WO2016127848A1 - 绿原酸在制备预防和治疗原发性皮肤t细胞淋巴癌的药物中的用途 - Google Patents

绿原酸在制备预防和治疗原发性皮肤t细胞淋巴癌的药物中的用途 Download PDF

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WO2016127848A1
WO2016127848A1 PCT/CN2016/073125 CN2016073125W WO2016127848A1 WO 2016127848 A1 WO2016127848 A1 WO 2016127848A1 CN 2016073125 W CN2016073125 W CN 2016073125W WO 2016127848 A1 WO2016127848 A1 WO 2016127848A1
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chlorogenic acid
cell lymphoma
primary cutaneous
preparation
medicament
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French (fr)
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张洁
殷蕊蕊
黄骏
黄望
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四川九章生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]

Definitions

  • the invention relates to the field of biomedicine, in particular to the field of treatment of primary cutaneous T-cell lymphoma, in particular to the use of chlorogenic acid for the preparation of a medicament for preventing and treating primary cutaneous T-cell lymphoma.
  • CTL Primary cutaneous T cell lymphoma
  • granuloma fungoid is a skin primary origin of T lymphocytes (especially T helper cell subpopulations). Lymphoma. It is a group of lymphoproliferative diseases with significant heterogeneity and lacks standardized treatment options.
  • interferon BCG or transfer factor
  • topical treatment can be used with nitrogen mustard or aromatic retinoic acid for external use, electron beam irradiation, X-ray, photochemotherapy And so on have a certain effect.
  • chemotherapeutic drugs and targeted therapeutic drugs for the treatment of this disease.
  • chlorogenic acid ie, 3-coffee quinic acid
  • chlorogenic acid has a polyhydroxyl, unsaturated ester and ortho-diphenol structure in its structure, which makes chlorogenic acid highly resistant to oxygen.
  • US 5,788,971 reports the effect of the antioxidant action of chlorogenic acid on scavenging oxygen free radicals and the treatment of inflammatory response.
  • WO 99/34812 reports the anti-viral, anti-bacterial or immunomodulatory functions of formulations consisting of trihydroxyketone, forsythia alcohol and chlorogenic acid.
  • US20050282892 describes the treatment of chronic myeloid leukemia with chlorogenic acid. SanR.H.C.
  • CN200610021897.1 discloses the use of chlorogenic acid for the preparation of a medicament for preventing and treating nasopharyngeal cancer
  • CN200610021591.6 discloses the preparation of chlorogenic acid for preventing and treating cervical cancer. Application in medicine.
  • An object of the present invention is to provide a use of chlorogenic acid for the preparation of a medicament for preventing and treating primary cutaneous T-cell lymphoma.
  • the present invention proves that chlorogenic acid can activate CD4 T lymphocytes and CD8 T lymphocytes, and target CD4 T lymphocytes and CD8 T lymphocytes to prevent and treat primary cutaneous T cell lymphoma.
  • the invention promotes the proliferation of T lymphocytes of the body through chlorogenic acid and activates T lymphocytes to achieve the purpose of treating primary cutaneous T-cell lymphoma.
  • chlorogenic acid can also inhibit the proliferation of primary skin T-cell lymphoma cells, and the inhibitory effect is similar to that of interferon.
  • chlorogenic acid for the preparation of a medicament for the prevention and treatment of primary cutaneous T-cell lymphoma.
  • chlorogenic acid for the preparation of a medicament for the prevention and treatment of primary cutaneous T-cell lymphoma with CD4 lymphocytes as a target.
  • chlorogenic acid for the preparation of a medicament for the prevention and treatment of primary cutaneous T-cell lymphoma with CD8 lymphocytes as a target.
  • chlorogenic acid for the preparation of a medicament for the prevention and treatment of primary cutaneous T-cell lymphoma with CD4 and CD8 as targets.
  • the chlorogenic acid is used as an active ingredient, and a pharmaceutically acceptable adjuvant or auxiliary ingredient is used as a medicine.
  • the dosage form of the medicament is an injection preparation or an oral preparation.
  • each preparation unit contains 1-100 mg of chlorogenic acid.
  • the clinical dose of the drug is 1-100 mg/kg.
  • chlorogenic acid and an antitumor drug for the preparation of a combination therapy for primary cutaneous T-cell lymphoma, wherein the anti-tumor drug is cyclophosphamide, 5-fluorouracil, interleukin 12, interleukin 2, gamma interferon One or several.
  • the dose ratio of the chlorogenic acid to the antitumor drug is 1:5 to 5:1.
  • Primary cutaneous lymphoma is an extranodal non-Hodgkin's lymphoma. Studies have shown that primary cutaneous lymphoma and primary lymph node lymphoma with the same histological subtype are clinically and histologically characterized when involved in the skin. Biological behavior and prognosis are significantly different. In addition, gene metastasis, oncogene expression, viral fragments, and adhesion molecules of cutaneous lymphoma are different from those of lymph node lymphoma. Morphologically consistent lymphomas of different origins are monoclonal amplifications of many different, organ-associated lymphocyte subsets that retain many of the characteristics of their corresponding benign parts.
  • Primary cutaneous T-cell lymphoma (PCTCL) is the primary primary cutaneous lymphoma, characterized by monoclonal expansion of helper T cells in the skin, with death and prognosis within a few years. difference.
  • chlorogenic acid for the preparation of a medicament for the prevention and treatment of primary cutaneous T-cell lymphoma.
  • Applicants have found through research that chlorogenic acid can activate T cell function by targeting T lymphocyte subsets CD4 and CD8 cells to prevent and treat primary cutaneous T-cell lymphoma.
  • chlorogenic acid can also inhibit the proliferation of primary skin T-cell lymphoma cells, and the inhibitory effect is similar to that of interferon.
  • chlorogenic acid can be formulated into a drug with a pharmaceutically acceptable adjuvant or an auxiliary ingredient, and can be prepared into an injection preparation, an oral preparation or a transdermal administration preparation by various pharmaceutical techniques.
  • Fig. 1 is a graph showing the results of T lymphocyte proliferation assay (p ⁇ 0.05) in Example 1.
  • Fig. 2 is a graph showing the results of detection of CD4 T lymphocytes in Example 1.
  • Fig. 3 is a graph showing the results of detection of primary cutaneous T-cell lymphatic cancer cells (p ⁇ 0.05) in Example 1.
  • Fig. 4 is a graph showing the results of T lymphocyte proliferation assay (p ⁇ 0.05) in Example 2.
  • Fig. 5 is a graph showing the results of detection of CD8 T lymphocytes in Example 2.
  • Fig. 6 is a graph showing the results of detection of primary cutaneous T-cell lymphatic cancer cells (p ⁇ 0.05) in Example 2.
  • a mouse model of primary cutaneous T-cell lymphoma was selected from adult BABL/c mice, male, 18-22 g. During the experiment, the tumor tissue with good growth was taken, cut, ground, filtered, and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension. Each mouse was inoculated with 0.2 ml of tumor cell suspension. .
  • the animals were randomly divided into 8 groups on the next day after inoculation, which were: (1) negative control group (saline group, NS), (2) chlorogenic acid administration group (CHA, 5 mg/kg), (3) Chlorogenic acid administration group (CHA, 10 mg/kg), (4) chlorogenic acid administration group (CHA, 20 mg/kg), (5) interferon administration group (IFN- ⁇ ), (6) green Acid and interferon simultaneous administration group (CHA + IFN- ⁇ , 5 mg / kg), (7) chlorogenic acid and interferon simultaneous administration group (CHA + IFN- ⁇ , 10 mg / kg), (8) green The acid and interferon were administered simultaneously (CHA + IFN- ⁇ , 20 mg/kg); 20 rats in each group were weighed and started to be administered.
  • the chlorogenic acid administration group was intraperitoneally administered with each dose of chlorogenic acid for injection (the time to be administered was 15 days); the interferon administration group was administered intraperitoneally, 500 units per day. Interferon; chlorogenic acid and interferon were administered by intraperitoneal administration, 500 units of interferon and each dose of green genus for injection were injected every other day; negative control group was injected with the same dose every day by subcutaneous administration. Physiological saline. On the 3rd, 6th, 9th, 12th and 15th day after administration, 3 mice in each group were taken for blood collection by eyeball method and centrifuged. At the same time, the mice that had been sacrificed were dissected and the spleen was observed. The thymus and tumor were evaluated for the effect of administration. The isolated mouse serum, spleen, thymus and tumor were preserved by biological sample preservation method for later detection.
  • mice The spleen of the mice was taken under aseptic conditions, and the appropriate amount of Hank's solution was ground, filtered through a 200-mesh cell sieve, centrifuged at 1500 r/m for 5 minutes, the supernatant was discarded, and the Hank's solution was repeatedly washed twice.
  • the spleen cells were collected, and the appropriate amount of RPMI1640 medium was suspended and counted by 0.4% trypan blue exclusion staining. The number of viable cells was not less than 95%, diluted with RPMI1640 complete medium, and the cell concentration was adjusted to 1 ⁇ 10 7 cells/ml. .
  • a 96-well microplate 100 ⁇ L of spleen cell suspension and an equal volume of ConA solution (final concentration of 5 ⁇ g/ml), LPS solution (final concentration of 10 ⁇ g/ml) or RPMI 1640 medium were added to each well, and 3 wells were repeated. A blank control group was also set up. Then, after further culturing at 37 ° C, 5% CO 2 for 4 hours, 50 ⁇ l of MTT solution (2 mg/ml) was added to each well, and the culture was continued for 4 hours. Then, the cells were centrifuged at 1000 r/m for 5 minutes, and the supernatants of each well were discarded. 150 ⁇ l of an acidic DMSO solution was added thereto, shaken, and allowed to stand in the dark at room temperature for 15 minutes, and the OD value was measured at a wavelength of 578 nm by a microplate reader.
  • ConA solution final concentration of 5 ⁇ g/ml
  • LPS solution final concentration of 10 ⁇ g/
  • the tumor block of the mouse was taken, and the appropriate amount of Hank's solution was ground, filtered through a 200-mesh cell sieve, centrifuged at 1500 r/m for 5 minutes, the supernatant was discarded, and Hank's solution was repeatedly washed twice, and 5 ml of the medium was added. Resuspend the cells and count the cells under the microscope. The cells were collected by EDTA-pancreatin digestion, centrifuged at 200 g for 10 mins, and the cells were washed twice with PBS; resuspended in 1 ⁇ Binding buffer to make a 1 ⁇ 10 6 /ml cell suspension; 100 ⁇ L of the cell suspension was transferred to a 5 ml flow tube.
  • FIG. 1 is a T lymphocyte proliferation test result (p ⁇ 0.05)
  • FIG. 2 is a CD4 T lymphocyte test result
  • FIG. 3 is a primary skin T cell lymphocyte test result (p ⁇ 0.05).
  • chlorogenic acid can activate CD4 T lymphocytes and target CD4 T lymphocytes as a target for the treatment of primary cutaneous T-cell lymphoma, ie, chlorogenic acid promotes the proliferation of T lymphocytes and activates T. Lymphocytes to achieve the purpose of treating primary cutaneous T-cell lymphoma.
  • chlorogenic acid can inhibit the proliferation of primary cutaneous T-cell lymphoma cells, and the inhibitory effect is similar to that of interferon.
  • a mouse model of primary cutaneous T-cell lymphoma was selected from adult BABL/c mice, male, 18-22 g. During the experiment, the tumor tissue with good growth was taken, cut, ground, filtered, and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension. Each mouse was inoculated with 0.2 ml of tumor cell suspension. .
  • the animals were randomly divided into 8 groups on the next day after inoculation, which were: (1) negative control group (saline group, NS), (2) chlorogenic acid administration group (CHA, 5 mg/kg), (3) Chlorogenic acid administration group (CHA, 10 mg/kg), (4) chlorogenic acid administration group (CHA, 20 mg/kg), (5) interferon administration group (IFN- ⁇ ), (6) green Acid and interferon simultaneous administration group (CHA + IFN- ⁇ , 5 mg / kg), (7) chlorogenic acid and interferon simultaneous administration group (CHA + IFN- ⁇ , 10 mg / kg), (8) green The acid and interferon were administered simultaneously (CHA + IFN- ⁇ , 20 mg/kg); 20 rats in each group were weighed and started to be administered.
  • the chlorogenic acid administration group was intraperitoneally administered with each dose of chlorogenic acid for injection (the time to be administered was 15 days); the interferon administration group was administered intraperitoneally, 500 units per day. Interferon; chlorogenic acid and interferon were administered by intraperitoneal administration, 500 units of interferon and each dose of green genus for injection were injected every other day; negative control group was injected with the same dose every day by subcutaneous administration. Physiological saline. On the 3rd, 6th, 9th, 12th and 15th day after administration, 3 mice in each group were taken for blood collection by eyeball method and centrifuged. At the same time, the mice that had been sacrificed were dissected and the spleen was observed. The thymus and tumor were evaluated for the effect of administration. The isolated mouse serum, spleen, thymus and tumor were preserved by biological sample preservation method for later detection.
  • mice The spleen of the mice was taken under aseptic conditions, and the appropriate amount of Hank's solution was ground, filtered through a 200-mesh cell sieve, centrifuged at 1500 r/m for 5 minutes, the supernatant was discarded, and the Hank's solution was repeatedly washed twice.
  • the spleen cells were collected, and the appropriate amount of RPMI1640 medium was suspended and counted by 0.4% trypan blue exclusion staining. The number of viable cells was not less than 95%, diluted with RPMI1640 complete medium, and the cell concentration was adjusted to 1 ⁇ 10 7 cells/ml. .
  • a 96-well microplate 100 ⁇ L of spleen cell suspension and an equal volume of ConA solution (final concentration of 5 ⁇ g/ml), LPS solution (final concentration of 10 ⁇ g/ml) or RPMI 1640 medium were added to each well, and 3 wells were repeated. A blank control group was also set up. Then, after further culturing at 37 ° C, 5% CO 2 for 4 hours, 50 ⁇ l of MTT solution (2 mg/ml) was added to each well, and the culture was continued for 4 hours. Then, the cells were centrifuged at 1000 r/m for 5 minutes, and the supernatants of each well were discarded. 150 ⁇ l of an acidic DMSO solution was added thereto, shaken, and allowed to stand in the dark at room temperature for 15 minutes, and the OD value was measured at a wavelength of 578 nm by a microplate reader.
  • ConA solution final concentration of 5 ⁇ g/ml
  • LPS solution final concentration of 10 ⁇ g/
  • the tumor block of the mouse was taken, and the appropriate amount of Hank's solution was ground, filtered through a 200-mesh cell sieve, centrifuged at 1500 r/m for 5 minutes, the supernatant was discarded, and Hank's solution was repeatedly washed twice, and 5 ml of the medium was added. Resuspend the cells and count the cells under the microscope. The cells were collected by EDTA-pancreatin digestion, centrifuged at 200 g for 10 mins, and the cells were washed twice with PBS; resuspended in 1 ⁇ Binding buffer to make a 1 ⁇ 10 6 /ml cell suspension; 100 ⁇ L of the cell suspension was transferred to a 5 ml flow tube.
  • FIG. 4 is a T lymphocyte proliferation test result (p ⁇ 0.05)
  • FIG. 5 is a CD8 T lymphocyte test result
  • FIG. 6 is a primary skin T cell lymphocyte test result (p ⁇ 0.05).
  • chlorogenic acid can activate CD8 T lymphocytes and treat CD8 T lymphocytes as a target for the treatment of primary cutaneous T-cell lymphoma, that is, chlorogenic acid promotes the proliferation of T lymphocytes and activates T. Lymphocytes to achieve the purpose of treating primary cutaneous T-cell lymphoma.
  • chlorogenic acid can inhibit the proliferation of primary cutaneous T-cell lymphoma cells, and the inhibitory effect is similar to that of interferon.
  • Example 3 Inhibition rate of chlorogenic acid on primary cutaneous T-cell lymphoma
  • a mouse model of primary cutaneous T-cell lymphoma was selected from adult BABL/c mice, male, 18-22 g. During the experiment, the tumor tissue with good growth was taken, cut, ground, filtered, and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension. Each mouse was inoculated with 0.2 ml of tumor cell suspension. . The animals were randomly divided into 8 groups on the next day after inoculation, which were: (1) negative control group (saline group, NS), and (2) chlorogenic acid administration group (CHA, 5 mg/kg).
  • chlorogenic acid administration group (CHA, 10 mg/kg), (4) chlorogenic acid administration group (CHA, 20 mg/kg), (5) interferon administration group (IFN- ⁇ ), (6) ) chlorogenic acid and interferon simultaneously administered (CHA + IFN- ⁇ , 5 mg / kg), (7) chlorogenic acid and interferon simultaneously administered (CHA + IFN- ⁇ , 10 mg / kg), (8) The chlorogenic acid and interferon were administered simultaneously (CHA + IFN- ⁇ , 20 mg/kg); 20 rats in each group were weighed and started to be administered.
  • the chlorogenic acid administration group was intraperitoneally administered with each dose of chlorogenic acid for injection (the time to be administered was 15 days); the interferon administration group was administered intraperitoneally, 500 units per day. Interferon; chlorogenic acid and interferon were administered by intraperitoneal administration, 500 units of interferon and each dose of green genus for injection were injected every other day; negative control group was injected with the same dose every day by subcutaneous administration. Physiological saline. After the chlorogenic acid was stopped, the animals were sacrificed, weighed, and the tumor was weighed and weighed. The tumor inhibition rate (%) was calculated from the tumor weight. Body weight and tumor weight mean ⁇ standard deviation Indicated and carried out between each administration group and the negative control group.
  • chlorogenic acid 20 mg. /kg can significantly enhance the role of interferon in inhibiting tumor growth.
  • chlorogenic acid had no significant effect on animal body weight.
  • chlorogenic acid can activate the function of T cells by targeting T lymphocyte subsets CD4 and CD8 cells, and achieve the purpose of effectively treating primary cutaneous T-cell lymphoma.
  • Example 4 Inhibition rate of chlorogenic acid on primary cutaneous T-cell lymphoma
  • a mouse model of primary cutaneous T-cell lymphoma was selected from adult BABL/c mice, male, 18-22 g. During the experiment, the tumor tissue with good growth was taken, cut, ground, filtered, and diluted with a 1:3 ratio of sterile physiological saline to prepare a tumor cell suspension. Each mouse was inoculated with 0.2 ml of tumor cell suspension. .
  • the animals were randomly divided into 7 groups after the inoculation, and were divided into 7 groups: (1) negative control group, (2) chlorogenic acid 5 mg/kg, (3) 10 mg/kg, (4) 20 mg/kg administration group, (5) Cyclophosphamide 60mg/kg single use group, (6) chlorogenic acid 10mg/kg and cyclophosphamide 60mg/kg combined group, (7) chlorogenic acid 20mg/kg combined with cyclophosphamide 60mg/kg Group; 20 per group.
  • the negative control group was intraperitoneally injected with 0.2 ml of physiological saline per 10 g of mice once a day.
  • the cyclophosphamide injection was administered in an amount of 0.2 ml per 10 g of mouse peritoneal injection. Both cyclophosphamide alone and in combination were injected with cyclophosphamide once a day on the next day of inoculation.
  • the chlorogenic acid injection was administered in an amount of 0.2 ml per 10 g of mice, once a day for 14 days.
  • the combination of chlorogenic acid and cyclophosphamide was injected intraperitoneally with chlorogenic acid in the left side and cyclophosphamide was injected into the right side. The animals were sacrificed the day after withdrawal, weighing, weighing and weighing.
  • the tumor inhibition rate (%) was calculated from the tumor weight. Body weight and tumor weight mean ⁇ standard deviation The t-test between the combination group and the negative control group, the combination group and the cyclophosphamide single-use group was performed.
  • the results of the experiment are shown in Table 2.
  • the intraperitoneal injection of chlorogenic acid showed a significant dose-dependent inhibition of the growth of mouse primary cutaneous T-cell lymphoma.
  • the chlorogenic acid 20 mg/kg can enhance the inhibition of tumor growth by cyclophosphamide. effect. No significant toxic side effects were observed with chlorogenic acid at the doses used.
  • the invention is not limited to the specific embodiments described above.
  • the invention extends to any new feature or any new combination disclosed in this specification, as well as any novel method or process steps or any new combination disclosed.

Abstract

本发明提供一种绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。绿原酸能够激活CD4 T淋巴细胞和CD8 T淋巴细胞，抑制皮肤T细胞淋巴癌细胞的增殖。

Description

绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途 技术领域
本发明涉及生物医药领域，尤其是原发性皮肤T细胞淋巴癌治疗领域，具体为绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
背景技术
原发性皮肤T细胞淋巴瘤(cutaneous T cell lymphoma,CTCL)，曾被称为蕈状肉芽肿(granuloma fungoid)，是T淋巴细胞(特别是T辅助细胞亚群)起源的一种皮肤原发淋巴癌。其作为一组具有明显异质性的淋巴增生性疾病，缺乏标准化治疗方案。
在其发病早期，以增强患者免疫力和局部治疗为主，可用干扰素、卡介菌或转移因子等；局部治疗可选用氮芥或芳香维A酸外用，电子束照射，X线、光化学疗法等均有一定疗效。目前，尚未见用于该病治疗的新的化疗药及靶向治疗药物的报道。
绿原酸(即3-咖啡奎宁酸)作为一种多酚类的化合物，其结构中的多羟基、不饱和酯以及邻二酚结构可使绿原酸具有高抗氧性。目前，对绿原酸生理/药理活性研究报道的文献已有许多，如US5,788,971中报道了绿原酸的抗氧化作用对清除氧自由基的影响及治疗炎症反应的作用。WO99/34812报道了由三羟基酮、连翘精醇和绿原酸组成的制剂具有的抗病毒、抗菌或免疫调节剂的功能。US20050282892记载了绿原酸治疗慢性粒细胞白血病。SanR.H.C.等在MutaionRes.1987，117：229～239中报道了关于多酚类化合物绿原酸对黄曲霉素B1和苯并[α]芘致癌物质活性的抑制作用。同时，中国专利CN201110373137.8公开了绿原酸在制备治疗肾癌的药物中的用途，CN201210086313.4公开了一种治疗膀胱癌的药物组合物，CN200710140602.7公开了绿原酸在制备治疗小细胞肺癌的药物中的用途，CN200610021897.1公开了绿原酸在制备具有预防和治疗鼻咽癌功效的药物中的应用，CN200610021591.6公开了绿原酸在制备具有预防和治疗宫颈癌功效的药物中的应用。
目前，还没有任何文献公开绿原酸用于治疗原发性皮肤T细胞淋巴癌的报道。
发明内容
本发明的发明目的提供一种绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。本发明通过实验证明，绿原酸能够激活CD4T淋巴细胞和CD8T淋巴细胞，并以CD4T淋巴细胞和CD8T淋巴细胞为靶点，预防和治疗原发性皮肤T细胞淋巴癌。本发明通过绿原酸促进机体T淋巴细胞的增殖，并激活T淋巴细胞，以达到治疗原发性皮肤T细胞淋巴癌的目的。同时，绿原酸还能抑制原发性皮肤T细胞淋巴癌细胞的增殖，且抑制效果与干扰素的抑制效果相近。
为了实现上述目的，本发明采用如下技术方案：
绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
绿原酸在制备以CD4淋巴细胞为靶点预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
绿原酸在制备以CD8淋巴细胞为靶点预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
绿原酸在制备以CD4和CD8为靶点预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
以绿原酸为有效成分，加上药学上可接受的辅料或辅助性成分制成药物。
其中，所述药物的剂型为注射制剂或口服制剂。
其中，每制剂单位含有绿原酸1-1000mg。
其中，药物临床使用剂量为1-100mg/kg。
绿原酸与抗肿瘤药物在制备治疗原发性皮肤T细胞淋巴癌的联合用药物中的用途，所述抗肿瘤药物为环磷酰胺、5-氟尿嘧啶、白介素12、白介素2、γ干扰素中的一种或几种。
其中，所述绿原酸与抗肿瘤药物的剂量配比为1:5～5:1。
原发性皮肤淋巴瘤属结外非霍奇金淋巴瘤，研究证明：原发性皮肤淋巴瘤与有相同组织学亚型的原发性淋巴结淋巴瘤在累及皮肤时，在临床及组织学特征、生物学行为及预后，都有明显不同。此外，皮肤淋巴瘤的基因易位，癌基因表达，病毒片段，黏附分子，均有不同于淋巴结淋巴瘤的特点。不同部位起源的形态学一致的淋巴瘤是许多不同的、器官相关的淋巴细胞亚群的单克隆扩增，这些淋巴细胞保留了他们相应良性部分的许多特征。原发性皮肤T细胞淋巴瘤(primary cutaneous T-cell lymphoma，PCTCL)是主要的原发性皮肤淋巴瘤，以皮肤内辅助T细胞的单克隆扩增为特征，患都在数年内死亡，预后差。
针对这一问题，申请人提供绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。申请人通过研究发现，绿原酸能够以T淋巴细胞亚群CD4、CD8细胞为靶点，激活T细胞的功能，以达到预防和治疗原发性皮肤T细胞淋巴瘤。同时，绿原酸还能抑制原发性皮肤T细胞淋巴癌细胞的增殖，且抑制效果与干扰素的抑制效果相近。
基于上述发现，绿原酸可以和药学上可接受的辅料或辅助性成分制成药物，采用各种制药技术，制备成注射制剂、口服制剂或外用透皮给药制剂等剂型。
以下通过实验对绿原酸所具有的上述功效加以证实。应该理解的是，本发明的实验例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
附图说明
本发明将通过例子并参照附图的方式说明，其中：
图1为实施例1中，T淋巴细胞增殖检测结果(p<0.05)图。
图2为实施例1中，CD4T淋巴细胞检测结果图。
图3为实施例1中，原发性皮肤T细胞淋巴癌细胞检测结果(p<0.05)图。
图4为实施例2中，T淋巴细胞增殖检测结果(p<0.05)图。
图5为实施例2中，CD8T淋巴细胞检测结果图。
图6为实施例2中，原发性皮肤T细胞淋巴癌细胞检测结果(p<0.05)图。
具体实施方式
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
本说明书中公开的任一特征，除非特别叙述，均可被其他等效或具有类似目的的替代特征加以替换。即，除非特别叙述，每个特征只是一系列等效或类似特征中的一个例子而已。
实施例1以CD4T淋巴细胞为靶点治疗原发性皮肤T细胞淋巴癌
(1)动物模型建立及分组
小鼠原发性皮肤T细胞淋巴癌模型，选取成年BABL/c小鼠，雄性，18-22g。实验时，取生长良好的肿瘤组织，剪碎，研磨，过滤，用无菌生理盐水按1：3比例稀释后，制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml肿瘤细胞悬液。接种后次日动物随机分组，分为8组，分别为：(1)阴性对照组(生理盐水组，NS)，(2)绿原酸给药组(CHA，5mg/kg)，(3)绿原酸给药组(CHA，10mg/kg)，(4)绿原酸给药组(CHA，20mg/kg)，(5)干扰素给药组(IFN-γ)，(6)绿原酸和干扰素同时给药组(CHA+IFN-γ，5mg/kg)，(7)绿原酸和干扰素同时给药组(CHA+IFN-γ，10mg/kg)，(8)绿原酸和干扰素同时给药组(CHA+IFN-γ，20mg/kg)；每组20只，称重，并开始给药。
绿原酸给药组每天采用腹腔给药的方式注射各剂量的注射用绿原酸(拟给药时间为15天)；干扰素给药组以腹腔给药的方式，隔天注射500单位的干扰素；绿原酸和干扰素同时给药组以腹腔给药的方式，隔天注射500单位的干扰素和各剂量的注射用绿原；阴性对照组每天采用皮下给药的方式注射相同剂量的生理盐水。分别于给药的第3、6、9、12和15天分别各组小鼠3只，采用眼球取血法进行取血，离心后检测；同时对已经处死的小鼠进行解剖，观察脾脏、胸腺和肿瘤，评价给药的效果。采用生物样品保存法对分离得到的小鼠血清、脾脏、胸腺和肿瘤进行保存以备后期检测。
(2)T淋巴细胞增殖实验
无菌条件下取小鼠的脾脏，加适量的Hank’s液研磨，以200目细胞筛滤过，1500r/m离心5分钟，弃上清，加Hank’s液重复洗涤2次。收集脾细胞，加适量的RPMI1640培养液混悬，以0.4％的台盼兰拒染色法计数，活细胞数不小于95％，加RPMI1640完全培养液稀释，并调整细胞浓度至1x107个/ml。于96孔微量板中，每孔加100μL脾细胞悬液和等体积的ConA溶液(终浓度为5μg/ml)、LPS溶液(终浓度为10μg/ml)或RPMI1640培养液，重复3孔。另设空白对照组。然后，再在37℃、5％CO2培养4小时后，各孔加入50μl MTT溶液(2mg/ml)，继续培养4小时。然后，再1000r/m离心5分钟，弃去各孔上清，分别加入150μl酸性DMSO溶液，振荡，于室温暗处放15分钟，以酶标仪于波长578nm处测定OD值。
(3)CD4T淋巴细胞检测
取血加抗体，取小鼠血1ml，用EDTAk3血常规管抗凝全血，试管标号。取50μl抗凝全血，分别加入试管①、试管②，直接加至底部，不可触试管壁。试管①加入5μl抗体CD4+，试管②统一加入5μl抗体CD3+和5μl抗体CD4+，用振荡器混匀后暗室放置20～30分钟，使抗体与血样充分的结合；避光常温30分钟后，加裂解液：试管在振荡中加入500μl裂解液，在30℃水浴中放置15分钟，达到透亮；裂解后，1500r/m离心5分钟，用PBS液洗2次，加1mlPBS液1500r/m离心5分钟后去上液；再加入1mlPBS液，1500r/m离心5分钟后去上液，加500μlPBS液，用流式细胞仪检测。
(4)原发性皮肤T细胞淋巴癌细胞检测
用CFSE流式细胞实验检测原发性皮肤T细胞淋巴癌细胞。
无菌条件下，取小鼠的瘤块，加适量的Hank’s液研磨，以200目细胞筛滤过，1500r/m离心5分钟，弃上清，加Hank’s液重复洗涤2次，加入5ml培养基重悬液，显微镜下计数细胞。用EDTA-胰酶消化收集细胞，200g离心10mins，细胞用PBS液洗2次；用1xBinding缓冲液重悬制成1x106/ml细胞悬液；将100μL细胞悬液转移至5ml流式管中，加入5μL CFSE-SE，混匀并室温避光孵育15mins；向各流式管中加入400μ 1xBinding缓冲液，涡旋震荡后上流式细胞仪进行检测。实验结果用FlowJo软件进行分析。
(5)实验结果
图1、2、3分别为测定结果。其中，图1为T淋巴细胞增殖检测结果(p<0.05)图，图2为CD4T淋巴细胞检测结果图，图3为原发性皮肤T细胞淋巴癌细胞检测结果(p<0.05)图。
(6)结论
从实验结果可以看出：绿原酸能够激活CD4T淋巴细胞，并以CD4T淋巴细胞为靶点治疗原发性皮肤T细胞淋巴癌，即绿原酸通过促进机体T淋巴细胞的增殖，并激活T淋巴细胞，以达到治疗原发性皮肤T细胞淋巴癌的目的。同时，实验结果还表明：绿原酸能抑制原发性皮肤T细胞淋巴癌细胞的增殖，且抑制效果与干扰素的抑制效果相近。
实施例2以CD8T淋巴细胞为靶点治疗原发性皮肤T细胞淋巴癌
(1)动物模型建立及分组
小鼠原发性皮肤T细胞淋巴癌模型，选取成年BABL/c小鼠，雄性，18-22g。实验时，取生长良好的肿瘤组织，剪碎，研磨，过滤，用无菌生理盐水按1：3比例稀释后，制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml肿瘤细胞悬液。接种后次日动物随机分组，分为8组，分别为：(1)阴性对照组(生理盐水组，NS)，(2)绿原酸给药组(CHA，5mg/kg)，(3)绿原酸给药组(CHA，10mg/kg)，(4)绿原酸给药组(CHA，20mg/kg)，(5)干扰素给药组(IFN-γ)，(6)绿原酸和干扰素同时给药组(CHA+IFN-γ，5mg/kg)，(7)绿原酸和干扰素同时给药组(CHA+IFN-γ，10mg/kg)，(8)绿原酸和干扰素同时给药组(CHA+IFN-γ，20mg/kg)；每组20只，称重，并开始给药。
绿原酸给药组每天采用腹腔给药的方式注射各剂量的注射用绿原酸(拟给药时间为15天)；干扰素给药组以腹腔给药的方式，隔天注射500单位的干扰素；绿原酸和干扰素同时给药组以腹腔给药的方式，隔天注射500单位的干扰素和各剂量的注射用绿原；阴性对照组每天采用皮下给药的方式注射相同剂量的生理盐水。分别于给药的第3、6、9、12和15天分别各组小鼠3只，采用眼球取血法进行取血，离心后检测；同时对已经处死的小鼠进行解剖，观察脾脏、胸腺和肿瘤，评价给药的效果。采用生物样品保存法对分离得到的小鼠血清、脾脏、胸腺和肿瘤进行保存以备后期检测。
(2)T淋巴细胞增殖实验
无菌条件下取小鼠的脾脏，加适量的Hank’s液研磨，以200目细胞筛滤过，1500r/m离心5分钟，弃上清，加Hank’s液重复洗涤2次。收集脾细胞，加适量的RPMI1640培养液混悬，以0.4％的台盼兰拒染色法计数，活细胞数不小于95％，加RPMI1640完全培养液稀释，并调整细胞浓度至1x107个/ml。于96孔微量板中，每孔加100μL脾细胞悬液和等体积的ConA溶液(终浓度为5μg/ml)、LPS溶液(终浓度为10μg/ml)或RPMI1640培养液，重复3孔。另设空白对照组。然后，再在37℃、5％CO2培养4小时后，各孔加入50μl MTT溶液(2mg/ml)，继续培养4小时。然后，再1000r/m离心5分钟，弃去各孔上清，分别加入150μl酸性DMSO溶液，振荡，于室温暗处放15分钟，以酶标仪于波长578nm处测定OD值。
(3)CD8T淋巴细胞检测
取血加抗体，取小鼠血1ml，用EDTAk3血常规管抗凝全血，试管标号。取50μl抗凝全血，分别加入试管①、试管②，直接加至底部，不可触试管壁。试管①加入5μl抗体CD8+，试管②统一加入5μl抗体CD3+和5μl抗体CD4+，用振荡器混匀后暗室放置20～30分钟，使抗体与血样充分的结合；避光常温30分钟后，加裂解液：试管在振荡中加入500μl裂解液，在30℃水浴中放置15分钟，达到透亮；裂解后，1500r/m离心5分钟，用PBS液洗2次，加1mlPBS液1500r/m离心5分钟后去上液；再加入1mlPBS液，1500r/m离心5分钟后去上液，加500μlPBS液，用流式细胞仪检测。
(4)原发性皮肤T细胞淋巴癌细胞检测
用CFSE流式细胞实验检测原发性皮肤T细胞淋巴癌细胞。
无菌条件下，取小鼠的瘤块，加适量的Hank’s液研磨，以200目细胞筛滤过，1500r/m离心5分钟，弃上清，加Hank’s液重复洗涤2次，加入5ml培养基重悬液，显微镜下计数细胞。用EDTA-胰酶消化收集细胞，200g离心10mins，细胞用PBS液洗2次；用1xBinding缓冲液重悬制成1x106/ml细胞悬液；将100μL细胞悬液转移至5ml流式管中，加入5μL CFSE-SE，混匀并室温避光孵育15mins；向各流式管中加入400μ 1xBinding缓冲液，涡旋震荡后上流式细胞仪进行检测。实验结果用FlowJo软件进行分析。
(5)实验结果
图4、5、6分别为测定结果。其中，图4为T淋巴细胞增殖检测结果(p<0.05)图，图5为CD8T淋巴细胞检测结果图，图6为原发性皮肤T细胞淋巴癌细胞检测结果(p<0.05)图。
(6)结论
从实验结果可以看出：绿原酸能够激活CD8T淋巴细胞，并以CD8T淋巴细胞为靶点治疗原发性皮肤T细胞淋巴癌，即绿原酸通过促进机体T淋巴细胞的增殖，并激活T淋巴细胞，以达到治疗原发性皮肤T细胞淋巴癌的目的。同时，实验结果还表明：绿原酸能抑制原发性皮肤T细胞淋巴癌细胞的增殖，且抑制效果与干扰素的抑制效果相近。
实施例3绿原酸对原发性皮肤T细胞淋巴癌抑瘤率实验
(1)动物模型建立及分组
小鼠原发性皮肤T细胞淋巴癌模型，选取成年BABL/c小鼠，雄性，18-22g。实验时，取生长良好的肿瘤组织，剪碎，研磨，过滤，用无菌生理盐水按1：3比例稀释后，制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml肿瘤细胞悬液。接种后次日动物随机分组，分为8组，分别为：(1)阴性对照组(生理盐水组，NS)，(2)绿原酸给药组(CHA，5mg/kg)，
(3)绿原酸给药组(CHA，10mg/kg)，(4)绿原酸给药组(CHA，20mg/kg)，(5)干扰素给药组(IFN-γ)，(6)绿原酸和干扰素同时给药组(CHA+IFN-γ，5mg/kg)，(7)绿原酸和干扰素同时给药组(CHA+IFN-γ，10mg/kg)，(8)绿原酸和干扰素同时给药组(CHA+IFN-γ，20mg/kg)；每组20只，称重，并开始给药。
绿原酸给药组每天采用腹腔给药的方式注射各剂量的注射用绿原酸(拟给药时间为15天)；干扰素给药组以腹腔给药的方式，隔天注射500单位的干扰素；绿原酸和干扰素同时给药组以腹腔给药的方式，隔天注射500单位的干扰素和各剂量的注射用绿原；阴性对照组每天采用皮下给药的方式注射相同剂量的生理盐水。绿原酸停药后处死动物，称体重，剥瘤并称瘤重。根据肿瘤重量计算肿瘤抑制率(％)。体重及瘤重用均值±标准差
Figure PCTCN2016073125-appb-000001
表示，并进行各给药组与阴性对照组之间。
(2)实验结果
实验结果如下表1所示。
表1 实施例3的测定结果
Figure PCTCN2016073125-appb-000002
注：***P<0.01，与阴性对照组比较。###P<0.01，与溶剂对照比较。
(3)结论
通过上述实验结果，可以看出：腹腔注射给予荷瘤小鼠绿原酸对小鼠原发性皮肤T细胞淋巴癌的生长有明显的抑制作用，且呈一定的剂量效应关系，绿原酸20mg/kg可显著增强干扰素抑制肿瘤生长的作用。在所用剂量下，绿原酸对动物体重无明显影响。
通过上述实验，能够看出，绿原酸能够以T淋巴细胞亚群CD4、CD8细胞为靶点，激活T细胞的功能，达到有效治疗原发性皮肤T细胞淋巴瘤的目的。
实施例4.绿原酸对原发性皮肤T细胞淋巴癌抑瘤率实验
(1)动物模型建立及分组
小鼠原发性皮肤T细胞淋巴癌模型，选取成年BABL/c小鼠，雄性，18-22g。实验时，取生长良好的肿瘤组织，剪碎，研磨，过滤，用无菌生理盐水按1：3比例稀释后，制成肿瘤细胞悬液，每只小鼠腋背部接种0.2ml肿瘤细胞悬液。接种后次日动物随机分组，分为7组：(1)阴性对照组，(2)绿原酸5mg/kg，(3)10mg/kg，(4)20mg/kg给药组，(5)环磷酰胺60mg/kg单用组，(6)绿原酸10mg/kg与环磷酰胺60mg/kg联合给药组，(7)绿原酸20mg/kg与环磷酰胺60mg/kg联合给药组；每组20只。阴性对照组按每10g小鼠腹腔注射0.2ml生理盐水，每日1次。环磷酰胺注射液给药体积为每10g小鼠腹腔注射0.2ml。环磷酰胺单用及联合用药均于接种次日注射环磷酰胺1次。绿原酸注射液给药体积为每10g小鼠腹腔注射0.2ml，每日1次，连续给药14天。绿原酸及环磷酰胺联合用药组先于左侧腹腔注射绿原酸，再于右侧腹腔注射环磷酰胺。于停药后次日处死动物，称体重，剥瘤并称瘤重。根据肿瘤重量计算肿瘤抑制率(％)。体重及瘤重用均值±标准差
Figure PCTCN2016073125-appb-000003
表示，并进行各给药组与阴性对照组之间，联合用药组与环磷酰胺单用组之间的t检验。
Figure PCTCN2016073125-appb-000004
(2)结果
实验结果见表2，腹腔注射给予绿原酸对小鼠原发性皮肤T细胞淋巴癌的生长呈显著的剂量依赖性的抑制作用，绿原酸20mg/kg可增强环磷酰胺抑制肿瘤生长的作用。绿原酸在所用剂量下未观察到明显毒副作用。
表2.绿原酸与环磷酰胺联合用药抑瘤率
Figure PCTCN2016073125-appb-000005
Figure PCTCN2016073125-appb-000006
注：***P<0.01，与阴性对照组比较。
本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的组合。

Claims (9)

  1. 绿原酸在制备预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于：绿原酸在制备以CD4淋巴细胞为靶点预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
  3. 根据权利要求1所述的用途，其特征在于：绿原酸在制备以CD8淋巴细胞为靶点预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
  4. 根据权利要求1-3任一项所述的用途，其特征在于：绿原酸在制备以CD4和CD8为靶点预防和治疗原发性皮肤T细胞淋巴癌的药物中的用途。
  5. 根据权利要求1-5任一项所述的用途，其特征在于：以绿原酸为有效成分，加上药学上可接受的辅料或辅助性成分制成药物。
  6. 根据权利要求5所述的用途，其特征在于：所述药物的剂型为注射制剂或口服制剂。
  7. 根据权利要求5-6所述的用途，其特征在于：每制剂单位含有绿原酸1-1000mg。
  8. 绿原酸与抗肿瘤药物在制备治疗原发性皮肤T细胞淋巴癌的联合用药物中的用途，其特征在于：所述抗肿瘤药物为环磷酰胺、5-氟尿嘧啶、白介素12、白介素2、γ干扰素中的一种或几种。
  9. 根据权利要求8所述的用途，其特征在于，所述绿原酸与抗肿瘤药物的剂量配比为1:5～5:1。
PCT/CN2016/073125 2015-02-13 2016-02-02 绿原酸在制备预防和治疗原发性皮肤t细胞淋巴癌的药物中的用途 WO2016127848A1 (zh)

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