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

Abstract

The invention relates to the technical field of biological medicines, and discloses an application of a composition of Tazofelone and taxus medicines in treatment of solid tumors. According to the application disclosed by the invention, the condition that the combination of the Tazofelone and the paclitaxel medicines can be used for treating the generic solid tumors is proposed for the first time, and the tumor killing effect of the low-concentration paclitaxel medicines can be obviously improved by the Tazofelone. 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 effects of singly using Tazofelone and jointly using Tazofelone and paclitaxel on inhibiting the progress of the generic solid tumor are detected by detecting the area of PTCs, the ATP content and other indexes. Results show that the development of various solid tumors can be effectively inhibited when the Tazofelone is combined with the paclitaxel, the Tazofelone can obviously enhance the effect of the paclitaxel, the dosage of the paclitaxel can be properly reduced during clinical use, and adverse reactions are reduced while the development of the tumors is effectively inhibited, so that the Tazofelone and the paclitaxel have great application potential clinically.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to application of a combination of Tazofelone 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 order to improve the effect of paclitaxel, a variety of dosage forms have been developed, including liposomal paclitaxel and albumin-bound paclitaxel, which have improved the efficacy of paclitaxel to a certain extent, but serious adverse reactions still occur. In clinical practice, the commonly used combination regimen of paclitaxel is often to increase its efficacy, so it is very necessary to develop a drug combination that can reduce toxic side effects while improving the efficacy of taxanes.

[0003] In recent years, with the development of various drug screening technologies and the popularization of the concept of new uses for old drugs, the application of cyclooxygenase (COX) inhibitors in anti-tumor has attracted more and more attention. Many in vivo and in vitro studies have shown that COX II inhibitors can inhibit the progression of various tumors to a certain extent, and have fewer toxic side effects. Therefore, the combination of COX II inhibitors and paclitaxel may be able to enhance the efficacy while reducing adverse reactions, which is worthy of further study.

[0004] Tazofelone, a COX II inhibitor that passed Phase I clinical trials but failed subsequent clinical trials, cannot effectively inhibit inflammation, but has good safety. The present invention finds that the drug combination of Tazofelone and paclitaxel can significantly increase the anti-tumor effect of a lower dose of paclitaxel. Summary of the invention

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

[0006] To achieve the above object, the present invention provides the following technical solution: use of a combination of Tazofelone 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] Among them, Tazofelone was purchased from MCE Company with a CAS number of 107902-67-0, and Paclitaxel was purchased from Selleck Company with a CAS number of 33069-62-4.

[0010] In a specific embodiment, the concentration ratio of the taxane to Tazofelone is 1:1-1000.

[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 Tazofelone combined with taxanes can be used for the treatment of pan-solid tumors. The present invention proves that Tazofelone can significantly improve the tumor killing effect of low-concentration 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 effects of Tazofelone 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 PTCs. The results show that Tazofelone combined with paclitaxel can effectively inhibit the progression of various solid tumors. Since Tazofelone can significantly enhance the effect of paclitaxel, the dose of paclitaxel can be appropriately reduced during clinical use, effectively inhibiting tumor progression while reducing adverse reactions. Therefore, the present invention has considerable application potential in the clinic. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is a schematic diagram of the results of normalization of the ratio of the PTCs area on the 7th day after drug treatment and that without treatment in Example 1 of the present invention;

[0015] Figure 2 This is a schematic diagram of the normalized results of ATP signal values ​​after 7 days of drug treatment in Example 1 of the present invention;

[0016] Figure 3 This is a schematic diagram of the results of normalization of the ratio of the PTCs area on the 7th day after drug treatment and without treatment in Example 2 of the present invention;

[0017] Figure 4 This is a schematic diagram of the normalized results of ATP signal values ​​after 7 days of drug treatment in Example 2 of the present invention;

[0018] Figure 5This is a schematic diagram of the results of normalization of the ratio of the PTCs area on the 7th day after drug treatment and that without treatment in Example 3 of the present invention;

[0019] Figure 6 This is a schematic diagram of the normalized results of ATP signal values ​​after 7 days of drug treatment in Example 3 of the present invention.

[0020] In the figure, ns means that there is no significant difference between the two groups after statistical analysis; * or # means that there is a significant difference between the two groups after statistical analysis, P<0.05; ** or ## 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<0.001; **** or #### means that there is a significant difference between the two groups after statistical analysis, P<0.0001. DETAILED DESCRIPTION

[0021] 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.

[0022] 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.

[0023] Example 1

[0024] The application of the combination of tazofelone and taxanes in the treatment of solid tumors is as follows:

[0025] (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 tazofelone group (100 μM), and a paclitaxel (0.75 μM) + tazofelone (100 μM) group, with three replicates in each group. The corresponding drugs were added on the day of spotting and treated for seven days.

[0026] (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, compared with the paclitaxel group alone, the drug combination group significantly reduced the average area of ​​lung cancer PTCs. In addition, Tazofelone alone can also reduce the average area of ​​PTCs to a certain extent. The results show that Tazofelone can significantly increase the inhibitory effect of paclitaxel on lung cancer, and Tazofelone alone can also inhibit the growth of lung cancer PTCs.

[0027] (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, the ability of Tazofelone combined with paclitaxel to kill PTCs is significantly better than that of paclitaxel alone. In addition, Tazofelone alone can also play a killing role. This result further confirms that Tazofelone can significantly increase the inhibitory effect of paclitaxel on lung cancer, and Tazofelone alone can also effectively inhibit the growth of lung cancer PTCs.

[0028] Example 2

[0029] The application of the combination of tazofelone and taxanes in the treatment of solid tumors is as follows:

[0030] (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, with about 30-50 PTCs in each well. They were then divided into a negative control group, a paclitaxel group (0.75 μM), a tazofelone (100 μM), and a paclitaxel (0.75 μM) + tazofelone (100 μM) group, with three replicate wells in each group. The corresponding drugs were added on the day of spotting and treated for seven days.

[0031] (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 3As shown, paclitaxel alone could not inhibit the growth of PTCs, but the combination group could significantly inhibit the growth of PTCs. Tazofelone alone also had a certain inhibitory effect. The results showed that Tazofelone combined with paclitaxel could significantly enhance the inhibitory effect of paclitaxel on tumor progression.

[0032] (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 PTCs, and the signal value was normalized relative to the control group. Figure 4 As shown, paclitaxel alone cannot effectively kill PTCs, while the combination group showed excellent killing ability, and Tazofelone alone can also play a certain killing role. The results show that paclitaxel combined with Tazofelone can significantly affect tumor survival. In addition, Tazofelone alone can also interfere with tumor survival to a certain extent.

[0033] Example 3

[0034] The application of the combination of tazofelone and taxanes in the treatment of solid tumors is as follows:

[0035] (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, with about 30-50 PTCs in each well. They were then divided into a negative control group, a paclitaxel group (0.75 μM), a tazofelone (100 μM), and a paclitaxel (0.75 μM) + tazofelone (100 μM) group, with three replicate wells in each group. The corresponding drugs were added on the day of spotting and treated for seven days.

[0036] (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 5 As shown, paclitaxel alone could not reduce the average size of PTCs, but combined with Tazofelone, it could effectively inhibit the growth of PTCs. In addition, Tazofelone alone could also significantly inhibit the growth of PTCs. The results show that Tazofelone alone or in combination with paclitaxel can effectively inhibit tumor progression.

[0037] (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 6 As shown, paclitaxel alone has no killing effect, and combined use with Tazofelone can significantly enhance its anti-tumor effect. The results show that Tazofelone can effectively enhance the killing effect of paclitaxel on tumors.

[0038] In summary, Tazofelone combined with paclitaxel can significantly enhance the inhibitory effect of paclitaxel on tumors, and Tazofelone can also inhibit tumor progression to a certain extent.

[0039] 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 tazofelone and taxanes in the treatment of solid tumors.

2. Use of the combination of Tazofelone and taxanes according to claim 1 in the treatment of 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 Tazofelone and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The taxane drug is paclitaxel.

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

5. Use of the combination of Tazofelone 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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