Application of EZH2 inhibitor in preparation of medicine for preventing and / or treating lymphedema

Abstract

The invention relates to application of an EZH2 inhibitor in preparation of a medicine for preventing and / or treating lymphedema. Experiments prove that the EZH2 inhibitor can remarkably inhibit the skin fibrosis symptom of a lymphedema subject for the first time, so that the progress of the lymphedema can be effectively blocked, and the purposes of relieving, relieving and / or improving the lymphedema and related symptoms are achieved. In addition, the inventor also finds that the EZH2 inhibitor has relatively good medication safety. Therefore, the EZH2 inhibitor is expected to become a candidate therapeutic drug for lymphedema and has great clinical application prospect and value.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to the use of EZH2 inhibitors in the preparation of drugs for preventing and / or treating lymphedema. Background Art

[0002] Lymphedema is a chronic, progressive and incurable disease caused by lymphatic system dysfunction. Lymphedema is divided into primary lymphedema and secondary lymphedema. Among them, primary lymphedema is relatively rare, and lymphedema after cancer treatment is the main cause of secondary lymphedema. Lymphedema seriously affects the shape and function of the patient's limbs, resulting in a significant decline in the patient's quality of life, and at the same time, it is extremely prone to psychological problems such as anxiety and depression. Early lymphedema is mainly manifested as edema. As the disease progresses, the late stage is characterized by chronic inflammation, fat deposition and tissue fibrosis. Since lymph fluid is rich in macromolecular substances such as proteins and hyaluronic acid, it can stimulate fibroblasts to synthesize collagen. When collagen fibers are deposited excessively, the skin tissue will become hard and thickened, thereby causing the limb volume to increase and deform, which not only further weakens the transport capacity of the lymphatic system, but also makes the skin and lymphatic vessels more susceptible to infection. And recurrent cellulitis will in turn exacerbate lymphedema, forming a vicious cycle. Therefore, anti-fibrotic treatment is crucial throughout the treatment process of lymphedema.

[0003] In the treatment of lymphedema, early-stage patients can adopt conservative treatment, that is, complex decongestive therapy, which includes methods such as postural drainage, compression bandaging, and massage. However, this therapy has obvious drawbacks. It requires patients to adhere to daily care, has extremely high requirements for patient compliance, and the treatment effect is limited. In particular, for patients with moderate to severe or chronic edema, the effect is difficult to last, and the effect in inhibiting tissue fibrosis is not significant.

[0004] Drug treatment is also one of the common treatment means for lymphedema. For example, the use of antibiotics can relieve acute inflammation, but it lacks long-term efficacy; although diuretics can relieve acute edema symptoms, there is a risk of side effects, and long-term use may cause electrolyte disorders. More importantly, the existing drug treatment does not target the tissue fibrosis process, and there is currently no anti-lymph edema fibrosis drug available on the market.

[0005] Lymphedema can also be treated by physical therapy methods, including baking treatment, soaking and washing, wet compress, intermittent pneumatic compression treatment, etc. However, the efficacy of these methods highly depends on continuous treatment. Once interrupted, the disease is extremely likely to relapse, and for patients with severe skin fibrosis or in the late stage of the disease, the treatment effect is poor.

[0006] Surgical treatment is also an option for the treatment of lymphedema, such as lymphaticovenular anastomosis and tissue resection surgery. Among them, lymphaticovenular anastomosis requires ultra-microsurgical equipment and experienced doctors, which limits the wide application of this technique; although tissue resection surgery can remove hyperplastic fibroadipose tissue, it may damage normal tissues during the operation, and the probability of postoperative recurrence or infection is relatively high.

[0007] Therefore, the current treatment methods for lymphedema all have certain limitations, and there is an urgent need to develop new effective treatment means to improve the condition of lymphedema patients.

[0008] The histone methyltransferase EZH2 (Enhancer of zeste homolog 2) is a core subunit of the polycomb repressive complex 2 (PRC2). PRC2 can trimethylate lysine 27 of histone H3 (H3K27) in the promoter region of target genes, resulting in the inhibition of target gene transcription. Currently, two EZH2 inhibitors, EPZ6438 and GSK126, designed for the active site of the EZH2 enzyme have been developed, and they can specifically inhibit the methyltransferase function of EZH2. EPZ6438 (Tazemetostat, Chinese name: Tazemetostat) is the world's first approved EZH2 inhibitor and has been used in the treatment of epithelioid sarcoma and follicular lymphoma; GSK126 also showed significant effects of inhibiting the proliferation of lung cancer cells and inducing apoptosis in preclinical studies. Summary of the Invention

[0009] Objective of the Invention

[0010] Aiming at the needs or defects existing in the prior art, the purpose of the present invention is to provide the use of EZH2 inhibitors in the preparation of drugs for preventing and / or treating lymphedema.

[0011] Solution

[0012] To achieve the above purpose, the present invention adopts the following technical solutions:

[0013] In the first aspect, the present invention provides the use of EZH2 inhibitors in the preparation of drugs for preventing and / or treating lymphedema.

[0014] In a feasible embodiment, the EZH2 inhibitor is any one or more selected from the following: EPZ6438, GSK126, and their pharmaceutically acceptable salts.

[0015] In a feasible embodiment, the lymphedema is primary lymphedema and / or secondary lymphedema.

[0016] Preferably, the lymphedema is secondary lymphedema after cancer surgical treatment.

[0017] In a feasible embodiment, the treatment of lymphedema includes reducing, alleviating, and / or improving lymphedema or its symptoms.

[0018] Preferably, the symptom of lymphedema that is reduced, alleviated, and / or improved is skin fibrosis.

[0019] In a feasible embodiment, the subject is a mammal;

[0020] And / or, in the drug for preventing and / or treating lymphedema, the EZH2 inhibitor is used as the sole active ingredient or as one of the active ingredients;

[0021] And / or, the drug further includes a pharmaceutically acceptable carrier and / or excipient.

[0022] In a feasible embodiment, the subject is a human;

[0023] And / or, for human subjects, the prophylactically effective amount of the EZH2 inhibitor is 1 - 3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutically effective amount is 3 - 5 mg / kg body weight, preferably 4 mg / kg body weight. For example, in a feasible embodiment, for lymphedema in human subjects, the prophylactically effective amount of EPZ6438 or GSK126 is 1 - 3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutically effective amount is 3 - 5 mg / kg body weight, preferably 4 mg / kg body weight.

[0024] In a feasible embodiment, the drug is in a dosage form selected from the following: oral dosage form, injection dosage form, implant dosage form, and / or transdermal dosage form.

[0025] Preferably, the oral dosage form is selected from: tablets, capsules, granules, oral liquids, pills, powders, tinctures, syrups;

[0026] Preferably, the injection dosage form is an injection solution or a powder for injection;

[0027] Preferably, the implant dosage form is selected from: implant tablets, implant rods, implant microspheres, and / or implant nanoparticles;

[0028] Preferably, the transdermal dosage form is selected from: ointments, creams, gels, patches, and / or aerosols.

[0029] Second aspect, the present invention provides a method for preventing and / or treating lymphedema, the method comprising: administering to a subject in need a prophylactically and / or therapeutically effective amount of an EZH2 inhibitor.

[0030] In a feasible embodiment, the EZH2 inhibitor is any one or more selected from the following: EPZ6438, GSK126, and pharmaceutically acceptable salts thereof.

[0031] In a feasible embodiment, the lymphedema is primary lymphedema and / or secondary lymphedema.

[0032] Preferably, the lymphedema is secondary lymphedema after cancer surgical treatment.

[0033] In a feasible embodiment, treating the lymphedema includes reducing, alleviating, and / or improving lymphedema or its symptoms.

[0034] Preferably, the symptom of lymphedema that is reduced, alleviated, and / or improved is skin fibrosis.

[0035] In a feasible embodiment, the EZH2 inhibitor is provided in the form of a pharmaceutical preparation, in which the EZH2 inhibitor is the sole active ingredient or one of the active ingredients; in addition to the EZH2 inhibitor, the pharmaceutical preparation further includes a pharmaceutically acceptable carrier and / or excipient.

[0036] In a feasible embodiment, the pharmaceutical preparation is a dosage form selected from the following: oral dosage form, injection dosage form, implant dosage form, and / or transdermal dosage form.

[0037] Preferably, the oral dosage form is selected from: tablets, capsules, granules, oral liquids, pills, powders, tinctures, syrups;

[0038] Preferably, the injection dosage form is an injection or a powder for injection;

[0039] Preferably, the implant dosage form is selected from: implant tablets, implant rods, implant microspheres, and / or implant nanoparticles;

[0040] Preferably, the transdermal dosage form is selected from: ointments, creams, gels, patches, and / or aerosols.

[0041] In a feasible embodiment, the subject is a human;

[0042] For human subjects, preferably, the prophylactically effective amount of the EZH2 inhibitor is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutically effective amount is 3-5 mg / kg body weight, preferably 4 mg / kg body weight. For example, in a feasible embodiment, for lymphedema in human subjects, the prophylactically effective amount of EPZ6438 or GSK126 is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutically effective amount is 3-5 mg / kg body weight, preferably 4 mg / kg body weight.

[0043] The term "effective amount" refers to the amount or dose of an active ingredient that, when administered to a subject singly or in multiple doses, provides the desired effect to the subject being prophylaxed or treated. The effective amount can be determined by a diagnostician, who is a person skilled in the art, based on known techniques and observations in similar situations. When determining the effective amount or dose of the active ingredient to be administered, the diagnostician involved should consider various factors, including but not limited to: the species of mammal; volume, age, and general health; the specific disease involved; the degree or severity of the involvement of the disease; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability properties of the formulation administered; the dosing regimen selected; the use of concomitant drug therapy; and other relevant circumstances.

[0044] Beneficial Effects

[0045] The present invention provides the use of an EZH2 inhibitor in the preparation of a drug for preventing and / or treating lymphedema. The inventors have confirmed through experiments that the EZH2 inhibitor can significantly inhibit the degree of skin fibrosis in lymphedema patients, manifested in that: it can significantly reduce the skin thickness, epidermal thickness, and fibro-fatty tissue thickness of lymphedema patients, and the degree of fibrosis is also significantly reduced; this effective inhibition of skin fibrosis can effectively block the progression of lymphedema in patients, and thus achieve the purpose of reducing, alleviating, and / or improving lymphedema and its related symptoms.

[0046] In addition, safety is a key consideration in drug application. The research of the present invention has found that no obvious side effects have been produced on any internal organs during the process of using the EZH2 inhibitor to treat lymphedema mice, which fully shows that the EZH2 inhibitor has good safety.

[0047] In summary, in view of the significant effect of the EZH2 inhibitor in inhibiting lymphedema skin fibrosis and its excellent safety, it has great potential and broad application prospects as a lymphedema treatment drug and is a highly promising candidate treatment drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] One or more embodiments are illustrated by way of example in the corresponding drawings, and such illustrative descriptions do not constitute a limitation on the embodiments. The special term "exemplary" herein means "serving as an example, embodiment, or illustration". Any embodiment illustrated as "exemplary" herein need not be construed as superior to or better than other embodiments.

[0049] Figure 1 The staining results of the affected skin of lymphedema patients versus healthy control skin tissue are shown, where Figure A is the hematoxylin-eosin staining result, Figure B is the Sirius red staining result, and Figure C is the Masson staining result.

[0050] Figure 2 The detection results of the expression levels of EZH2 and H3K27me3 in the affected skin of lymphedema patients versus healthy control skin tissue by immunofluorescence are shown; where Figure A is the immunofluorescence staining result using an antibody against EZH2, Figure B is the bar graph obtained by statistically analyzing the result of Figure A, Figure C is the immunofluorescence staining result using an antibody against H3K27me3, and Figure D is the bar graph obtained by statistically analyzing the result of Figure C; where, * indicates: compared with the control, P < 0.05.

[0051] Figure 3 It is a schematic flow chart of treating a mouse model of lower limb lymphedema with an EZH2 inhibitor, as described in Example 2.

[0052] Figure 4 The staining results of the skin tissue of mice in each experimental group in Example 2 are shown, where Figure A is the hematoxylin-eosin staining result, Figure B is the Sirius red staining result, and Figure C is the Masson staining result.

[0053] Figure 5 The detection results of the skin thickness (A), epidermal thickness (B), fibro-fatty thickness (C), and fibrosis quantification (D) of mice in each experimental group in Example 2 are shown; where, * indicates: compared with the two specified groups, P < 0.05; ** indicates: compared with the two specified groups, P < 0.01; *** indicates: compared with the two specified groups, P < 0.001.

[0054] Figure 6 The hematoxylin-eosin staining results of the heart (A), liver (B), spleen (C), lung (D), kidney (E), and small intestine (F) of mice in each experimental group in Example 3 are shown. Detailed implementation manners

[0055] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the scope of protection of the present invention.

[0056] In addition, for a better illustration of the present invention, numerous specific details are given in the following detailed description. Those skilled in the art should understand that the present invention can be implemented without some specific details. In some embodiments, details of materials, components, methods, means, etc. well-known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.

[0057] Unless otherwise clearly stated, throughout the specification and claims, the term "comprise" or its variations such as "comprises" or "including" etc. will be understood to include the stated elements or components, without excluding other elements or other components.

[0058] The present invention will be further described in detail below through examples.

[0059] In the following examples, the materials, animals, reagents, etc. used, unless otherwise specified, can be obtained through commercial channels.

[0060] Example 1: Structural characterization of skin tissues of patients with lymphedema and expression of EZH2 and H3K27me3 proteins

[0061] (1) Histological structure and fibrosis of skin tissues of lymphedema patients

[0062] Discarded skin tissue samples of patients with secondary lymphedema after cancer surgery (i.e., the affected skin tissues of patients with lymphedema) were collected as the experimental group skin tissues. In addition, discarded skin tissue samples of normal healthy subjects after plastic surgery (i.e., healthy control skin tissues) were collected as the control group skin tissues. The collected skin tissues of the experimental group and the control group were respectively fixed in 4% paraformaldehyde for 48 h, then tissue dehydration treatment was carried out using gradient alcohol, paraffin embedding was performed after dehydration was completed, and sections were made; subsequently, hematoxylin-eosin staining kit, modified Sirius red staining kit, and Masson's trichrome staining kit (all purchased from Beijing Solarbio Science & Technology Co., Ltd., and the catalog numbers of the three kits are G1120, G1473, and G1340 respectively) were used to stain the tissue sections respectively according to the instructions of their respective kit manuals to evaluate the changes in tissue structure and fibrosis.

[0063] The hematoxylin-eosin, Sirius red, and Masson staining results are respectively as Figure 1As shown in Figures A, B, and C, it shows that a large amount of fibrotic tissue can be seen in the affected skin tissue of lymphedema patients; in contrast, there is little fibrotic tissue in the skin tissue of healthy controls.

[0064] (2) Expression of EZH2 and H3K27me3 in skin tissues of lymphedema patients

[0065] According to the conventional immunofluorescence staining procedure, the affected skin tissue of lymphedema patients and the skin tissue of healthy controls collected in 1) above were immunofluorescently stained with an antibody against EZH2 (Cell Signaling Technology, #5246, 1:200) and an antibody against H3K27me3 (Cell Signaling Technology, #9733, 1:200), respectively.

[0066] The immunofluorescence staining results of the antibody against EZH2 are as shown in Figure A in Figure 2 and its statistical results are as shown in Figure B in Figure 2 As can be seen from Figures A and B in Figure 2 compared with the skin tissue of healthy controls, the expression level of EZH2 in the affected skin tissue of lymphedema patients increased significantly, by about 62 times.

[0067] The immunofluorescence staining results of the antibody against H3K27me3 are as shown in Figure C in Figure 2 and its statistical results are as shown in Figure D in Figure 2 As can be seen from Figures C and D in Figure 2 compared with the skin tissue of healthy controls, the expression level of H3K27me3 in the affected skin tissue of lymphedema patients increased significantly, by about 63 times.

[0068] Example 2: EZH2 inhibitor can effectively relieve skin fibrosis in a lymphedema mouse model

[0069] In this example, male C57BL6 mice at about 8 weeks of age and weighing 20 - 25 g (purchased from Zhuhai Biosystems Co., Ltd.) were used as experimental animals, and the therapeutic effects of the EZH2 inhibitors EPZ6438 or GSK126 on lymphedema mice were investigated respectively.

[0070] The C57BL6 mice used in this example were purchased from Zhuhai Biosystems Co., Ltd., and the inhibitor drugs EPZ6438 and GSK126 were both purchased from Selleck Chemicals. Among them, the catalog number of EPZ6438 is S7128, and the catalog number of GSK126 is S7061.

[0071] (1) Preparation of EPZ6438 injection, GSK126 injection and control injection

[0072] When preparing the injection solution, first dissolve the drug powder of EPZ6438 or GSK126 in DMSO to prepare a stock solution with a concentration of 50 mg / mL. Before use, add corn oil to the EPZ6438 or GSK126 stock solution to dilute it 10 times to prepare a solution with a concentration of 5 mg / mL, which is the EPZ6438 or GSK126 injection solution.

[0073] In addition, take DMSO, add corn oil to it and dilute it 10 times to prepare a control injection solution.

[0074] During injection, calculate the injection volume according to the body weight of the mice. The dosage of EPZ6438 or GSK126 is 50 mg / kg body weight, and the dosage of the control injection solution is 10 mL / kg body weight (that is, the injection volume per kilogram of mouse body weight is equivalent to that of the EPZ6438 or GSK126 injection solution).

[0075] (2) Construction of a mouse model of lower limb lymphedema

[0076] According to the method for constructing and identifying the mouse lower limb lymphedema model described in the applicant's published article Chen, Z., et al., PPARγ agonist treatment reduces fibroadipose tissue in secondary lymphedema by exhausting fibroadipogenic PDGFRα+ mesenchymal cells. JCI insight, 2023.8(24), a mouse lower limb lymphedema model was constructed by surgically destroying the lower limb lymphatic system of the mice (including removing the popliteal lymph nodes, superficial inguinal lymph nodes, deep inguinal lymph nodes and femoral lymphatic vessels) of the mice.

[0077] (3) Effects of EZH2 inhibitors EPZ6438 or GSK126 on lymphedema mice

[0078] The experimental grouping and the treatment methods for each group are as follows:

[0079] 1) EPZ6438 treatment group: Construct a mouse lower limb lymphedema model according to the method described in (2) above. On the 1st day and the 4th day after surgery, inject the EPZ6438 injection solution prepared in (1) above into the abdominal cavity of the mice at a dose of 50 mg / kg body weight as subsequent treatment;

[0080] 2) GSK126 treatment group: Construct a mouse lower limb lymphedema model according to the method described in (2) above. On the 1st day and the 4th day after surgery, inject the GSK126 injection solution prepared in (1) above into the abdominal cavity of the mice at a dose of 50 mg / kg body weight as subsequent treatment;

[0081] 3) Lymphedema model group: A mouse lower limb lymphedema model was established according to the method described in (2) above. On the first day and the fourth day after surgery, the control injection solution prepared in (1) above was intraperitoneally injected into the mice at a dose of 10 mL / kg body weight as a subsequent treatment;

[0082] 4) Sham operation group: The mouse skin was incised according to the surgical path used to construct the mouse lower limb lymphedema model, and the regional lymph nodes were fully exposed but the lymph node tissue was not removed. The mouse skin was then sutured as in the construction of the lymphedema model; then, on the first day and the fourth day after the operation, the control injection solution prepared in the above (1) was injected into the mouse peritoneum at a dose of 10 mL / kg body weight as a follow-up treatment.

[0083] Each of the above experimental groups contained 6 mice. For each experimental group of mice, skin tissue samples of the lower limbs of the mice were collected on the 7th day after surgery for subsequent testing. The specific flow chart of the above procedure is shown in Figure 3 .

[0084] Next, according to the method described in Example 1, the lower limb skin tissue of each experimental group of mice was prepared into tissue sections; then, using a hematoxylin-eosin staining kit, a modified Sirius red staining kit, and a Masson's trichrome staining kit, according to the instructions of each kit manual, the lower limb skin tissue sections of each experimental group of mice were subjected to hematoxylin-eosin staining, Sirius red staining, and Masson's trichrome staining, respectively. The staining results are shown as follows: Figure 4 As shown in Figures A, B and C.

[0085] Furthermore, according to the above staining results of the lower limb skin tissue samples of mice in each experimental group, the thickness of the skin tissue, epidermal tissue thickness and fibrofat tissue thickness were measured, and fibrosis was quantified (the fibrosis quantification method was described in Chen, Z., et al., and the ratio of the fibrosis area to the total tissue area calculated by the image analysis software ImageJ was used for quantitative evaluation). The results are as follows: Figure 5 As shown in Figures A, B, C and D.

[0086] Depend on Figure 4 Figures A, B, and C in Figure 5 From Figures A, B, C, and D in the figure, we can conclude that:

[0087] Compared with the mice in the sham operation group, the skin tissue of the mice in the lymphedema model group was significantly thickened, the fibrous tissue was significantly hyperplastic, and the degree of fibrosis was significantly higher, indicating the successful establishment of the lymphedema model. After treating the lymphedema mice with the EZH2 inhibitor EPZ6438 or GSK126, the thickness of the skin tissue, epidermal tissue, fibro-fatty tissue, and the degree of fibrosis in the mice were significantly decreased compared with those in the lymphedema model group, and even reached a level close to that of the sham operation mice.

[0088] The above results indicate that after treating the lower limb lymphedema mice with the EZH2 inhibitor EPZ6438 or GSK126, the symptoms of skin fibrosis were significantly alleviated, and the lymphedema process was significantly inhibited. This suggests that the EZH2 inhibitor can significantly reduce the degree of fibrosis of lymphedema, thereby significantly inhibiting the process of lymphedema.

[0089] Example 3: Safety evaluation of EZH2 inhibitor in a lymphedema mouse model

[0090] In this example, based on the mice in each experimental group in Example 2, the drug safety of the EZH2 inhibitor EPZ6438 or GSK126 in a lymphedema mouse model was evaluated.

[0091] Specifically, on the 7th day after the modeling surgery, the heart, liver, spleen, lung, kidney, and small intestine tissues of the mice in each experimental group were collected; the collected tissue samples were fixed in 4% paraformaldehyde for 48 h, then dehydrated with gradient alcohol, embedded in paraffin after dehydration, and sections were made; according to the instructions in the hematoxylin-eosin staining kit manual, the hematoxylin-eosin staining was performed on each tissue section, and the tissue structure was observed through a microscope to evaluate the tissue structure.

[0092] The results are shown in Figures A-F in Figure 6 ; as can be seen from Figure 6 , the lower limb lymphedema modeling surgery in mice did not affect the tissue structure of other internal organs; moreover, after treatment with the EZH2 inhibitor EPZ6438 or GSK126, there was no significant difference in the tissue structure of each internal organ of the mice compared with that of the sham operation group. These results fully demonstrate that the EZH2 inhibitor exhibits good safety in a lymphedema mouse model.

[0093] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. Use of an EZH2 inhibitor in the preparation of a medicament for preventing and / or treating lymphedema.

2. The use according to claim 1, characterized in that The EZH2 inhibitor is any one or more selected from the following: EPZ6438, GSK126 and pharmaceutically acceptable salts thereof.

3. The use according to claim 1, characterized in that The lymphedema is primary lymphedema and / or secondary lymphedema.

4. The use according to claim 3, characterized in that The lymphedema is secondary lymphedema after cancer surgery.

5. The use according to claim 1, characterized in that: The treatment of lymphedema includes alleviating, relieving and / or ameliorating lymphedema or its symptoms.

6. The use according to claim 5, characterized in that The symptom of lymphedema that was alleviated, relieved and / or improved was skin fibrosis.

7. The use according to claim 1, characterized in that The subject is a mammal; And / or, in the drug for preventing and / or treating lymphedema, the EZH2 inhibitor is used as the sole active ingredient or as one of the active ingredients; And / or, the drug further comprises a pharmaceutically acceptable carrier and / or excipient.

8. The use according to claim 7, characterized in that The subjects were human; And / or, for human subjects, the preventive effective amount of the EZH2 inhibitor is 1-3 mg / kg body weight, preferably 2 mg / kg body weight, and the therapeutic effective amount is 3-5 mg / kg body weight, preferably 4 mg / kg body weight.

9. The use according to claim 1, characterized in that The drug is in a dosage form selected from the following: an oral dosage form, an injection dosage form, an implantation dosage form and / or a transdermal dosage form.

10. The use according to claim 9, characterized in that The oral dosage form is selected from the group consisting of tablets, capsules, granules, oral liquids, pills, powders, tinctures, and syrups; And / or, the injection dosage form is an injection solution or a powder injection; and / or, the implantable dosage form is selected from: implantable tablets, implantable rods, implantable microspheres and / or implantable nanoparticles; And / or, the transdermal dosage form is selected from: ointment, cream, gel, patch and / or aerosol.

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