Application of composition of Tepoxalin and taxus medicines in treatment of solid tumors

Abstract

The invention relates to the technical field of biological medicines, and discloses application of a composition of Tepoxalin and taxus medicines in treatment of solid tumors. According to the application, it is proposed for the first time that the combination of Tepoxalin and the taxus medicines can be used for treating the generic solid tumors, it is proved that Tepoxalin can significantly improve the effect of the taxus medicines, and adverse reactions of the taxus medicines are reduced by reducing the concentration of the taxus medicines. The PTCs model is used for simulating the tumor microenvironment, and the drug screening result and the clinical result have high correlation. According to the invention, a plurality of solid tumor PTC models are constructed, and the effect of inhibiting the progress of the generic solid tumor by single use of Tepoxalin and combination of Tepoxalin and paclitaxel is detected by detecting the area of PTC, the ATP content and other indexes. Results show that the development of various solid tumors can be effectively inhibited by combining the Tepoxalin with the paclitaxel, and adverse reactions of organisms can be reduced due to the reduction of the dosage of the paclitaxel, so that the Tepoxalin has a relatively great clinical application prospect.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to application of a combination of Tepoxalin and taxane drugs in treating solid tumors. Background Art

[0002] Paclitaxel is a broad-spectrum anti-tumor drug that has been widely used in the treatment of various solid tumors such as lung cancer, breast cancer and ovarian cancer. Although paclitaxel has good therapeutic effects, its complex and diverse adverse reactions limit its use to a certain extent. In addition, the commonly used combination regimens of paclitaxel in clinical practice include anthracyclines, platinum drugs, targeted drugs or immunotherapy drugs, which are often used to increase its efficacy. The paclitaxel dose is not significantly reduced, and the combination drugs also have certain toxic side effects, so the combination regimen will still have more serious adverse reactions.

[0003] In recent years, with the development of various drug screening technologies and the popularization of the concept of new uses for old drugs, people are paying more and more attention to other indications of existing compounds. Many in vivo and in vitro studies have shown that some cyclooxygenase (COX) inhibitors such as meloxicam and celecoxib can inhibit tumor progression to a certain extent when used alone or in combination in addition to their anti-inflammatory effects, and have fewer toxic side effects. Therefore, the combination of COX inhibitors and paclitaxel may be able to enhance the efficacy while reducing adverse reactions, which is a potential combination drug development strategy.

[0004] At present, the research on the anti-tumor effect of COX inhibitors is often focused on drugs that have been marketed. In fact, there are many COX inhibitors that have passed Phase I clinical trials but failed to pass subsequent clinical trials. Although they cannot effectively inhibit inflammation, they have good safety and have broad prospects for the development of anti-tumor drugs. Summary of the invention

[0005] The purpose of the present invention is to provide a combination of Tepoxalin and taxane drugs for use in treating solid tumors, so as to solve the problem that the existing paclitaxel combination regimen has multiple toxic side effects.

[0006] To achieve the above object, the present invention provides the following technical solution: use of a combination of Tepoxalin and taxanes in the treatment of solid tumors.

[0007] In a specific embodiment, the solid tumor includes lung cancer, brain cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, liver cancer, kidney cancer, stomach cancer, head and neck cancer, ovarian cancer, esophageal cancer, pancreatic cancer, and osteosarcoma.

[0008] In a specific embodiment, the taxane is paclitaxel.

[0009] In a specific embodiment, the concentration ratio of the taxane to Tepoxalin is 1:1-1000.

[0010] In a specific embodiment, Tepoxalin was purchased from MCE Company with a CAS number of 103475-41-8; Paclitaxel was purchased from Selleck Company with a CAS number of 33069-62-4.

[0011] In a specific embodiment, the dosage form of the composition is one of capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment and suppository.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention proposes for the first time that Tepoxalin and taxanes can be used in combination for the treatment of pan-solid tumors. The present invention proves that Tepoxalin can significantly improve the effect of taxanes and reduce their adverse reactions by reducing the concentration of taxanes. The present invention uses the PTCs model to simulate the tumor microenvironment, and the drug screening results are highly correlated with the clinical results. The present invention constructs a variety of solid tumor PTC models, and detects the effect of Tepoxalin alone and in combination with paclitaxel in inhibiting the progression of pan-solid tumors by detecting indicators such as the area and ATP content of PTC. The results show that Tepoxalin combined with paclitaxel can effectively inhibit the progression of a variety of solid tumors. Due to the reduction in the dose of paclitaxel, the adverse reactions of the organism will also be reduced, and it has great application prospects in clinical practice. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 The normalized result is the ratio of the area of ​​ovarian cancer PTCs on the 7th day after drug treatment in Example 1 of the present invention to that without drug treatment;

[0015] Figure 2 This is the normalized result of the ATP signal value after 7 days of drug treatment in Example 1 of the present invention;

[0016] Figure 3 The normalized result is the ratio of the area of ​​lung cancer PTCs on the 7th day after drug treatment in Example 2 of the present invention to that without treatment;

[0017] Figure 4 This is the normalized result of the ATP signal value after 7 days of drug treatment in Example 2 of the present invention.

[0018] In the figure, ns means that there is no significant difference between the two groups after statistical analysis; ** means that there is a significant difference between the two groups after statistical analysis, P<0.01; **** or #### means that there is a significant difference between the two groups after statistical analysis, P<0.0001. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0020] Patient-Derived Tumor-Like Cell Cluster (PTC), referred to as microtumor or microtumor PTC, is a new type of primary 3D tumor model. The model maintains a high degree of similarity with the original tumor tissue in terms of pathological histological characteristics and molecular genetic characteristics. At the same time, the model retains the fibroblasts and immune cells in the original tumor tissue during the culture process, thereby highly restoring the microenvironment characteristics of the original tumor tissue. The microtumor PTC model can be widely used in the fields of basic scientific research on tumors, precision treatment, and new drug development.

[0021] Example 1

[0022] The application of the combination of Tepoxalin and taxanes in the treatment of solid tumors is as follows:

[0023] (1) Grouping and treatment: After digestion, the tumor samples were cultured in a special culture medium for PTCs to obtain PTCs. After a period of growth, PTCs with a diameter greater than 40 μm were evenly spotted on a Genex Health 100-well plate (purchased from Beijing Cornerstone Life Science Co., Ltd.), with about 30-50 PTCs in each well. They were then divided into a negative control group, a paclitaxel group (0.75 μM), a tepoxalin group (20 μM), and a paclitaxel (0.75 μM) + tepoxalin (20 μM) group, with three replicates in each group. The corresponding drugs were added on the day of spotting and treated for seven days.

[0024] (2) Evaluation of PTCs area: Before and seven days after drug treatment, the area of ​​PTCs in each group was measured using the analysis software provided by the microscope, and the ratio of the average area of ​​PTCs in each group after drug treatment was obtained, and then the normalized result was obtained by comparing it with the control group. Figure 1 As shown, Tepoxalin or paclitaxel alone could not effectively inhibit the growth of PTCs, while the combination of the two could significantly inhibit the growth of PTCs. The results showed that Tepoxalin combined with paclitaxel can effectively inhibit the progression of ovarian cancer.

[0025] (3) Evaluation of PTCs activity: ATP is an indicator of living cell metabolism and often reflects the number of living cells. Seven days after drug treatment, the CellTiter-Glo detection kit (purchased from Promega Biotech Co., Ltd.) was used to detect the fluorescence signal value generated by ATP to reflect the activity of PTCs, and the signal value was normalized relative to the control group. The results are shown in Figure 2 As shown, Tepoxalin or paclitaxel alone could not effectively inhibit the activity of PTCs, but the combination of the two could significantly kill PTCs. The results showed that when paclitaxel alone was ineffective, Tepoxalin combined with paclitaxel could effectively inhibit the progression of ovarian cancer.

[0026] Example 2

[0027] The application of the combination of Tepoxalin and taxanes in the treatment of solid tumors is as follows:

[0028] (1) Grouping and treatment: After digestion, the tumor samples were cultured in a PTC-specific culture medium to obtain PTCs. After a period of growth, PTCs with a diameter greater than 40 μm were evenly spotted on a Genex Health 100-well plate, with about 30-50 PTCs in each well. They were then divided into a negative control group, a paclitaxel group (0.75 μM), a Tepoxalin group (20 μM), and a paclitaxel (0.75 μM) + Tepoxalin (20 μM) group, with three replicates in each group. The corresponding drugs were added on the day of spotting and treated for seven days.

[0029] (2) Evaluation of PTCs area: Before and seven days after drug treatment, the area of ​​PTCs in each group was measured using the analysis software provided by the microscope, and the ratio of the average area of ​​PTCs in each group after drug treatment was obtained, and then the normalized result was obtained by comparing it with the control group. Figure 3 As shown, paclitaxel alone cannot effectively inhibit the growth of lung cancer PTCs, while tepoxalin alone or in combination with paclitaxel can significantly reduce the area of ​​lung cancer PTCs. The results show that tepoxalin alone or in combination with paclitaxel can effectively inhibit the growth of lung cancer PTCs.

[0030] (3) Evaluation of PTCs activity: Seven days after drug treatment, the fluorescence signal value generated by ATP was detected using the CellTiter-Glo detection kit to reflect the activity of lung cancer PTCs, and the signal value was normalized relative to the control group. Figure 4As shown, paclitaxel alone or Tepoxalin alone can effectively inhibit the activity of lung cancer PTC, but the inhibitory effect of the combination group is significantly better than that of paclitaxel alone. The results show that Tepoxalin combined with paclitaxel can significantly inhibit the progression of lung cancer, and the effect is better than paclitaxel alone.

[0031] It can be seen from the above examples that the combination of Tepoxalin and paclitaxel in the present application can significantly enhance the inhibitory effect of paclitaxel on various solid tumors, and Tepoxalin can also inhibit the progression of various solid tumors to a certain extent.

[0032] In summary, the combination of Tepoxalin and taxanes in this application can be used for the treatment of pan-solid tumors. The present invention proves that Tepoxalin can significantly improve the effect of taxanes and reduce their adverse reactions by reducing the concentration of taxanes. The present invention uses the PTCs model to simulate the tumor microenvironment, and the drug screening results are highly correlated with the clinical results. The present invention constructs a variety of solid tumor PTC models, and detects the effect of Tepoxalin alone and in combination with paclitaxel in inhibiting the progression of pan-solid tumors by detecting indicators such as the area of ​​PTC and the ATP content. The results show that Tepoxalin combined with paclitaxel can effectively inhibit the progression of various solid tumors. Due to the reduction in the dose of paclitaxel, the adverse reactions of the organism will also be reduced, and it has great application prospects in clinical practice.

[0033] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making any creative work shall fall within the scope of protection of the present invention.

Claims

1. Application of a combination of Tepoxalin and taxanes in the treatment of solid tumors.

2. The use of the combination of Tepoxalin and taxanes according to claim 1 in treating solid tumors, characterized in that: The solid tumors include lung cancer, brain cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, liver cancer, kidney cancer, stomach cancer, head and neck cancer, ovarian cancer, esophageal cancer, pancreatic cancer, and osteosarcoma.

3. Use of the combination of Tepoxalin and taxanes according to claim 1 in treating solid tumors, characterized in that: The taxane drug is paclitaxel.

4. The use of the combination of Tepoxalin and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The concentration ratio of the taxane to Tepoxalin is 1:1-1000.

5. Use of the combination of Tepoxalin and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The dosage form of the composition is one of capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment and suppository.

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