Application of valine restrictive diet or combination of valine restrictive diet and poly ADP-ribose polymerase inhibitor in preparation of medicine for preventing and / or treating tumors

Abstract

The invention relates to an application of valine-restricted diet or a combination of valine-restricted diet and a poly ADP-ribose polymerase inhibitor in preparation of drugs for preventing and / or treating tumors, especially in prevention and treatment of colorectal cancer, and has the advantages that the valine-restricted diet can induce cells to generate DNA damage, so that the effect of preventing and treating colorectal cancer is achieved. Limiting the amount of valine in food has an obvious inhibiting effect on occurrence and development of tumors. The poly ADP-ribose polymerase inhibitor for blocking DNA damage repair by combining the valine restricted diet and the poly ADP-ribose polymerase inhibitor can block or inhibit DNA damage repair and more effectively inhibit DNA damage repair, so that cell proliferation is inhibited, cell death is promoted, and occurrence and development of tumors are further inhibited.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, in particular to the field of restrictive diet and tumor treatment technology, and specifically to an application of a valine-restricted diet or a valine-restricted diet combined with a poly (ADP-ribose) polymerase inhibitor in the preparation of a drug for preventing and / or treating tumors. Background Art

[0002] The relationship between restrictive diet and cancer treatment is an active research area involving a variety of dietary interventions, including intermittent fasting, restriction of specific nutrients (such as methionine-restricted diet), and fasting-mimicking diet (FMD). These dietary interventions affect tumor growth, metabolism, and response to treatment through different mechanisms. In cancer treatment, intermittent fasting is believed to be able to fight tumors by lowering insulin levels, improving glucose tolerance, reducing blood cholesterol levels, and promoting fat metabolism and cell health. Restricting methionine intake can significantly reduce S-adenosylmethionine (SAM) levels in cancer cells, thereby reducing cGAS methylation modification and enhancing anti-tumor immune response. Fasting-mimicking diets change the metabolic environment of cancer cells by providing low-protein, low-carbohydrate, and high-fat nutrition, affecting their drug sensitivity, proliferation rate, and metabolic requirements. FMD has been shown to enhance the effectiveness of immunotherapy by affecting the tumor microenvironment, especially in triple-negative breast cancer. Intermittent fasting and dietary patterns with specific nutrient restrictions have shown potential benefits for cancer patients in some clinical trials, including improved treatment compliance, reduced side effects, and improved quality of life. However, the clinical application of these dietary interventions still requires more research to verify their effectiveness and safety.

[0003] A methionine-restricted diet is combined with the chemotherapy drug 5-fluorouracil (5-FU) or radiotherapy to treat tumors. The researchers performed methionine restriction on two patient-derived colon cancer mouse models. The results showed that both models showed significant tumor growth inhibition after undergoing methionine dietary restriction. More importantly, methionine dietary restriction before this mouse model was treated with the chemotherapy drug 5-FU can significantly improve the efficacy of 5-FU. In addition, the researchers also conducted methionine dietary restriction experiments on a mouse model of soft tissue sarcoma. Although methionine dietary restriction itself did not significantly inhibit tumor growth in this tumor model, it could significantly improve the efficacy of radiotherapy.

[0004] In the study of valine-restricted diet for the treatment of T-cell acute lymphoblastic leukemia, researchers found that the level of tRNA (valine-tRNA) that transports valine in T-cell acute lymphoblastic leukemia (T-ALL) was increased. Restricting valine intake by diet can inhibit the translation of mitochondrial complex 1-related subunit mRNA, alleviate T-ALL mouse-related symptoms and prolong their survival time. The specific operation method is that the food does not contain valine at all, and only different concentrations of valine are added to the water for restriction experiments (the valine content in the water is 1 / 10 and 1 / 20 of that in the diet). It was found that both can prolong the survival of T-ALL mice, but the side effects are significantly less than the valine complete removal group or no valine at all. The researchers once again used CRISPR-Cas9 experiments to screen out that knocking out SLC7A5 and BCL2 can promote valine restriction to inhibit T-ALL, and found that their corresponding inhibitors and valine restriction can synergistically inhibit the proliferation of T-ALL cell lines.

[0005] At present, the valine restriction diet therapy has been mainly studied in T-cell acute lymphoblastic leukemia, a blood tumor. In its specific operation method, the food does not contain valine at all, and only different concentrations of valine are added to the water for restriction experiments (the valine content in the water is 1 / 10 and 1 / 20 of that in the diet). However, the water feeding treatment will cause uneven valine intake, and the restriction diet directly in the food has not been compared. In addition, the study of valine restriction diet therapy and its combination with chemotherapy in solid tumors (colorectal cancer) has not been reported. Summary of the invention

[0006] The purpose of the present invention is to address at least one of the deficiencies in the prior art and to provide a valine-restricted diet or its combined use with a poly ADP-ribose polymerase inhibitor (abbreviated as PARP) in the preparation of a drug for preventing and / or treating tumors, so as to solve the problems existing in the related art, such as uneven valine uptake caused by water feeding, and the lack of research reports on valine-restricted diet therapy and its combination with chemotherapy in the prevention and treatment of solid tumors (colorectal cancer).

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention is to provide an application of a valine-restricted diet in the preparation of a drug for preventing and / or treating tumors, wherein the valine-restricted diet is used to limit the intake of valine in food.

[0009] Furthermore, the tumor is selected from colorectal cancer and leukemia, preferably colorectal cancer.

[0010] Furthermore, the drug is a drug that inhibits the growth and development of tumors by promoting DNA damage.

[0011] Furthermore, in the valine-restricted diet, the mass percentage of valine to the total food intake is 0.16% to 0.9%, preferably 0.41%.

[0012] The second aspect of the present invention is to provide a valine-restricted diet combined with a poly (ADP-ribose) polymerase inhibitor for use in the preparation of a drug for preventing and / or treating tumors, wherein the valine-restricted diet is used to limit the intake of valine in food, and the poly (ADP-ribose) polymerase inhibitor includes at least one of talazoparib, olaparib, and niraparib, preferably talazoparib.

[0013] Furthermore, the tumor is selected from colorectal cancer and leukemia, preferably colorectal cancer.

[0014] Furthermore, the drug is a drug that inhibits cell proliferation and promotes cell death by inducing DNA damage in cells through valine restriction and blocking or inhibiting DNA damage repair with a poly ADP-ribose polymerase inhibitor, thereby inhibiting the occurrence and development of tumors.

[0015] Furthermore, in the valine-restricted diet, the mass percentage of valine to total food intake is 0.16% to 0.9%, preferably 0.41%; and the dosage of the poly ADP-ribose polymerase inhibitor is 0.2 to 0.4 mg / kg.

[0016] Furthermore, the dosage of the poly (ADP-ribose) polymerase inhibitor is preferably 0.33 mg / kg.

[0017] Furthermore, when used to treat colorectal cancer cell lines, a poly (ADP-ribose) polymerase inhibitor and valine restriction are used in combination for treatment, and the concentration ratio of valine to the poly (ADP-ribose) polymerase inhibitor is: 0.4mM~0.8mM: 0.01μM~0.5μM. Preferably, the administration concentration ratio of tarazoparib, olaparib and niraparib in the poly (ADP-ribose) polymerase inhibitor is: 0.04μM: 0.4μM: 0.1μM.

[0018] Furthermore, the poly ADP-ribose polymerase inhibitor is preferably tarazoparib.

[0019] The third aspect of the present invention is to provide a therapeutic agent based on a valine-restricted diet, wherein the valine-restricted diet is used to limit the intake of valine in food, and the therapeutic agent comprises a valine-restricted diet and a poly (ADP-ribose) polymerase inhibitor.

[0020] Furthermore, in the valine restricted diet, the concentration ratio of the valine to the poly (ADP-ribose) polymerase inhibitor is: 0.4 mM to 0.8 mM: 0.03 μM to 0.6 μM.

[0021] Furthermore, the concentration ratio of the valine to the poly (ADP-ribose) polymerase inhibitor is preferably 0.41 mM: 0.04 μM.

[0022] Furthermore, the poly ADP-ribose polymerase inhibitor includes at least one of tarazoparib, olaparib and niraparib, preferably tarazoparib.

[0023] Furthermore, the tumor includes colorectal cancer.

[0024] In a specific embodiment, when the subject is a mouse, in the valine restricted diet, the concentration ratio of valine to the poly ADP-ribose polymerase inhibitor is: 0.4mM-0.8mM: 0.03μM-0.6μM, and the dosage of the poly ADP-ribose polymerase inhibitor is 0.2-0.4mg / kg, preferably, the concentration ratio of valine to the poly ADP-ribose polymerase inhibitor is 0.41mM: 0.04μM, and the dosage of the poly ADP-ribose polymerase inhibitor is 0.33mg / kg. It is understood that when it is used for other animals or humans, its dosage can be adaptively adjusted based on safety and efficacy.

[0025] The present invention adopts the above technical solution, and has the following technical effects compared with the prior art:

[0026] The present invention is based on a valine-restricted diet. Restricting the amount of valine in food can significantly inhibit the occurrence and development of tumors (especially colorectal cancer). It also shows that the valine-restricted diet can inhibit the occurrence and development of tumors by promoting DNA damage in cells. It can not only prevent the occurrence of tumors, but also inhibit the occurrence and development of tumors. The valine-restricted diet combined with a poly ADP-ribose polymerase inhibitor that blocks DNA damage repair can enhance the inhibitory effect on the occurrence and development of colorectal cancer, block or inhibit DNA damage repair, more effectively inhibit DNA damage repair, and then inhibit cell proliferation and promote cell death, significantly improving the effect of inhibiting the occurrence and development of tumors. The valine-restricted diet or its combined chemotherapy provided by the present invention can be used as a potential treatment plan for tumor patients, which provides an important reference basis for clinical treatment plans. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of the present invention. The exemplary embodiments of the present invention and their descriptions are only used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0028] Figure 1 This is a schematic diagram showing the effect of different concentrations of valine restriction on the occurrence and development of tumors in one embodiment of the present invention;

[0029] Figure 2 This is a schematic diagram of the experimental steps of the effect of a valine-restricted diet on patient-derived xenograft tumors in one embodiment of the present invention;

[0030] Figure 3 It is a schematic diagram of the results of the tumor growth curve and tumor weight in the patient-derived xenograft tumor experiment of a valine-restricted diet in one embodiment of the present invention;

[0031] Figure 4 This is a schematic diagram of the results of quantitative γH2AX-positive cells in the tumor prevention group in the patient-derived xenograft tumor experiment of a valine-restricted diet in one embodiment of the present invention;

[0032] Figure 5 This is a schematic diagram of the results of quantitative γH2AX-positive cells in the tumor treatment group in a patient-derived xenograft tumor experiment under a valine-restricted diet in one embodiment of the present invention;

[0033] Figure 6 This is a result diagram showing the efficacy of a valine-restricted diet combined with a PARP inhibitor in the treatment of colorectal cancer in one embodiment of the present invention. DETAILED DESCRIPTION

[0034] The following will be combined with the accompanying drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work belong to the scope of protection of the present invention. The experimental methods without specific conditions in the following embodiments are usually measured according to national standards. The experimental materials without the source indicated in the following embodiments are all commercially available raw materials. The equipment used in each step in the following embodiments is conventional equipment. If there is no corresponding national standard, it is carried out according to the general international standards, conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, all parts are weight parts and all percentages are mass percentages. Unless otherwise defined or specified, all professional and scientific terms used in the present invention have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equal to the recorded content can be applied to the method of the present invention.

[0035] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other. The present invention is further described below in conjunction with the drawings and specific embodiments, but is not intended to be a limitation of the present invention.

[0036] The feeds with different valine contents used in the examples of the present invention were purchased from Nantong Trophi Biotechnology Co., Ltd., PARP inhibitors (Talazoparib, Olaparib, Niraparib) were purchased from MedChenExpress; nude mice were purchased from Shanghai Slake Experimental Animal Co., Ltd.; HCT116 colorectal cancer cells were purchased from the Cell Bank of the Chinese Academy of Sciences.

[0037] Other reagents not specifically marked with manufacturers in the examples can be obtained through conventional commercial purchases.

[0038] The present invention is described below by way of example.

[0039] Example 1 - Effects of different concentrations of valine restriction on tumor development

[0040] This embodiment is a preferred embodiment of the present invention. Based on the valine restricted dietary therapy, mouse feeds containing different valine concentrations are fed to subcutaneous tumor-bearing mice to obtain a preferred valine restricted dietary therapy regimen.

[0041] This example uses a nude mouse subcutaneous tumor transplantation model to verify the in vivo therapeutic effect of valine restriction at different concentrations. The specific steps are as follows:

[0042] (1) Construction of nude mouse subcutaneous tumor transplantation model: In this experiment, 5-week-old nude mice were selected and 5×10 6 HCT116 colorectal cancer cells (purchased from the Chinese Academy of Sciences Cell Bank) were used when the tumor volume reached 50 mm 3 (length × width × width × 1 / 2), the mice were randomly divided into groups.

[0043] (2) The tumor-bearing mice in different groups in step (1) were fed with mouse feed containing different concentrations of valine, and the growth and proliferation of subcutaneous tumors were detected. The mice were randomly divided into four groups, as follows: Figure 1 The different treatment groups described in: 0.82% valine group; 0.70% valine group; 0.41% valine group; 0.16% valine group (the amounts are all mass percentages).

[0044] The food intake of mice was recorded every day, and the food intake was calculated according to the formula: food intake = (initial food weight - remaining food weight) (g) / average weight of mice (kg) / day.

[0045] Tumor volume and mouse body weight were measured weekly until endpoint.

[0046] (3) At the end of the experiment, mouse plasma and tumor tissue were collected. After the mouse tumor was collected, the whole tumor tissue was photographed and weighed. After separating part of the tumor tissue and weighing it, the valine content of the tumor tissue and plasma was detected. Part of the tumor tissue was fixed, embedded and sectioned, and γH2AX immunofluorescence staining was performed to quantify the proportion of γH2AX-positive cells.

[0047] The results are as follows Figure 1 As shown in the figure, according to the tumor growth curve and tumor weight statistics, the growth and proliferation of tumors in the experimental groups treated with valine-restricted diet (0.70% valine, 0.41% valine and 0.16% valine) were significantly inhibited compared with the control group (0.82% valine). Figure 1 It can be seen that valine restriction can inhibit the growth and proliferation of subcutaneous tumors in tumor-bearing mice (such as Figure 1 The valine content in tumor tissue and plasma also decreased accordingly (as shown in parts A, B, and C of Figure 1 More tumor cells had DNA damage (as shown in parts F and G). Figure 1 It is worth noting that the body weight and food intake of mice in the 0.70% valine and 0.41% valine groups were not significantly affected (as shown in the H part of the figure). Figure 1 In the D and E parts of the figure, the 0.41% valine feeding group can more significantly inhibit the occurrence and development of tumors, while the 0.16% valine feeding group has a significant decrease in the body weight of mice (as shown in Figure 1 (shown in part D).

[0048] From the above, it can be seen that a valine-restricted diet can significantly inhibit the occurrence and development of colorectal cancer. When the valine intake of mice is 0.41% of the total weight of food intake, it can more significantly inhibit the occurrence and development of tumors without affecting the weight and food intake of mice.

[0049] Example 2 - Effects of a valine-restricted diet on patient-derived xenograft tumors

[0050] In this example, the preferred valine-restricted diet regimen in Example 1 was used to treat mice to study the effect of the valine-restricted diet on a xenograft tumor model derived from colorectal cancer patients.

[0051] In this example, a xenograft tumor model derived from colorectal cancer patients was transplanted subcutaneously in nude mice to verify the therapeutic effect of a valine-restricted diet in mice, wherein the valine intake in the valine-restricted diet was 0.41% (weight percentage) of the total food intake. The specific steps are as follows:

[0052] (1) Construction of nude mouse subcutaneous transplanted tumor model: 5-week-old nude mice were selected for this experiment. This example is divided into two treatment methods: ① tumor prevention group and ② tumor treatment group. The specific steps are as follows Figure 2 shown.

[0053] ① Tumor prevention group Before inoculation of patient-derived tumors, mice were randomly divided into two groups: the experimental group was treated with a valine-restricted diet with 0.41% valine 2 weeks in advance; the control group was treated with 0.82% valine. Two weeks later, each nude mouse was implanted with a 2-3 mm 3 Tumor mass. Tumor volume and mouse body weight were measured weekly until endpoint.

[0054] ② In the tumor treatment group, each nude mouse was implanted with 2-3 mm 3 Tumor mass, when the tumor volume reaches 10mm 3 (length × width × width × 1 / 2), the mice were randomly divided into two groups: the experimental group was treated with valine-restricted diet with 0.41% valine; the control group was treated with 0.82% valine. Tumor volume and mouse body weight were measured once a week until the end point.

[0055] (2) Tumor tissue was collected at the end of the experiment. After the mouse tumor was collected, the whole tumor tissue was photographed and weighed, and the tumor weight of each group was calculated (the results are shown in Figure 3As shown). Take part of the tumor tissue, rinse with PBS to remove blood or other body fluids, fix with 4% paraformaldehyde at room temperature for 18-24 hours, dehydrate, make transparent, dip in wax and embed after fixation; fix the embedded tissue on a slicer for slicing; dewax and hydrate the tissue slices, and perform antigen repair; after antigen repair and inactivation, use blocking solution to block nonspecific binding sites. Incubate overnight with PAR (antibody dilution ratio of 1:100) and γH2AX (antibody dilution ratio of 1:100) primary antibodies. After incubation with the secondary antibody, perform DAPI staining. Observe and take pictures under a microscope, quantify the proportion of γH2AX-positive cells, and characterize the DNA damage in the tumor tissue (the results are shown in Figure 4 , Figure 5 shown).

[0056] from Figure 3 It can be seen that in the xenograft tumor model derived from colorectal cancer patients, valine-restricted diet (0.41% valine) was used for 2 weeks of pretreatment and when the tumor volume reached 10 mm 3 (length × width × width × 1 / 2) post-processing, from the real-time statistical tumor growth curve, it can be seen that after statistical growth curve and tumor weight, it was found that in the tumor prevention group (such as the restricted diet 2 weeks in advance) Figure 3 B, C) and tumor treatment group (eg Figure 3 In parts D and E of the figure, compared with the control group, the weight and volume of the tumor in the experimental group were significantly inhibited; Figure 4 (Cancer Prevention Group) and Figure 5 (Tumor treatment group) It can be seen that compared with the control group, DNA damage occurred in tumor cells in the tumor tissue of the experimental group (0.41% valine treatment).

[0057] From the above, it can be seen that a valine-restricted diet can significantly prevent the occurrence and development of colorectal cancer. In addition, a valine-restricted diet after tumor loading can also inhibit the occurrence and development of colorectal cancer.

[0058] Example 3 - Efficacy of a valine-restricted diet combined with a PARP inhibitor in the treatment of colorectal cancer

[0059] In this example, the colorectal cancer cell line HCT116 cells were treated with a PARP inhibitor in combination with valine restriction, cell proliferation was detected, and the effect of this combined treatment on tumor occurrence and development was verified.

[0060] The colorectal cancer cell line HCT116 cells in this example were purchased from the Cell Bank of the Chinese Academy of Sciences.

[0061] The specific steps are as follows:

[0062] (1) PARP inhibitors (Talazoparib, Olaparib, Niraparib) combined with valine restriction enhance the inhibitory effect on the proliferation of colorectal cancer cell HCT116:

[0063] PARP inhibitor treatment of HCT116 colorectal cancer cell line: cells were expressed at 1×10 3 6-well plates were plated, and each well was treated with DMSO (0.8mM valine) or valine restriction group (0.4mM valine), and PARP inhibitors were added to the control group and restriction group, including Talazoparib (0.04μM), Olaparib (0.4μM), and Niraparib (0.1μM); after 10-15 days, crystal violet staining was used, and photos were taken and the number of clones in each group was counted. By counting the number of cell clones, the results showed that the treatment method of valine restriction combined with PARP inhibitor significantly reduced the number of tumor cell clones compared with the control group, the valine restriction group alone, and the PARP inhibitor treatment group alone.

[0064] (2) PARP inhibitors (Talazoparib, Olaparib, Niraparib) combined with valine restriction reduce the IC50 of PARP inhibitors:

[0065] PARP inhibitor treatment of HCT116 colorectal cancer cell line: cells were counted at 6×10 3 96-well plates were plated, and each well was treated with a control group DMSO (0.8 mM valine) or a valine restriction group (0.4 mM valine), and PARP inhibitors were added to the control group and the restriction group, including Talazoparib (0.04 μM), Olaparib (0.4 μM), and Niraparib (0.1 μM). After 24-48 hours, crystal violet staining was used, and photos were taken and the number of clones in each group was counted (the results are shown in the figure). Figure 6 According to the ratio of clone numbers, IC50 was calculated. The IC50 value was determined by fitting the curve obtained by experiment using Prism software (the results are shown in Figure 6 As shown in parts B, C, D, and E in the figure, it can be seen that valine restriction combined with PARP inhibitors (Talazoparib, Olaparib, Niraparib) to treat HCT116 colorectal cancer cell line can significantly reduce the IC50 of the above three PARP inhibitors and sensitize the inhibitory effects of the three PARP inhibitors.

[0066] (3) PARP inhibitor (Talazoparib) combined with valine-restricted diet enhances the inhibitory effect on the occurrence and development of colorectal cancer:

[0067] Five-week-old nude mice were used in the experiment, and 5×10 6 HCT116 colorectal cancer cell line, when the tumor volume reaches 50mm 3 (length × width × width × 1 / 2), the mice were randomly divided into Figure 6 The different treatment groups described:

[0068] Control group (0.82% valine), PARP inhibitor (Talazoparib) was injected intraperitoneally daily at a dose of 0.33 mg / kg (10% DMAC + 6% Solutol + 84% PBS); restricted diet group (0.41% valine); combined treatment group (0.33 mg / kg Talazoparib + 0.41% valine); tumor volume was measured once a week until the endpoint.

[0069] At the end of the experiment, tumor tissue was collected. After the mouse tumor was collected, the whole tumor tissue was photographed and the size of the tumor was recorded. After the tumor tissue was weighed, the changes in the weight of the tumor tissue were counted (the results are shown in Figure 6 (as shown in parts F, G, and H in the figure). Figure 6 It can be seen that the tumor growth of mice treated with PARP inhibitors and valine restricted diet (0.41% valine) alone was significantly slowed compared with the control group. In addition, compared with the PARP inhibitor and valine restricted diet (0.41% valine) alone treatment group, the tumor volume and tumor in the combined PARP inhibitor and valine restricted diet treatment group were significantly suppressed, that is, the valine restricted diet combined with PARP inhibitors showed a more significant therapeutic advantage.

[0070] In summary, the present invention is based on a valine restricted diet, formulates mouse feeds containing different valine concentrations (0.82%, 0.70%, 0.41%, 0.16% valine), and feeds subcutaneous tumor-bearing mice with mouse feeds with different valine concentrations. The weight of the mice, the amount of food intake, and the volume and weight of the tumor are monitored in real time. The results show that feeding subcutaneous tumor-bearing mice with 0.41% valine not only does not affect the weight and feeding ability of the mice, but also can significantly inhibit the occurrence and development of colorectal cancer, and at the same time indicates that the valine restricted diet therapy can inhibit the occurrence and development of tumors by promoting DNA damage.

[0071] The present invention experiments on the effect of valine-restricted dietary therapy in patient-derived xenograft (PDX) models, directly transplants tumor tissues from tumor patients into immunodeficient mice to form tumor transplants, supplemented with valine-restricted dietary therapy (0.41% valine), and sets up valine-restricted diet colorectal cancer prevention and treatment groups. The results show that valine-restricted dietary therapy can not only prevent the occurrence of colorectal cancer, but also inhibit the occurrence and development of colorectal cancer.

[0072] The present invention also verifies that a valine-restricted diet combined with blocking PARP inhibitors (Talazoparib, Olaparib, Niraparib) can enhance the inhibitory effect on the occurrence and development of colorectal cancer and promote the effect of a valine-restricted diet on colorectal cancer. Therefore, the valine-restricted diet provided by the present invention and its combined use with a poly ADP-ribose polymerase inhibitor in the preparation of drugs for the prevention and / or treatment of tumors have important application significance and value.

[0073] The above description is only a preferred embodiment of the present invention, and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the description and illustrations of the present invention should be included in the protection scope of the present invention.

Claims

1. Use of a valine-restricted diet in the preparation of a drug for preventing and / or treating tumors, characterized in that: The valine-restricted diet is used to restrict the intake of valine in food.

2. The use according to claim 1, characterized in that: The tumor is selected from colorectal cancer and leukemia.

3. The use according to claim 1, characterized in that: The drug is a drug that inhibits the growth and development of tumors by promoting DNA damage.

4. The use according to claim 1, characterized in that: In the valine-restricted diet, the mass percentage of valine to the total food intake is 0.16% to 0.9%.

5. Use of a valine-restricted diet combined with a poly (ADP-ribose) polymerase inhibitor in the preparation of a drug for preventing and / or treating tumors, characterized in that: The valine-restricted diet is used to limit the intake of valine in food, and the poly ADP-ribose polymerase inhibitor includes at least one of tarazoparib, olaparib, and niraparib.

6. The use according to claim 5, characterized in that: The tumor is selected from colorectal cancer and leukemia.

7. The use according to claim 5, characterized in that: The drug is a drug that inhibits cell proliferation and promotes cell death by inducing DNA damage in cells through valine restriction and blocking or inhibiting DNA damage repair by a poly ADP-ribose polymerase inhibitor, thereby inhibiting the occurrence and development of tumors.

8. The use according to claim 5, characterized in that: In the valine-restricted diet, the mass percentage of valine to the total food intake is 0.16% to 0.9%, preferably 0.41%; the dosage of the poly ADP-ribose polymerase inhibitor is 0.2 to 0.4 mg / kg.

9. The use according to claim 5, characterized in that: When used to treat colorectal cancer cell lines, a poly (ADP-ribose) polymerase inhibitor and valine restriction are used in combination, and the concentration ratio of valine to the poly (ADP-ribose) polymerase inhibitor is: 0.4mM-0.8mM: 0.01μM-0.5μM.

10. A therapeutic agent based on a valine restricted diet, characterized in that The valine-restricted diet is used to restrict the intake of valine in food, and the therapeutic agent comprises the valine-restricted diet and a poly (ADP-ribose) polymerase inhibitor.

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