Combined medication composition of antitumor drugs

Abstract

The invention provides a drug combination composition of antitumor drugs. The drug combination composition comprises a therapeutically effective amount of platinum chemotherapeutic drugs, a therapeutically effective amount of an NAMPT inhibitor and a therapeutically effective amount of interleukin-2. Compared with a single anti-tumor drug, the drug combination composition provided by the invention has higher sensitivity to cancers such as liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer and breast cancer, and the effective rate is remarkably improved, so that the drug combination composition has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a combined drug composition of anti-tumor drugs. Background Art

[0002] Tumor refers to a new organism formed by the proliferation of local tissue cells under the action of various tumorigenic factors. It is divided into benign tumors and malignant tumors. Cancer refers to all malignant tumors. It is a disease caused by abnormal cell proliferation and can occur in any part of the body. It has unlimited proliferation and metastasis capabilities. Cancer has become a global public health issue. It is one of the main causes of death in countries around the world today and the second killer of humans after cardiovascular disease. In recent years, cancer has become younger, and the incidence and mortality rates have increased year by year, becoming a major malignant disease threatening human life and health.

[0003] Conventional treatments for tumors include surgery, chemotherapy, and radiotherapy. Surgery is generally only suitable for benign tumors and early malignant tumors that have not metastasized. Comprehensive treatment plans are often used for mid- and late-stage malignant tumors. Now biological therapy (mainly targeted therapy and immune enhancement, such as immune checkpoint inhibitors) is gradually emerging. Targeted therapy is a hot area in current tumor treatment, and new immunotherapy technologies targeting immune checkpoints represented by PD-1 / PD-L1 have shown encouraging therapeutic effects. However, since many patients lack tumor targets, the application scope of targeted drugs is still limited. Therefore, chemotherapy still plays a major role in tumor treatment, and cancer treatment drugs are still mainly chemotherapy drugs.

[0004] Nicotinamide phosphoribosyltransferase (NAMPT) is a gene-encoded protein molecule distributed in the cytoplasm, nucleus and mitochondria. It is the rate-limiting enzyme in the salvage synthesis pathway of nicotinamide adenine dinucleotide (NAD+) in mammals and is involved in the cell's material energy metabolism, DNA repair and protein synthesis. Unlike normal cells, tumor cells mainly rely on the glycolysis pathway to quickly obtain adenosine triphosphate (ATP) to provide energy for their rapid proliferation and survival. Therefore, tumor cells have a high demand for nicotinamide adenine dinucleotide (NAD+), an important coenzyme in the glycolysis pathway. + ) is significantly higher than that of normal cells. Studies have shown that tumor cells mainly obtain NAD through the salvage synthesis pathway. + , and nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in this pathway. NAMPT can regulate NAD + The synthesis of NAD directly regulates cell metabolism; it can also +Relying on the activity of enzymes, it upregulates the level of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and indirectly regulates cell metabolism to improve cell survival. Currently, NAMPT is considered an important target for tumor treatment, and many studies have confirmed that NAMPT inhibitors have significant anti-tumor effects.

[0005] Interleukin-2 (IL-2) was first discovered in the supernatant of mouse spleen cells in 1976. It was originally named T cell growth factor because it can maintain and promote the growth of T cells in vitro. In a series of subsequent in vitro and in vivo experiments, interleukin-2 showed significant anti-tumor effects. After a number of clinical trials, the high-dose interleukin-2 regimen was approved by the US Food and Drug Administration (FDA) as a standard immunotherapy for metastatic renal cancer as early as the 1990s. In the treatment of renal cancer for more than 20 years, researchers have conducted many studies on interleukin-2-related immunotherapy and improved it from various aspects, including combining with other anti-tumor drugs, reducing the dosage of interleukin-2, changing the route of administration, and screening patients sensitive to interleukin-2 treatment from the histological and pathological levels, so as to maximize its clinical efficacy and reduce treatment toxicity. Although there are many immunotherapies for renal cancer, interleukin-2 is still listed as one of the first-line drugs in many metastatic renal cancer treatment guidelines around the world. Currently, recombinant interleukin-2 is widely used to treat leukemia, lymphoma, melanoma and renal cancer, and has also achieved certain therapeutic effects in other solid tumors.

[0006] Platinum drugs are non-specific drugs for the cell cycle. They mainly form Pt-DNA adducts with DNA after entering tumor cells, thereby mediating tumor cell necrosis or apoptosis, thereby producing anti-cancer effects. Since the discovery of cisplatin's anti-cancer activity in 1967, the application and research of platinum metal anti-cancer drugs have developed rapidly. In clinical practice, almost all chemotherapy regimens for tumors are monotherapy or combination therapy based on platinum chemotherapy. Platinum anti-tumor drugs have become the cornerstone of chemotherapy. Platinum drugs such as oxaliplatin, cisplatin, carboplatin, etc. are first-line chemotherapy drugs for various solid tumors such as liver cancer, colorectal cancer, and cervical cancer.

[0007] However, the anti-tumor effect of using NAMPT inhibitors, interleukin-2 or platinum drugs alone is not ideal. How to enhance their anti-cancer effect has always been a clinical issue of great concern. There is no ideal solution in the prior art. Summary of the invention

[0008] In order to effectively solve the above problems, the present invention provides a combination drug composition of anti-tumor drugs, which includes a therapeutically safe and effective amount of a platinum chemotherapy drug, a therapeutically safe and effective amount of a NAMPT inhibitor, and a therapeutically safe and effective amount of interleukin-2.

[0009] In some embodiments, the platinum chemotherapy drug is selected from any one or more of cisplatin, carboplatin, cyclothiaplatin, nedaplatin, oxaliplatin or lobaplatin.

[0010] In some embodiments, the platinum is oxaliplatin.

[0011] In some embodiments, the NAMPT inhibitor is selected from any one or more of FK866, CHS828, CB30865, and IS001;

[0012] In some embodiments, the NAMPT inhibitor is FK866.

[0013] In some embodiments, the therapeutically safe and effective amount of the platinum chemotherapy drug is administered in a dosage of 3 to 10 mg / kg / week; the therapeutically safe and effective amount of the NAMPT inhibitor is administered in a dosage of 2 to 20 mg / kg / day; and the therapeutically safe and effective amount of interleukin-2 is administered in a dosage of 0.5 to 3 μg / kg / day.

[0014] In some embodiments, the administration of the pharmaceutical composition includes any one or more of gastrointestinal administration, peritumoral subcutaneous administration, and intratumoral injection.

[0015] In some embodiments, the pharmaceutical composition is administered by intraperitoneal injection.

[0016] Application of a NAMPT inhibitor combined with interleukin-2 in the preparation of an anti-tumor enhancer for platinum-based chemotherapy drugs.

[0017] In some embodiments, the tumor includes one or more of liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer, and breast cancer.

[0018] The beneficial effects of the present invention are:

[0019] The combined drug composition provided by the present invention includes a platinum chemotherapy drug, a NAMPT inhibitor and interleukin-2. The three play a synergistic role. Compared with a single anti-tumor drug, it has higher sensitivity to cancers such as liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer, breast cancer, etc., and significantly improves the effective rate, thus having broad application prospects.

[0020] The NAMPT inhibitor and interleukin-2 in the combined drug composition provided by the present invention reduce the drug resistance of platinum chemotherapy drugs and improve the sensitivity and efficacy of platinum drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. It should be understood that the following drawings only show certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other related drawings can be obtained based on these drawings without paying creative work.

[0022] Figure 1 This is a statistical chart of the tumor weights of mice with liver cancer after group treatment in Example 1 of the present invention.

[0023] Figure 2 This is a statistical chart of the tumor volume of liver cancer mice after group treatment in Example 1 of the present invention.

[0024] Figure 3 This is a statistical chart of tumor weights of cervical cancer mice after group treatment in Example 2 of the present invention.

[0025] Figure 4 This is a statistical chart of the tumor volume of cervical cancer mice after group treatment in Example 2 of the present invention. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. Therefore, the following detailed description of the embodiments of the present invention provided in the drawings is not intended to limit the scope of the invention claimed for protection, but merely represents the selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0027] The embodiment of the present invention provides a combination drug composition of anti-tumor drugs, wherein the combination drug composition comprises a therapeutically safe and effective amount of a platinum chemotherapy drug, a therapeutically safe and effective amount of a NAMPT inhibitor, and a therapeutically safe and effective amount of interleukin-2.

[0028] In the embodiments of the present invention, NAMPT inhibitor, interleukin-2 and platinum chemotherapy drugs cooperate with each other, and the three play a synergistic role to jointly improve the anti-tumor effect.

[0029] In certain embodiments, the platinum chemotherapeutic drug is selected from any one or more of cisplatin, carboplatin, cyclothioplatin, nedaplatin, oxaliplatin or lobaplatin. For example, cisplatin can be used alone, or carboplatin can be used in combination with cyclothioplatin to achieve better therapeutic effect. In addition, nedaplatin or oxaliplatin can also be selected, or lobaplatin can be used in combination with other platinum drugs to achieve a wider range of treatment and higher efficacy.

[0030] In certain specific embodiments, the platinum drug selected is oxaliplatin. Oxaliplatin is a chemotherapy drug widely used in cancer treatment, especially in the treatment of colorectal cancer. It binds to the DNA of cancer cells to prevent their replication and proliferation, thereby achieving the purpose of inhibiting tumor growth. In clinical applications, oxaliplatin is usually used in combination with other chemotherapy drugs or targeted drugs to improve the therapeutic effect and reduce the occurrence of drug resistance.

[0031] In some embodiments, the NAMPT inhibitor is selected from any one or more of FK866 (also known as Daporinad), CHS828, CB30865, and IS001; these compounds have been studied and developed for inhibiting the activity of the NAMPT enzyme, thereby playing a role in treating certain diseases.

[0032] In some embodiments, the NAMPT inhibitor is FK866. FK866 is a drug that has been extensively studied and has shown significant efficacy in inhibiting the NAMPT enzyme, and is therefore preferred in certain treatment regimens.

[0033] In some embodiments, the dosage of the platinum chemotherapy drug with a safe and effective amount of treatment is 3 to 10 mg / kg / week; the dosage of the NAMPT inhibitor with a safe and effective amount of treatment is 2 to 20 mg / kg / day; the dosage of the interleukin-2 with a safe and effective amount of treatment is 0.5 to 3 μg / kg / day. Such a dosage range is intended to ensure that the drug exerts its anti-cancer effect while minimizing possible side effects and toxic reactions.

[0034] In some embodiments, the pharmaceutical composition can be administered through a variety of different routes of administration to ensure that the drug can effectively reach the target site and exert its expected therapeutic effect. These administration methods include, but are not limited to, gastrointestinal administration, peritumoral subcutaneous administration, and intratumoral injection. In some cases, these administration methods can be used alone or in combination as needed to achieve the best therapeutic effect.

[0035] In some embodiments, the pharmaceutical composition is administered by intraperitoneal injection. Intraperitoneal injection refers to injecting the drug directly into the abdominal cavity, so that the drug can directly enter the blood circulation in the abdominal cavity and be quickly distributed to various parts of the body. Intraperitoneal injection is particularly suitable for treatment situations that require a higher drug concentration in the abdominal cavity, such as certain intraperitoneal tumors or inflammatory diseases. Through intraperitoneal injection, the drug can directly act on the lesion site in the abdominal cavity, improve the treatment effect, and reduce the potential side effects of the drug on other tissues and organs.

[0036] A drug combination of a NAMPT inhibitor and interleukin-2 is used to prepare a synergist that can enhance the anti-tumor effect of platinum chemotherapy drugs. Although platinum chemotherapy drugs are the most widely used broad-spectrum anti-tumor drugs in clinical practice and have good therapeutic effects on a variety of cancers, platinum also has the disadvantages of large side effects, poor pharmacokinetics, and innate or acquired drug resistance. In particular, drug resistance inhibits the efficacy of platinum chemotherapy drugs, resulting in a continuous decrease in their anti-tumor sensitivity. According to statistics, the median survival time of patients with advanced cancer who receive chemotherapy is only 8 to 10 months, and resistance to platinum chemotherapy drugs is one of the important reasons for the shorter survival of patients. This synergist significantly improves the efficacy of platinum drugs through synergistic effects, thereby showing more significant anti-tumor activity in the treatment of various cancers.

[0037] In some specific embodiments, the tumor types include a variety of common malignant tumors, including but not limited to liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer and breast cancer. These cancer types have high morbidity and mortality rates clinically, so it is of great clinical significance to develop a synergist that can effectively enhance the effect of existing chemotherapy drugs. By combining the use of NAMPT inhibitors and interleukin-2, this synergist can play a significant synergistic role in the treatment of different types of tumors, thereby providing cancer patients with more effective treatment options.

[0038] Example 1: The effect of NAMPT inhibitor FK866, interleukin-2 and oxaliplatin in inhibiting the growth of liver cancer.

[0039] Animal model construction: 2-4 week old Balb / c male nude mice were taken and adapted to feeding for 2 weeks at 25±1℃ with a 12-hour light-dark cycle in an isolation barrier environment without specific pathogens. Animal husbandry and operation were strictly carried out in accordance with the ethical standards and operation guidelines for experimental animals. After 2 weeks, human liver cancer cells HuH-7 (purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences) were inoculated subcutaneously in the forelimbs of Balb / c male nude mice, and the tumors were allowed to grow freely for 2 weeks. The liver cancer animal model was completed.

[0040] Group intervention experiment: After 2 weeks, the model mice were randomly divided into 8 groups: ① control group, ② oxaliplatin group, ③ FK866 group, ④ interleukin-2 group, ⑤ oxaliplatin + interleukin-2 group, ⑥ FK866 + interleukin-2 group, ⑦ oxaliplatin + FK866, ⑧ oxaliplatin + FK866 + interleukin-2 group. FK866: intraperitoneal injection once a day (10 mg / kg mouse body weight); interleukin-2: intraperitoneal injection once a day (1 μg / mouse); oxaliplatin: intraperitoneal injection once a week (5 mg / kg mouse body weight); control group: intraperitoneal injection of an equal volume of normal saline once a day. Treatment continued for 2 weeks.

[0041] Experimental results measurement: After two weeks of group treatment, mice were killed by cervical dislocation, and the tumor tissues of mice were removed. The tumor weight was weighed with an analytical balance, and the tumor volume was measured with a vernier caliper. The tumor volume calculation formula was: tumor volume = 0.5 × long diameter × short diameter 2 (mm 3 The measurement results are shown in Table 1 and Figure 1 , Figure 2 shown.

[0042] Table 1 Effect of the combined drug of the present invention on tumor weight and volume in mice with liver cancer

[0043]

[0044] The analysis showed that two weeks after group treatment, the tumor weight and volume of the oxaliplatin group + FK866 + interleukin-2 were significantly smaller than those of other single-drug or two-drug combination groups. At the same time, compared with the control group, the sum of the reduction in tumor weight and volume of the three groups of FK866, interleukin-2, and oxaliplatin was still smaller than that of the FK866 + interleukin-2 + oxaliplatin group. This suggests that the FK866 group, interleukin-2 group, and oxaliplatin cooperated with each other, played a synergistic role, and jointly improved the inhibitory effect on the growth of liver cancer.

[0045] Example 2: The effect of NAMPT inhibitor FK866, interleukin-2 and oxaliplatin in inhibiting the growth of cervical cancer.

[0046] Animal model construction: 2-4 week old Balb / c female nude mice were taken and fed adaptively for 2 weeks at 25±1℃ with a 12-hour light-dark cycle in an isolation barrier environment without specific pathogens. Animal husbandry and operation were strictly carried out in accordance with the ethical standards and operation guidelines for experimental animals. After 2 weeks, human cervical cancer cells Hela (purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences) were inoculated subcutaneously in the forelimbs of Balb / c female nude mice, and the tumor was allowed to grow freely for 2 weeks. The cervical cancer animal model was completed.

[0047] Group intervention experiment: After 2 weeks, the model mice were randomly divided into 8 groups: ① control group, ② oxaliplatin group, ③ FK866 group, ④ interleukin-2 group, ⑤ oxaliplatin + interleukin-2 group, ⑥ FK866 + interleukin-2 group, ⑦ oxaliplatin + FK866, ⑧ oxaliplatin + FK866 + interleukin-2 group. FK866: intraperitoneal injection once a day (10 mg / kg mouse body weight); interleukin-2: intraperitoneal injection once a day (1 μg / mouse); oxaliplatin: intraperitoneal injection once a week (5 mg / kg mouse body weight); control group: intraperitoneal injection of an equal volume of normal saline once a day. Treatment continued for 2 weeks.

[0048] Experimental results measurement: After two weeks of group treatment, mice were killed by cervical dislocation, and the tumor tissues of mice were removed. The tumor weight was weighed with an analytical balance, and the tumor volume was measured with a vernier caliper. The tumor volume calculation formula was: tumor volume = 0.5 × long diameter × short diameter 2 (mm 3 The measurement results are shown in Table 2 and Figure 3 , Figure 4 shown.

[0049] Table 2 Effect of the combined drug of the present invention on tumor weight and volume of cervical cancer mice

[0050]

[0051] The analysis showed that two weeks after group treatment, the tumor weight and volume of the FK866+IL-2+oxaliplatin group were significantly smaller than those of other single-drug or two-drug combination groups. At the same time, compared with the control group, the sum of the reduction in tumor weight and volume of the FK866 group, IL-2 group, and oxaliplatin group was still smaller than that of the FK866+IL-2+oxaliplatin group. This suggests that the FK866 group, IL-2 group, and oxaliplatin cooperated with each other, played a synergistic role, and jointly improved the inhibitory effect on the growth of cervical cancer.

[0052] In summary, compared with a single anti-tumor drug, the combined drug composition provided by the present invention has a synergistic effect among the three drugs, has a higher sensitivity to cancers such as liver cancer and cervical cancer, and significantly improves the effective rate, thus having broad application prospects. The combination of NAMPT inhibitors and interleukin-2 significantly reduces the drug resistance of platinum chemotherapy drugs, improves the sensitivity and efficacy of platinum drugs, and enhances their anti-cancer effect.

[0053] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A combination drug composition of an anti-tumor drug, characterized in that: The combined drug composition comprises a therapeutically safe and effective amount of a platinum-based chemotherapy drug, a therapeutically safe and effective amount of a NAMPT inhibitor, and a therapeutically safe and effective amount of interleukin-2.

2. The combined pharmaceutical composition according to claim 1, characterized in that: The platinum chemotherapy drug is selected from any one or more of cisplatin, carboplatin, cyclothioplatin, nedaplatin, oxaliplatin or lobaplatin.

3. The combined pharmaceutical composition according to claim 1, characterized in that: The platinum compound is oxaliplatin.

4. The combined pharmaceutical composition according to claim 1, characterized in that: The NAMPT inhibitor is selected from any one or more of FK866, CHS828, CB30865, and IS001.

5. The combined pharmaceutical composition according to claim 1, characterized in that: The NAMPT inhibitor is FK866.

6. The pharmaceutical composition according to claims 1 to 5, characterized in that The dosage of the platinum chemotherapy drug with a safe and effective therapeutic amount is 3 to 10 mg / kg / week; the dosage of the NAMPT inhibitor with a safe and effective therapeutic amount is 2 to 20 mg / kg / day; and the dosage of the interleukin-2 with a safe and effective therapeutic amount is 0.5 to 3 μg / kg / day.

7. The pharmaceutical composition according to claims 1 to 5, characterized in that The administration method of the pharmaceutical composition includes any one or more of gastrointestinal administration, peritumoral subcutaneous administration, and intratumoral injection.

8. The pharmaceutical composition according to claims 1 to 5, characterized in that The pharmaceutical composition is administered by intraperitoneal injection.

9. Use of a NAMPT inhibitor combined with interleukin-2 in the preparation of an anti-tumor enhancer for platinum-based chemotherapy drugs.

10. The use according to claim 8, characterized in that The tumor includes one or more of liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer, and breast cancer.

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