A combination drug composition for use with an antitumor drug

Abstract

This invention provides a combination drug composition for antitumor treatment, comprising a therapeutically effective amount of a platinum-based chemotherapy drug, a therapeutically effective amount of a NAMPT inhibitor, and a therapeutically effective amount of interleukin-2. Compared with single antitumor drugs, the combination drug composition provided by this invention exhibits higher sensitivity against cancers such as liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer, and breast cancer, significantly improving the efficacy rate and thus showing broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a combination drug composition for the use of antitumor drugs. Background Technology

[0002] A tumor is a new growth formed by the proliferation of local tissue cells under the influence of various carcinogenic factors. Tumors are classified as benign or malignant. Cancer, broadly referring to all malignant tumors, is a disease caused by abnormal cell proliferation. It can occur in any part of the body and has the ability to proliferate and metastasize without limit. Cancer has become a global public health problem and is one of the leading causes of death worldwide, ranking second only to cardiovascular disease as the second leading cause of death. In recent years, cancer has shown a trend of affecting younger people, with incidence and mortality rates rising year by year, making it a major malignant disease threatening human life and health.

[0003] Conventional cancer treatment includes surgery, chemotherapy, and radiotherapy. Surgery is generally only suitable for benign tumors and early-stage malignant tumors that have not metastasized; mid-to-late-stage malignant tumors often require comprehensive treatment. Currently, biotherapy (mainly targeted therapy and immune enhancement therapies, such as immune checkpoint inhibitors) is gaining prominence. Targeted therapy is a hot area in current cancer treatment, and novel immunotherapies targeting immune checkpoints, such as PD-1 / PD-L1, have shown encouraging therapeutic effects. However, because many patients lack tumor targets, the application of targeted drugs remains limited. Therefore, chemotherapy still plays a major role in cancer treatment, and chemotherapy drugs remain the primary treatment for cancer.

[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 mammalian nicotinamide adenine dinucleotide (NAD+) salvage pathway, participating in cellular energy metabolism, DNA repair, and protein synthesis. Unlike normal cells, tumor cells primarily rely on glycolysis to rapidly obtain adenosine triphosphate (ATP) for their rapid proliferation and survival. Therefore, tumor cells rely heavily on nicotinamide adenine dinucleotide (NAD+), an important coenzyme in the glycolysis pathway. + The demand for NAD+ is significantly higher than that of normal cells. Studies show that tumor cells mainly obtain NAD+ through the salvage synthesis pathway. + Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in this pathway. NAMPT can control NAD+. + The synthesis of NAD+ directly regulates cellular metabolism; it can also affect NAD+ synthesis. +NAMPT indirectly regulates cell metabolism by upregulating the level of reduced nicotinamide adenine dinucleotide phosphate (NADPH) through enzyme activity, thereby enhancing cell viability. Currently, NAMPT is considered an important target for cancer therapy, and multiple studies have confirmed that NAMPT inhibitors have significant anti-tumor effects.

[0005] Interleukin-2 (IL-2) was first discovered in 1976 in the supernatant of mouse spleen cells. Initially named T-cell growth factor because it maintains and promotes T-cell growth in vitro, it has demonstrated significant anti-tumor effects in subsequent in vitro and in vivo experiments. After numerous clinical trials, high-dose IL-2 regimens were approved by the U.S. Food and Drug Administration (FDA) in the 1990s as a standard immunotherapy for metastatic renal cell carcinoma. In the subsequent two decades of renal cell carcinoma treatment, researchers have conducted extensive studies on IL-2-related immunotherapies and improved them in various ways, including combining them with other anti-tumor drugs, reducing the dosage of IL-2, changing the route of administration, and screening for patients sensitive to IL-2 treatment based on histological and pathological findings, thereby maximizing clinical efficacy and reducing treatment toxicity. Although there are now many immunotherapies available for renal cell carcinoma, IL-2 remains a first-line drug in many global guidelines for the treatment of metastatic renal cell carcinoma. Currently, recombinant interleukin-2 is widely used to treat leukemia, lymphoma, melanoma, and kidney cancer, and has also shown some efficacy in other solid tumors.

[0006] Platinum-based drugs are cell cycle non-specific agents. They primarily work by entering tumor cells and forming Pt-DNA adducts with DNA, thereby mediating tumor cell necrosis or apoptosis and producing an anti-cancer effect. Since the discovery of cisplatin's anti-cancer activity in 1967, the application and research of platinum-based anticancer drugs have developed rapidly. Clinically, almost all chemotherapy regimens for tumors are based on platinum-based chemotherapy, used alone or in combination. Platinum-based antitumor drugs have become the cornerstone of chemotherapy. Platinum-based drugs such as oxaliplatin, cisplatin, and carboplatin are first-line chemotherapy drugs for various solid tumors, including liver cancer, colorectal cancer, and cervical cancer.

[0007] However, the anti-tumor effects of using NAMPT inhibitors, interleukin-2, or platinum-based drugs alone are not ideal. How to enhance their anti-cancer effects has always been a major concern in clinical practice. Currently, there is no ideal solution in existing technologies. Summary of the Invention

[0008] To effectively address the above problems, the present invention provides a combination drug composition for antitumor drugs, wherein the combination 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.

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

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

[0011] In some embodiments, the NAMPT inhibitor is selected from 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 dose of platinum-based chemotherapy drugs is 3–10 mg / kg / week; the therapeutically safe and effective dose of NAMPT inhibitors is 2–20 mg / kg / day; and the therapeutically safe and effective dose of interleukin-2 is 0.5–3 μg / kg / day.

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

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

[0016] Application of a NAMPT inhibitor combined with interleukin-2 in the preparation of antitumor potentiators for platinum-based chemotherapy drugs.

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

[0018] The beneficial effects of this invention are:

[0019] The combination drug composition provided by this invention includes platinum-based chemotherapy drugs, NAMPT inhibitors, and interleukin-2. The three drugs exert a synergistic effect and, compared with single anti-tumor drugs, have higher sensitivity to cancers such as liver cancer, gastric cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer, and breast cancer, significantly improving the efficacy rate and thus having broad application prospects.

[0020] The NAMPT inhibitor and interleukin-2 in the combination drug composition provided by the present invention reduce the resistance to platinum-based chemotherapy drugs and improve the sensitivity and efficacy of platinum-based drugs. Attached Figure Description

[0021] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation of the scope. For those skilled in the art, other related drawings can be obtained from these drawings without creative effort.

[0022] Figure 1 This is a statistical graph showing the tumor weight of liver cancer mice after group treatment in Example 1 of the present invention.

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

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

[0025] Figure 4 This is a statistical graph showing the tumor volume of cervical cancer mice after group treatment in Example 2 of the present invention. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort 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 accompanying drawings is not intended to limit the scope of the claimed invention, but merely to represent selected embodiments of the invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] This invention provides a combination drug composition for antitumor drugs, the combination drug composition comprising 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.

[0028] In this embodiment of the invention, NAMPT inhibitors, interleukin-2, and platinum-based chemotherapy drugs work together to exert a synergistic effect, thereby improving the anti-tumor efficacy.

[0029] In some embodiments, the platinum-based chemotherapy drug is selected from one or more of cisplatin, carboplatin, cyclothioplatin, nedaplatin, oxaliplatin, or lobaplatin. For example, cisplatin can be used alone, or carboplatin can be combined with cyclothioplatin for better therapeutic effect. Furthermore, nedaplatin or oxaliplatin can be selected, or lobaplatin can be combined with other platinum-based drugs to achieve a wider range of treatments and higher efficacy.

[0030] In certain specific embodiments, the platinum-based drug used is oxaliplatin. Oxaliplatin is a widely used chemotherapy drug for cancer treatment, particularly showing significant efficacy in the treatment of colorectal cancer. It inhibits tumor growth by binding to the DNA of cancer cells, preventing their replication and proliferation. In clinical applications, oxaliplatin is often used in combination with other chemotherapy drugs or targeted therapies to improve treatment efficacy and reduce the occurrence of drug resistance.

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

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

[0033] In some embodiments, the therapeutically safe and effective dose of platinum-based chemotherapy drugs is 3–10 mg / kg / week; the therapeutically safe and effective dose of NAMPT inhibitors is 2–20 mg / kg / day; and the therapeutically safe and effective dose of interleukin-2 is 0.5–3 μg / kg / day. Such dosage ranges are designed to ensure that the drugs exert their anticancer effects while minimizing potential side effects and toxic reactions.

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

[0035] In some embodiments, the pharmaceutical composition is administered via intraperitoneal injection. Intraperitoneal injection refers to the direct injection of a drug into the peritoneal cavity, allowing the drug to directly enter the bloodstream and rapidly distribute to various parts of the body. Intraperitoneal injection is particularly suitable for treatments requiring high drug concentrations within the peritoneal cavity, such as certain intraperitoneal tumors or inflammatory diseases. Through intraperitoneal injection, the drug can act directly on the lesion site within the peritoneal cavity, improving treatment efficacy while reducing potential side effects on other tissues and organs.

[0036] A combination of a NAMPT inhibitor and interleukin-2 has been developed into a potentiator to enhance the antitumor effects of platinum-based chemotherapy drugs. Although platinum-based chemotherapy drugs are the most widely used broad-spectrum antitumor drugs in clinical practice and have good efficacy against various cancers, they also have drawbacks such as significant side effects, poor pharmacokinetics, and congenital or acquired resistance. In particular, resistance inhibits the efficacy of platinum-based chemotherapy drugs, leading to a continuous decrease in their antitumor sensitivity. Statistics show that the median survival of patients with advanced cancer receiving chemotherapy is only 8–10 months, and platinum-based chemotherapy drug resistance is one of the important reasons for this short survival. This potentiator, through synergistic effects, significantly improves the efficacy of platinum-based drugs, thus exhibiting more significant antitumor activity in the treatment of various cancers.

[0037] In some specific embodiments, the tumor types encompass a variety of common malignant tumors, including but not limited to liver cancer, stomach cancer, colorectal cancer, lung cancer, cervical cancer, kidney cancer, pancreatic cancer, and breast cancer. These cancer types have high morbidity and mortality rates clinically; therefore, developing potentiators that can effectively enhance the efficacy of existing chemotherapy drugs is of significant clinical importance. By combining NAMPT inhibitors and interleukin-2, such potentiators can exert a significant synergistic effect 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 combined with oxaliplatin on inhibiting liver cancer growth.

[0039] Animal model construction: 2-4 week old male Balb / c nude mice were used and acclimatized for 2 weeks in an isolation barrier environment free of specific pathogens, with a 12-hour light-dark cycle at 25±1℃. Animal feeding and handling were strictly performed in accordance with experimental animal ethics guidelines and operational procedures. After 2 weeks, human hepatocellular carcinoma cells HuH-7 (purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences) were subcutaneously inoculated into the forelimbs of male Balb / c nude mice, allowing the tumor to continue to grow freely for 2 weeks, thus completing the construction of the hepatocellular carcinoma animal model.

[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: once daily intraperitoneal injection (10 mg / kg mouse body weight); Interleukin-2: once daily intraperitoneal injection (1 μg / mouse); Oxaliplatin: once weekly intraperitoneal injection (5 mg / kg mouse body weight); Control group: once daily intraperitoneal injection of an equal volume of physiological saline. Treatment continued for 2 weeks.

[0041] Experimental Results Measurement: Two weeks after treatment in each group, mice were euthanized by cervical dislocation. Tumor tissue was harvested, and the tumor weight was measured using an analytical balance. The tumor volume was measured using calipers. The tumor volume was calculated using the formula: Tumor volume = 0.5 × major axis × minor axis 2 (mm 3 The measurement results are shown in Table 1 and... Figure 1 , Figure 2 As shown.

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

[0043]

[0044] Analysis showed that after two weeks of treatment, the tumor weight and volume in the oxaliplatin + FK866 + interleukin-2 group were significantly smaller than those in other single or dual-drug combination groups. Furthermore, compared to the control group, the combined reduction in tumor weight and volume among the FK866, interleukin-2, and oxaliplatin groups was still less than that in the FK866 + interleukin-2 + oxaliplatin group. This indicates that the FK866, interleukin-2, and oxaliplatin groups worked synergistically to enhance the inhibitory effect on liver cancer growth.

[0045] Example 2: The effect of NAMPT inhibitor FK866, interleukin-2 combined with oxaliplatin on inhibiting cervical cancer growth.

[0046] Animal model construction: 2-4 week old female Balb / c nude mice were used and acclimatized for 2 weeks in an isolated, pathogen-free environment at 25±1℃ with a 12-hour light-dark cycle. Animal feeding and handling were strictly performed in accordance with laboratory animal ethics guidelines and operational procedures. After 2 weeks, human cervical cancer cells (HeLa, purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences) were subcutaneously inoculated into the forelimbs of female Balb / c nude mice, allowing the tumor to continue growing freely for another 2 weeks, thus completing the construction of the cervical cancer animal model.

[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: once daily intraperitoneal injection (10 mg / kg mouse body weight); Interleukin-2: once daily intraperitoneal injection (1 μg / mouse); Oxaliplatin: once weekly intraperitoneal injection (5 mg / kg mouse body weight); Control group: once daily intraperitoneal injection of an equal volume of physiological saline. Treatment continued for 2 weeks.

[0048] Experimental Results Measurement: Two weeks after treatment in each group, mice were euthanized by cervical dislocation. Tumor tissue was harvested, and the tumor weight was measured using an analytical balance. The tumor volume was measured using calipers. The tumor volume was calculated using the formula: Tumor volume = 0.5 × major axis × minor axis 2 (mm 3 The measurement results are shown in Table 2 and... Figure 3 , Figure 4 As shown.

[0049] Table 2. Effects of the combined drug regimen of the present invention on tumor weight and volume in cervical cancer mice.

[0050]

[0051] Analysis showed that after two weeks of treatment, the tumor weight and volume in the FK866 + interleukin-2 + oxaliplatin group were significantly smaller than those in other single-drug or two-drug combination groups. Furthermore, compared to the control group, the combined reduction in tumor weight and volume among the FK866, interleukin-2, and oxaliplatin groups was still less than that in the FK866 + interleukin-2 + oxaliplatin group. This indicates that the FK866, interleukin-2, and oxaliplatin groups worked synergistically to enhance the inhibitory effect on cervical cancer growth.

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

[0053] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the invention by those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the invention should be included within the scope of protection of the invention.

Claims

1. A combination drug composition for treating cervical cancer, characterized in that, The combination drug composition includes 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; the platinum-based chemotherapy drug is oxaliplatin, and the NAMPT inhibitor is FK866.

2. The combination drug composition as described in claim 1, characterized in that, The therapeutically safe and effective dose of platinum-based chemotherapy drugs is 3–10 mg / kg / week; the therapeutically safe and effective dose of NAMPT inhibitors is 2–20 mg / kg / day; and the therapeutically safe and effective dose of interleukin-2 is 0.5–3 μg / kg / day.

3. The combination drug composition as described in claim 1, characterized in that, The drug composition can be administered via any one or more of the following routes: gastrointestinal administration, peritumoral subcutaneous administration, and intratumoral injection.

4. The combination drug composition as described in claim 1, characterized in that, The pharmaceutical composition is administered via intraperitoneal injection.

5. Application of a NAMPT inhibitor FK866 in combination with interleukin-2 in the preparation of an oxaliplatin-based cervical cancer potentiator.

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