apoptosis rate (early apoptosis+late apoptosis) as high as 92%.
EXAMPLE 3 flow cytometry detection of the number of T lymphocytes in recurrent tumor following tumor resection in mice
4T1 cells were cultured in RPMI1640 medium (containing 10% FBS) with 5% (v/v) CO 2 Cells were incubated in a 37℃cell incubator with 0.25% pancreatin (0.02% EDTA) to digest 4T1 cells, washed 2 times with phosphate buffer (pH 7.4) and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 4X 10 6 /ml. A50 ul cell suspension was inoculated with a sterile syringe on the pad of Balb/c mice (7-8 weeks old, purchased from Sichuan Biotech Co., ltd.). The vernier caliper measures the long diameter (a) and the short diameter (b) of the transplanted tumor, and the tumor volume (V) is calculated by the formula: v=a×b 2 /2. To grow up to 200 mm 3 At this time, mice were randomly divided into 4 groups of 6 mice each.
Tumor resection in mice was performed with different drugs given simultaneously according to the group:
1) Control group: administering physiological saline 100 ul to the tumor surgical resection site;
2) Dexamethasone group: administering 100 ul dexamethasone solution (concentration 10 mg/kg) to the tumor surgical resection site;
3) Oncolytic peptide LTX-315 is prepared to obtain a tumor cell vaccine group: 100 ul physiological saline (containing 5×10) is administered to tumor surgical excision site 5 A cell vaccine);
4) Combination group of dexamethasone and tumor cell vaccine prepared from oncolytic peptide LTX-315: 100 ul aqueous solution (containing dexamethasone 10 mg/kg and 5×10) was administered to the tumor surgical resection site 5 Individual cell vaccine).
Mice were sacrificed 15 days later, the postoperative recurrent tumors were removed and ground and passed through a 40 um cell screen to give the corresponding single cell suspensions. The cell suspension was first incubated with anti-16/32 antibody at 4℃for 20 min and cells were collected by centrifugation. Cells were resuspended in 1% BSA phosphate buffer containing anti-CD3-FITC, anti-CD8a-APC and incubated for 60min at 4 ℃. The cells were resuspended in phosphate buffer (pH 7.4) and the anti-CD 3-FITC-labeled T lymphocytes and CD8a expressed on the surface of the T lymphocytes were assayed by flow cytometry 2 times with phosphate buffer (pH 7.4) and the results are shown in FIG. 3.
Example 4 flow cytometry detection of bone marrow-derived suppressor cell numbers in recurrent tumors following tumor resection in mice
4T1 cells were cultured in RPMI1640 medium (containing 10% FBS) in a cell culture incubator containing 5% (v/v) CO2 at 37℃and then 4T1 cells were digested with 0.25% pancreatin (containing 0.02% EDTA), washed 2 times with phosphate buffer (pH 7.4) and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 4X 10 6 /ml. A50 ul cell suspension was inoculated with a sterile syringe on the pad of Balb/c mice (7-8 weeks old, purchased from Sichuan Biotech Co., ltd.). The vernier caliper measures the long diameter (a) and the short diameter (b) of the transplanted tumor, and the tumor volume (V) is calculated by the formula: v=a×b 2 /2. To grow up to 200 mm 3 At this time, mice were randomly divided into 4 groups of 6 mice each.
Tumor resection in mice was performed with different drugs given simultaneously according to the group:
1) Control group: administering physiological saline 100 ul to the tumor surgical resection site;
2) Dexamethasone group: administering 100 ul dexamethasone solution (concentration 10 mg/kg) to the tumor surgical resection site;
3) Oncolytic peptide LTX-315 is prepared to obtain a tumor cell vaccine group: in tumor100 ul physiological saline (containing 5×10) was administered to the site of surgical resection 5 A cell vaccine);
4) Combination group of dexamethasone and tumor cell vaccine prepared from oncolytic peptide LTX-315: 100 ul aqueous solution (containing dexamethasone 10 mg/kg and 5×10) was administered to the tumor surgical resection site 5 Individual cell vaccine).
Mice were sacrificed 15 days later, the postoperative recurrent tumors were removed and ground and passed through a 40 um cell screen to give the corresponding single cell suspensions. The cell suspension was first incubated with anti-16/32 antibody at 4℃for 20 min and cells were collected by centrifugation. Cells were resuspended in phosphate buffer containing anti-CD11b-FITC, anti-Gr1-APC and incubated for 60min at 4deg.C. The cells were resuspended in phosphate buffer (pH 7.4) and the flow cytometry was used to determine CD11b and Gr1 expression on the surface of tumor cells, as shown in FIG. 4, after 2 washes with phosphate buffer (pH 7.4).
FIG. 4 shows that the tumor cell vaccine prepared from dexamethasone and the oncolytic peptide LTX-315 can greatly reduce the number of myeloid-derived suppressor cells in tumors, and the effect is obviously better than that of a single drug group.
Example 5 flow cytometry detection of expression of cyclooxygenase in recurrent tumor cells following tumor resection in mice
4T1 cells were cultured in RPMI1640 medium (containing 10% FBS) in a cell culture incubator containing 5% (v/v) CO2 at 37℃and then 4T1 cells were digested with 0.25% pancreatin (containing 0.02% EDTA), washed 2 times with phosphate buffer (pH 7.4) and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 4X 10 6 /ml. A50 ul cell suspension was inoculated with a sterile syringe on the pad of Balb/c mice (7-8 weeks old, purchased from Sichuan Biotech Co., ltd.). The vernier caliper measures the long diameter (a) and the short diameter (b) of the transplanted tumor, and the tumor volume (V) is calculated by the formula: v=a×b 2 /2. To grow up to 200 mm 3 At this time, mice were randomly divided into 4 groups of 6 mice each.
Tumor resection in mice was performed with different drugs given simultaneously according to the group:
1) Control group: administering physiological saline 100 ul to the tumor surgical resection site;
2) Dexamethasone group: administering 100 ul dexamethasone solution (concentration 10 mg/kg) to the tumor surgical resection site;
3) Oncolytic peptide LTX-315 is prepared to obtain a tumor cell vaccine group: 100 ul physiological saline (containing 5×10) is administered to tumor surgical excision site 5 A cell vaccine);
4) Combination group of dexamethasone and tumor cell vaccine prepared from oncolytic peptide LTX-315: 100 ul aqueous solution (containing dexamethasone 10 mg/kg and 5×10) was administered to the tumor surgical resection site 5 Individual cell vaccine).
Mice were sacrificed 15 days later, the postoperative recurrent tumors were removed and ground and passed through a 40 um cell screen to give the corresponding single cell suspensions. The cell suspension was first incubated with Triton-X at 4℃for 30min, washed 2 times, and then added with blocking serum to incubate with the cells for 30min, and the cells were collected by centrifugation. Cells were resuspended in phosphate buffer containing anti-COX-2 and incubated at 4℃for 60 min. After washing 3 times with phosphate buffer (pH 7.4) and incubating the cells with AF647 fluorescent-labeled goat anti-rabbit antibody for 60min, washing 3 times, resuspending the cells in phosphate buffer (pH 7.4), and measuring the expression of COX-2 in tumor cells by flow cytometry, the results are shown in FIG. 5.
FIG. 5 shows that dexamethasone in combination with tumor cell vaccine prepared from oncolytic peptide LTX-315 can significantly reduce the expression of cyclooxygenase in tumor cells of recurrent tumor after tumor resection in mice, and the postoperative inflammatory environment is relieved.
Example 6 Elisa kit for detecting prostaglandin E2 expression in recurrent tumors after tumor resection in mice
4T1 cells were cultured in RPMI1640 medium (containing 10% FBS) in a cell culture incubator containing 5% (v/v) CO2 at 37℃and then 4T1 cells were digested with 0.25% pancreatin (containing 0.02% EDTA), washed 2 times with phosphate buffer (pH 7.4) and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 4X 10 6 /ml. Balb/c mice (7 to 8 weeks old, purchased from Sichuan Chengdu Biotech Co., ltd.) were injected with a sterile syringeIs inoculated with 50ul of cell suspension. The vernier caliper measures the long diameter (a) and the short diameter (b) of the transplanted tumor, and the tumor volume (V) is calculated by the formula: v=a×b 2 /2. To grow up to 200 mm 3 At this time, mice were randomly divided into 4 groups of 6 mice each.
Tumor resection in mice was performed with different drugs given simultaneously according to the group:
1) Control group: administering physiological saline 100 ul to the tumor surgical resection site;
2) Dexamethasone group: administering 100 ul dexamethasone solution (concentration 10 mg/kg) to the tumor surgical resection site;
3) Oncolytic peptide LTX-315 is prepared to obtain a tumor cell vaccine group: 100 ul physiological saline (containing 5×10) is administered to tumor surgical excision site 5 A cell vaccine);
4) Combination group of dexamethasone and tumor cell vaccine prepared from oncolytic peptide LTX-315: 100 ul aqueous solution (containing dexamethasone 10 mg/kg and 5×10) was administered to the tumor surgical resection site 5 Individual cell vaccine).
Mice were sacrificed 15 days later, the postoperative recurrent tumors were removed and ground and passed through a 40 um cell screen to give the corresponding single cell suspensions. The cell suspensions obtained by grinding were centrifuged, and after correction according to the tumor weight, the same amount of supernatant was used to determine the level of PGE2 in tumor by the method of PGE2 Elisa kit, and the results are shown in FIG. 6. FIG. 6 shows that dexamethasone in combination with tumor cell vaccine prepared from oncolytic peptide LTX-315 can significantly reduce prostaglandin E2 expression in recurrent tumors after tumor resection in mice, and this result further demonstrates that the postoperative inflammatory environment in mice is relieved.
Example 7 flow cytometry detection of tumor-associated macrophage content in recurrent tumor following tumor resection in mice
4T1 cells were cultured in RPMI1640 medium (containing 10% FBS) in a cell culture incubator containing 5% (v/v) CO2 at 37℃and then 4T1 cells were digested with 0.25% pancreatin (containing 0.02% EDTA), washed 2 times with phosphate buffer (pH 7.4) and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 4X 10 6 /ml. By using nothingThe bacterial syringes were inoculated with 50ul of cell suspension on the pads of Balb/c mice (7-8 weeks old, purchased from Sichuan Chengdu Biotech Co., ltd.). The vernier caliper measures the long diameter (a) and the short diameter (b) of the transplanted tumor, and the tumor volume (V) is calculated by the formula: v=a×b 2 /2. To grow up to 200 mm 3 At this time, mice were randomly divided into 4 groups of 6 mice each.
Tumor resection in mice was performed with different drugs given simultaneously according to the group:
1) Control group: administering physiological saline 100 ul to the tumor surgical resection site;
2) Dexamethasone group: administering 100 ul dexamethasone solution (concentration 10 mg/kg) to the tumor surgical resection site;
3) Oncolytic peptide LTX-315 is prepared to obtain a tumor cell vaccine group: 100 ul physiological saline (containing 5×10) is administered to tumor surgical excision site 5 A cell vaccine);
4) Combination group of dexamethasone and tumor cell vaccine prepared from oncolytic peptide LTX-315: 100 ul aqueous solution (containing dexamethasone 10 mg/kg and 5×10) was administered to the tumor surgical resection site 5 Individual cell vaccine).
Mice were sacrificed 15 days later, the postoperative recurrent tumors were removed and ground and passed through a 40 um cell screen to give the corresponding single cell suspensions. The cell suspension was first incubated with anti-16/32 antibody at 4℃for 20 min and cells were collected by centrifugation. Cells were resuspended in phosphate buffer containing anti-CD11b-PE, anti-F4/80-FITC and incubated for 60min at 4 ℃. The cells were resuspended in phosphate buffer (pH 7.4) and the flow cytometry assayed for CD11b and F4/80 expression on the tumor cell surface as shown in FIG. 7.
FIG. 7 shows that dexamethasone in combination with tumor cell vaccine prepared from oncolytic peptide LTX-315 can effectively reduce the proportion of tumor-associated macrophages in a recurrent tumor after tumor resection in mice, thereby improving the immune environment and inhibiting tumor growth.
EXAMPLE 8 Effect of dexamethasone on the volume of recurrent tumor after murine tumor resection in combination with tumor cell vaccine prepared from the oncolytic peptide LTX-315
4T1 cells were cultured in RPMI1640 medium (containing 10% FBS) in a cell culture incubator containing 5% (v/v) CO2 at 37℃and then 4T1 cells were digested with 0.25% pancreatin (containing 0.02% EDTA), washed 2 times with phosphate buffer (pH 7.4) and counted. The cells were resuspended in sterile phosphate buffer (pH 7.4) to adjust the cell density to 4X 10 6 /ml. A50 ul cell suspension was inoculated with a sterile syringe on the pad of Balb/c mice (7-8 weeks old, purchased from Sichuan Biotech Co., ltd.). The vernier caliper measures the long diameter (a) and the short diameter (b) of the transplanted tumor, and the tumor volume (V) is calculated by the formula: v=a×b 2 /2. To grow up to 200 mm 3 At this time, mice were randomly divided into 4 groups of 6 mice each.
Tumor resection in mice was performed with different drugs given simultaneously according to the group:
1) Control group: administering physiological saline 100 ul to the tumor surgical resection site;
2) Dexamethasone group: administering 100 ul dexamethasone solution (concentration 10 mg/kg) to the tumor surgical resection site;
3) Oncolytic peptide LTX-315 is prepared to obtain a tumor cell vaccine group: 100 ul physiological saline (containing 5×10) is administered to tumor surgical excision site 5 A cell vaccine);
4) Combination group of dexamethasone and tumor cell vaccine prepared from oncolytic peptide LTX-315: 100 ul aqueous solution (containing dexamethasone 10 mg/kg and 5×10) was administered to the tumor surgical resection site 5 Individual cell vaccine).
And simultaneously recording the recurrence condition of the tumor, measuring the long diameter (a) and the short diameter (b) of the metastatic tumor by using a vernier caliper, and calculating the tumor volume (V), wherein the formula is as follows: v=a×b 2 /2. The results are shown in FIG. 8.
The result shows that the combined use of dexamethasone and the tumor cell vaccine prepared from the oncolytic peptide LTX-315 can reduce the tumor recurrence rate after the tumor resection of the mice and reduce the volume of the recurrence tumor, and the method combines oncolytic treatment and anti-inflammatory treatment, thereby providing a new treatment idea for preventing postoperative tumor recurrence.
Claims (7)
1. An anti-tumor combined medicament for simultaneously killing tumors and improving immune microenvironment, which is characterized in that: comprising as active ingredients an oncolytic agent and a glucocorticoid anti-inflammatory agent, said combination being applied in anti-tumor therapy.
2. The combination of claim 1, wherein the combination is capable of killing tumor cells and improving immunosuppressive microenvironment to enhance anti-tumor effects, and is characterized by: the oncolytic medicine is at least one of oncolytic peptide LTX-315, LTX-302, LTX-401 and DTT-304.
3. The combination drug oncolytic therapy capable of killing tumor cells and improving immunosuppressive microenvironment to enhance anti-tumor effects according to claim 1, wherein the glucocorticoid drug is at least one of dexamethasone, betamethasone, prednisone and prednisolone.
4. The anti-tumor combination therapy according to claim 1, wherein the tumor comprises melanoma, liver cancer, lung cancer, breast cancer, colon cancer, nasopharyngeal cancer, bladder cancer, cervical cancer, esophageal cancer, stomach cancer and prostate cancer.
5. The anti-tumor combination therapy according to claim 4, wherein the tumor is a failed and/or recurrent tumor treated with a chemotherapeutic, a failed and/or recurrent tumor treated with a radiation, a failed and/or recurrent tumor treated with a targeted drug;
the anti-tumor combination therapy according to claim 1, wherein the anti-cancer composition is placed intratumorally or peritumorally.
6. Application of oncolytic medicine and glucocorticoid medicine in preparing antineoplastic medicine.
7. The use of an oncolytic drug and a glucocorticoid drug in the manufacture of an antitumor combination according to claim 7, wherein: the oncolytic medicine and the glucocorticoid medicine are used as active ingredients.
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