CN104622864A - Application of chlorogenic acid in preparing drugs for prevention and treatment of primary cutaneous T-cell lymphoma - Google Patents
Application of chlorogenic acid in preparing drugs for prevention and treatment of primary cutaneous T-cell lymphoma Download PDFInfo
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- 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
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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
- A61K31/33—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
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- 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]
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- 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]
Abstract
The invention aims to provide an application of chlorogenic acid in preparing drugs for prevention and treatment of primary cutaneous T-cell lymphoma. Experiments show that the chlorogenic acid can activate CD4 T-lymphocytes and CD8 T-lymphocytes, and prevent and treat primary cutaneous T-cell lymphoma by taking the CD4 T-lymphocytes and the CD8 T-lymphocytes as targets. According to the invention, the chlorogenic acid is adopted for promoting the proliferation of T-lymphocytes of a body and activating the T-lymphocytes so as to achieve the purpose of treating primary cutaneous T-cell lymphoma. Meanwhile, the chlorogenic acid also can inhibit the proliferation of primary cutaneous T-cell lymphoma cells, and the inhibition effect of the chlorogenic acid is similar to the inhibition effect of interferon.
Description
Technical field
The present invention relates to biomedicine field, especially primary cutaneous T cell lymphatic cancer treatment field, is specially the purposes of chlorogenic acid in the medicine preparing prevention and therapy primary cutaneous T cell lymphatic cancer.
Background technology
Primary cutaneous t cell lymphoma (cutaneous T cell lymphoma, CTCL), once being called as gill fungus shape granuloma (granuloma fungoid), is a kind of skin former lymphatic cancer that T lymphocyte (particularly t helper cell subgroup) originates from.It has obviously heterogeneous lymphoproliferative disorders as one group, lacks standardized therapeutic regimens.
Early stage in its morbidity, to strengthen patient's immunity and topical therapeutic, available interference element, bacill calmette-guerin or transfer factor etc.; Topical therapeutic can select chlormethine or fragrant tretinoin external, and electron beam irradiation, x-ray, photochemotherapy etc. all have certain curative effect.At present, there is not yet the report of new chemotherapeutic and the target therapeutic agent for the treatment of for this disease.
Chlorogenic acid (i.e. 3-coffee quininic acid) is as a kind of compound of Polyphenols, and the polyhydroxy in its structure, beta-unsaturated esters and adjacent diphenol structure can make chlorogenic acid have high antioxidant.At present, have many to the document of chlorogenic acid physiology/pharmacology activity research report, as US5,788, report the antioxidation of chlorogenic acid in 971 to the impact of scavenging activated oxygen and the effect for the treatment of inflammatory reaction.WO99/34812 reports the function of antiviral that the preparation that is made up of trihydroxy ketone, forsythiogenol and chlorogenic acid has, antibacterial or immunomodulator.US20050282892 describes chlorogenic acid treatment chronic myelocytic leukemia.SanR.H.C. wait and report in MutaionRes.1987,117:229 ~ 239 about the inhibitory action of polyphenol compound chlorogenic acid to aflatoxin B1 and benzo [α] pyrene carcinogen activity.Simultaneously, Chinese patent CN201110373137.8 discloses the purposes of chlorogenic acid in the medicine of preparation treatment renal carcinoma, CN201210086313.4 discloses a kind of pharmaceutical composition for the treatment of bladder cancer, CN200710140602.7 discloses the purposes of chlorogenic acid in the medicine of preparation treatment small cell lung cancer, CN200610021897.1 discloses chlorogenic acid and is preparing the application had in the medicine of prevention and therapy nasopharyngeal cancer function, and CN200610021591.6 discloses chlorogenic acid and preparing the application had in the medicine of prevention and therapy cervical cancer effect.
At present, the report of primary cutaneous T cell lymphatic cancer is also used for the treatment of without any the open chlorogenic acid of document.
Summary of the invention
Goal of the invention of the present invention provides the purposes of a kind of chlorogenic acid in the medicine preparing prevention and therapy primary cutaneous T cell lymphatic cancer.The present invention proves by experiment, and chlorogenic acid can activate CD4T lymphocyte and CD8T lymphocyte, and with CD4T lymphocyte and CD8T lymphocyte for target spot, prevention and therapy primary cutaneous T cell lymphatic cancer.The present invention promotes the lymphocytic propagation of body T by chlorogenic acid, and activated T lymphocytes, to reach the object for the treatment of primary cutaneous T cell lymphatic cancer.Meanwhile, chlorogenic acid can also suppress the propagation of primary cutaneous T cell lymphocytic cancer cell, and the inhibition of inhibition and interferon is close.
To achieve these goals, the present invention adopts following technical scheme:
The purposes of chlorogenic acid in the medicine preparing prevention and therapy primary cutaneous T cell lymphatic cancer.
The purposes in the medicine being target spot prevention and therapy primary cutaneous T cell lymphatic cancer with CD4 lymphocyte prepared by chlorogenic acid.
The purposes in the medicine being target spot prevention and therapy primary cutaneous T cell lymphatic cancer with CD8 lymphocyte prepared by chlorogenic acid.
The purposes in the medicine being target spot prevention and therapy primary cutaneous T cell lymphatic cancer with CD4 and CD8 prepared by chlorogenic acid.
Be effective ingredient with chlorogenic acid, add that pharmaceutically acceptable adjuvant or complementary composition make medicine.
Wherein, the dosage form of described medicine is ejection preparation or oral formulations.
Wherein, every preparation unit contains chlorogenic acid 1-1000mg.
Wherein, clinical drug using dosage is 1-100mg/kg.
The purposes in the combination medicine for the treatment of primary cutaneous T cell lymphatic cancer prepared by chlorogenic acid and antitumor drug, and described antitumor drug is one or more in cyclophosphamide, 5-fluorouracil, interleukin 12, interleukin-22, IFN-γ.
Wherein, the dosage ratio of described chlorogenic acid and antitumor drug is 1:5 ~ 5:1.
Primary cutaneous lymphoma belongs to the outer non-Hodgkin lymphoma of knot, research prove: primary cutaneous lymphoma with have homologue to learn the constitutional lymph node lymphoma of hypotype when involving skin, in clinical and histologic characteristics, biological behaviour and prognosis, there is obvious difference.In addition, the group translocation of lymphoma cutis, oncogene expression, viral fragment, adhesion molecule, is all different from the lymphadenomatous feature of lymph node.The consistent lymphoma of morphology of different parts origin is the monoclonal amplification of the lymphocyte subgroup that many different, organs are correlated with, and these lymphocytes remain many features of their corresponding benign portion.Primary cutaneous t cell lymphoma (primary cutaneous T-cell lymphoma, PCTCL) is main primary cutaneous lymphoma, with the amplification of the monoclonal of helper T cell in skin for feature, suffers from all dead within the several years, poor prognosis.
For this problem, applicant provides the purposes of chlorogenic acid in the medicine preparing prevention and therapy primary cutaneous T cell lymphatic cancer.Applicant is found by research, and chlorogenic acid can with t lymphocyte subset group CD4, cd8 cell for target spot, the function of activated T cell, to reach prevention and therapy primary cutaneous t cell lymphoma.Meanwhile, chlorogenic acid can also suppress the propagation of primary cutaneous T cell lymphocytic cancer cell, and the inhibition of inhibition and interferon is close.
Based on above-mentioned discovery, chlorogenic acid can make medicine with pharmaceutically acceptable adjuvant or complementary composition, adopts various pharmaceutical technology, is prepared into the dosage forms such as ejection preparation, oral formulations or externally applied transdermal drug-delivery preparation.
Below by way of experiment, above-mentioned effect that chlorogenic acid has is confirmed.It should be understood that experimental example of the present invention is for illustration of the present invention instead of limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Accompanying drawing explanation
Examples of the present invention will be described by way of reference to the accompanying drawings, wherein:
Fig. 1 is in embodiment 1, T lymphopoiesis testing result (p<0.05) figure.
Fig. 2 is in embodiment 1, CD4T lymphocyte testing result figure.
Fig. 3 is in embodiment 1, primary cutaneous T cell lymphocytic cancer cell testing result (p<0.05) figure.
Fig. 4 is in embodiment 2, T lymphopoiesis testing result (p<0.05) figure.
Fig. 5 is in embodiment 2, CD8T lymphocyte testing result figure.
Fig. 6 is in embodiment 2, primary cutaneous T cell lymphocytic cancer cell testing result (p<0.05) figure.
Detailed description of the invention
All features disclosed in this description, or the step in disclosed all methods or process, except mutually exclusive feature and/or step, all can combine by any way.
Arbitrary feature disclosed in this description, unless specifically stated otherwise, all can be replaced by other equivalences or the alternative features with similar object.That is, unless specifically stated otherwise, each feature is an example in a series of equivalence or similar characteristics.
Embodiment 1 with CD4T lymphocyte for target treatment primary cutaneous T cell lymphatic cancer
(1) Animal Model and grouping
Rat primary cutaneous T-cell lymphatic cancer model, chooses adult BABL/c mice, male, 18-22g.During experiment, get well-grown tumor tissues, shred, grinding, filter, after pressing 1:3 dilution proportion with physiological saline solution, make tumor cell suspension, every mice axil back inoculation 0.2ml tumor cell suspension.Inoculation animal random packet rear next day, be divided into 8 groups, be respectively: (1) negative control group (normal saline group, NS), (2) chlorogenic acid administration group (CHA, 5mg/kg), (3) chlorogenic acid administration group (CHA, 10mg/kg), (4) chlorogenic acid administration group (CHA, 20mg/kg), (5) interferon administration group (IFN-γ), (6) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 5mg/kg), (7) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 10mg/kg), (8) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 20mg/kg), often organize 20, weigh, and start administration.
Chlorogenic acid administration group adopts the mode of intraperitoneal administration to inject the chlorogenic acid for injection (intending administration time is 15 days) of each dosage every day; Interferon administration group, in the mode of intraperitoneal administration, injects the interferon of 500 units every other day; Chlorogenic acid and interferon administration simultaneously group is in the mode of intraperitoneal administration, and the injection of injecting the interferon of 500 units and each dosage is every other day green former; Negative control group adopts the mode of subcutaneous administration to inject the normal saline of same dose every day.Respectively at the 3rd, 6,9,12 and 15 day difference each group of mice 3 of administration, eyeball blood taking method is adopted to carry out getting blood, centrifugal rear detection; The mice of having put to death is dissected simultaneously, observe spleen, thymus and tumor, evaluate the effect of administration.Biological sample preservation method is adopted to carry out preservation in order to late detection to being separated the mice serum, spleen, thymus and the tumor that obtain.
(2) T lymphocyte proliferation assay
Get the spleen of mice under aseptic condition, add appropriate Hank ' s liquid grinding, with 200 order cell sievings, centrifugal 5 minutes of 1500r/m, abandons supernatant, adds Hank ' s liquid repeated washing 2 times.Collect splenocyte, add appropriate RPMI1640 culture fluid suspendible, the platform with 0.4% expects that orchid refuses staining counting, and viable count is not less than 95%, adds the dilution of RPMI1640 complete culture solution, and adjusts cell concentration to 1x10
7individual/ml.In 96 hole micro plates, every hole adds 100 μ L splenocyte suspensions and isopyknic ConA solution (final concentration is 5 μ g/ml), LPS solution (final concentration is 10 μ g/ml) or RPMI1640 culture fluid, repeats 3 holes.Separately establish blank group.Then, then at 37 DEG C, 5%CO
2cultivate after 4 hours, each hole adds 50 μ l MTT solution (2mg/ml), continues cultivation 4 hours.Then, more centrifugal 5 minutes of 1000r/m, discard each hole supernatant, add the acid DMSO solution of 150 μ l respectively, vibration, puts 15 minutes in room temperature dark place, with microplate reader in wavelength 578nm place mensuration OD value.
(3) CD4T lymphocyte detects
Get blood and add antibody, get Mouse Blood 1ml, with EDTAk3 routine blood test pipe anticoagulated whole blood, test tube label.Get 50 μ l anticoagulated whole bloods, add respectively test tube 1., test tube 2., directly add to bottom, can not test tube wall be touched.1. test tube adds 5 μ l antibody CD4
+, test tube 2. unification adds 5 μ l antibody CD3
+with 5 μ l antibody CD4
+, place 20 ~ 30 minutes with darkroom after agitator mixing, antibody be combined fully with blood sample; Lucifuge room temperature, after 30 minutes, adds lysate: test tube adds 500 μ l lysates in vibration, places 15 minutes, reach bright in 30 DEG C of water-baths; After cracking, centrifugal 5 minutes of 1500r/m, washes 2 times with PBS liquid, adds 1mlPBS liquid 1500r/m and removes liquid after centrifugal 5 minutes; Add 1mlPBS liquid again, 1500r/m removes liquid after centrifugal 5 minutes, adds 500 μ lPBS liquid, uses flow cytomery.
(4) primary cutaneous T cell lymphocytic cancer cell detects
Primary cutaneous T cell lymphocytic cancer cell is detected with CFSE Flow cytometry experiments.
Under aseptic condition, get the tumor block of mice, add appropriate Hank ' s liquid grinding, with 200 order cell sievings, centrifugal 5 minutes of 1500r/m, abandons supernatant, adds Hank ' s liquid repeated washing 2 times, adds 5ml culture medium re-suspension liquid, counted under microscope cell.With EDTA-collected by trypsinisation cell, the centrifugal 10mins of 200g, cell PBS liquid washes 2 times; 1x10 is made with 1xBinding buffer is resuspended
6/ ml cell suspension; Be transferred in 5ml streaming pipe by 100 μ L cell suspension, add 5 μ LCFSE-SE, 15mins is hatched in mixing also room temperature lucifuge; In each streaming pipe, add 400 μ 1xBinding buffer, after vortex concussion, flow cytometer detects.Experimental result FlowJo software is analyzed.
(5) experimental result
Fig. 1,2,3 is respectively measurement result.Wherein, Fig. 1 is T lymphopoiesis testing result (p<0.05) figure, Fig. 2 is CD4T lymphocyte testing result figure, Fig. 3 is primary cutaneous T cell lymphocytic cancer cell testing result (p<0.05) figure.
(6) conclusion
As can be seen from experimental result: chlorogenic acid can activate CD4T lymphocyte, and with CD4T lymphocyte for target treatment primary cutaneous T cell lymphatic cancer, namely chlorogenic acid is by promoting the lymphocytic propagation of body T, and activated T lymphocytes, to reach the object for the treatment of primary cutaneous T cell lymphatic cancer.Meanwhile, experimental result also shows: chlorogenic acid can suppress the propagation of primary cutaneous T cell lymphocytic cancer cell, and the inhibition of inhibition and interferon is close.
Embodiment 2 with CD8T lymphocyte for target treatment primary cutaneous T cell lymphatic cancer
(1) Animal Model and grouping
Rat primary cutaneous T-cell lymphatic cancer model, chooses adult BABL/c mice, male, 18-22g.During experiment, get well-grown tumor tissues, shred, grinding, filter, after pressing 1:3 dilution proportion with physiological saline solution, make tumor cell suspension, every mice axil back inoculation 0.2ml tumor cell suspension.Inoculation animal random packet rear next day, be divided into 8 groups, be respectively: (1) negative control group (normal saline group, NS), (2) chlorogenic acid administration group (CHA, 5mg/kg), (3) chlorogenic acid administration group (CHA, 10mg/kg), (4) chlorogenic acid administration group (CHA, 20mg/kg), (5) interferon administration group (IFN-γ), (6) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 5mg/kg), (7) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 10mg/kg), (8) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 20mg/kg), often organize 20, weigh, and start administration.
Chlorogenic acid administration group adopts the mode of intraperitoneal administration to inject the chlorogenic acid for injection (intending administration time is 15 days) of each dosage every day; Interferon administration group, in the mode of intraperitoneal administration, injects the interferon of 500 units every other day; Chlorogenic acid and interferon administration simultaneously group is in the mode of intraperitoneal administration, and the injection of injecting the interferon of 500 units and each dosage is every other day green former; Negative control group adopts the mode of subcutaneous administration to inject the normal saline of same dose every day.Respectively at the 3rd, 6,9,12 and 15 day difference each group of mice 3 of administration, eyeball blood taking method is adopted to carry out getting blood, centrifugal rear detection; The mice of having put to death is dissected simultaneously, observe spleen, thymus and tumor, evaluate the effect of administration.Biological sample preservation method is adopted to carry out preservation in order to late detection to being separated the mice serum, spleen, thymus and the tumor that obtain.
(2) T lymphocyte proliferation assay
Get the spleen of mice under aseptic condition, add appropriate Hank ' s liquid grinding, with 200 order cell sievings, centrifugal 5 minutes of 1500r/m, abandons supernatant, adds Hank ' s liquid repeated washing 2 times.Collect splenocyte, add appropriate RPMI1640 culture fluid suspendible, the platform with 0.4% expects that orchid refuses staining counting, and viable count is not less than 95%, adds the dilution of RPMI1640 complete culture solution, and adjusts cell concentration to 1x10
7individual/ml.In 96 hole micro plates, every hole adds 100 μ L splenocyte suspensions and isopyknic ConA solution (final concentration is 5 μ g/ml), LPS solution (final concentration is 10 μ g/ml) or RPMI1640 culture fluid, repeats 3 holes.Separately establish blank group.Then, then at 37 DEG C, 5%CO
2cultivate after 4 hours, each hole adds 50 μ l MTT solution (2mg/ml), continues cultivation 4 hours.Then, more centrifugal 5 minutes of 1000r/m, discard each hole supernatant, add the acid DMSO solution of 150 μ l respectively, vibration, puts 15 minutes in room temperature dark place, with microplate reader in wavelength 578nm place mensuration OD value.
(3) CD8T lymphocyte detects
Get blood and add antibody, get Mouse Blood 1ml, with EDTAk3 routine blood test pipe anticoagulated whole blood, test tube label.Get 50 μ l anticoagulated whole bloods, add respectively test tube 1., test tube 2., directly add to bottom, can not test tube wall be touched.1. test tube adds 5 μ l antibody CD8
+, test tube 2. unification adds 5 μ l antibody CD3
+with 5 μ l antibody CD4
+, place 20 ~ 30 minutes with darkroom after agitator mixing, antibody be combined fully with blood sample; Lucifuge room temperature, after 30 minutes, adds lysate: test tube adds 500 μ l lysates in vibration, places 15 minutes, reach bright in 30 DEG C of water-baths; After cracking, centrifugal 5 minutes of 1500r/m, washes 2 times with PBS liquid, adds 1mlPBS liquid 1500r/m and removes liquid after centrifugal 5 minutes; Add 1mlPBS liquid again, 1500r/m removes liquid after centrifugal 5 minutes, adds 500 μ lPBS liquid, uses flow cytomery.
(4) primary cutaneous T cell lymphocytic cancer cell detects
Primary cutaneous T cell lymphocytic cancer cell is detected with CFSE Flow cytometry experiments.
Under aseptic condition, get the tumor block of mice, add appropriate Hank ' s liquid grinding, with 200 order cell sievings, centrifugal 5 minutes of 1500r/m, abandons supernatant, adds Hank ' s liquid repeated washing 2 times, adds 5ml culture medium re-suspension liquid, counted under microscope cell.With EDTA-collected by trypsinisation cell, the centrifugal 10mins of 200g, cell PBS liquid washes 2 times; 1x10 is made with 1xBinding buffer is resuspended
6/ ml cell suspension; Be transferred in 5ml streaming pipe by 100 μ L cell suspension, add 5 μ L CFSE-SE, 15mins is hatched in mixing also room temperature lucifuge; In each streaming pipe, add 400 μ 1xBinding buffer, after vortex concussion, flow cytometer detects.Experimental result FlowJo software is analyzed.
(5) experimental result
Fig. 4,5,6 is respectively measurement result.Wherein, Fig. 4 is T lymphopoiesis testing result (p<0.05) figure, Fig. 5 is CD8T lymphocyte testing result figure, Fig. 6 is primary cutaneous T cell lymphocytic cancer cell testing result (p<0.05) figure.
(6) conclusion
As can be seen from experimental result: chlorogenic acid can activate CD8T lymphocyte, and with CD8T lymphocyte for target treatment primary cutaneous T cell lymphatic cancer, namely chlorogenic acid is by promoting the lymphocytic propagation of body T, and activated T lymphocytes, to reach the object for the treatment of primary cutaneous T cell lymphatic cancer.Meanwhile, experimental result also shows: chlorogenic acid can suppress the propagation of primary cutaneous T cell lymphocytic cancer cell, and the inhibition of inhibition and interferon is close.
Embodiment 3 chlorogenic acid is tested primary cutaneous T cell lymphatic cancer tumour inhibiting rate
(1) Animal Model and grouping
Rat primary cutaneous T-cell lymphatic cancer model, chooses adult BABL/c mice, male, 18-22g.During experiment, get well-grown tumor tissues, shred, grinding, filter, after pressing 1:3 dilution proportion with physiological saline solution, make tumor cell suspension, every mice axil back inoculation 0.2ml tumor cell suspension.Inoculation animal random packet rear next day, be divided into 8 groups, be respectively: (1) negative control group (normal saline group, NS), (2) chlorogenic acid administration group (CHA, 5mg/kg), (3) chlorogenic acid administration group (CHA, 10mg/kg), (4) chlorogenic acid administration group (CHA, 20mg/kg), (5) interferon administration group (IFN-γ), (6) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 5mg/kg), (7) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 10mg/kg), (8) chlorogenic acid and interferon administration simultaneously group (CHA+IFN-γ, 20mg/kg), often organize 20, weigh, and start administration.
Chlorogenic acid administration group adopts the mode of intraperitoneal administration to inject the chlorogenic acid for injection (intending administration time is 15 days) of each dosage every day; Interferon administration group, in the mode of intraperitoneal administration, injects the interferon of 500 units every other day; Chlorogenic acid and interferon administration simultaneously group is in the mode of intraperitoneal administration, and the injection of injecting the interferon of 500 units and each dosage is every other day green former; Negative control group adopts the mode of subcutaneous administration to inject the normal saline of same dose every day.Put to death animal after chlorogenic acid drug withdrawal, weigh, stripping tumor also claims tumor weight.Tumor control rate (%) is calculated according to tumor weight.Body weight and tumor reuse means standard deviation
represent, and carry out between each administration group and negative control group.
(2) experimental result
Experimental result is as shown in table 1 below.
The measurement result of table 1 embodiment 3
Note: * * * P<0.01, compares with negative control group.###P<0.01, compares with solvent control.
(3) conclusion
By above-mentioned experimental result, can find out: lumbar injection gives the growth of tumor-bearing mice chlorogenic acid to rat primary cutaneous T-cell lymphatic cancer obvious inhibitory action, and in certain dose-effect relationship, chlorogenic acid 20mg/kg significantly can strengthen the effect of interferon Tumor suppression growth.Under dosage used, chlorogenic acid has no significant effect the weight of animals.
By above-mentioned experiment, can find out, chlorogenic acid can with t lymphocyte subset group CD4, cd8 cell for target spot, the function of activated T cell, reaches the object of effectively treatment primary cutaneous t cell lymphoma.
Embodiment 4. chlorogenic acid is tested primary cutaneous T cell lymphatic cancer tumour inhibiting rate
(1) Animal Model and grouping
Rat primary cutaneous T-cell lymphatic cancer model, chooses adult BABL/c mice, male, 18-22g.During experiment, get well-grown tumor tissues, shred, grinding, filter, after pressing 1:3 dilution proportion with physiological saline solution, make tumor cell suspension, every mice axil back inoculation 0.2ml tumor cell suspension.Inoculation animal random packet rear next day, be divided into 7 groups: (1) negative control group, (2) chlorogenic acid 5mg/kg, (3) 10mg/kg, (4) 20mg/kg administration group, (5) alone group of cyclophosphamide 60mg/kg, (6) chlorogenic acid 10mg/kg and cyclophosphamide 60mg/kg administering drug combinations group, (7) chlorogenic acid 20mg/kg and cyclophosphamide 60mg/kg administering drug combinations group; Often organize 20.Negative control group injects 0.2ml normal saline by every 10g mouse peritoneal, every day 1 time.Cyclophosphamide Injection administration volume is every 10g mouse peritoneal injection 0.2ml.Alone and the drug combination of cyclophosphamide all injects cyclophosphamide 1 time in inoculation next day.Chlorogenic acid injection administration volume is every 10g mouse peritoneal injection 0.2ml, every day 1 time, successive administration 14 days.Chlorogenic acid and cyclophosphamide combined medication group prior to left side lumbar injection chlorogenic acid, then in right side intraperitoneal injection of cyclophosphamide.After drug withdrawal, next day puts to death animal, weighs, and stripping tumor also claims tumor weight.Tumor control rate (%) is calculated according to tumor weight.Body weight and tumor reuse means standard deviation
represent, and carry out between each administration group and negative control group, the t between drug combination group and alone group of cyclophosphamide checks.
(2) result
Experimental result is in table 2, and lumbar injection gives the inhibitory action that the growth of chlorogenic acid to rat primary cutaneous T-cell lymphatic cancer is significant dose dependent, and chlorogenic acid 20mg/kg can strengthen the effect of cyclophosphamide Tumor suppression growth.Chlorogenic acid does not observe obvious toxic-side effects under dosage used.
Table 2. chlorogenic acid and cyclophosphamide combined medication tumour inhibiting rate
Note: * * * P<0.01, compares with negative control group.
The present invention is not limited to aforesaid detailed description of the invention.The present invention expands to any new feature of disclosing in this manual or any combination newly, and the step of the arbitrary new method disclosed or process or any combination newly.
Claims (9)
1. the purposes of chlorogenic acid in the medicine preparing prevention and therapy primary cutaneous T cell lymphatic cancer.
2. purposes according to claim 1, is characterized in that: the purposes in the medicine being target spot prevention and therapy primary cutaneous T cell lymphatic cancer with CD4 lymphocyte prepared by chlorogenic acid.
3. purposes according to claim 1, is characterized in that: the purposes in the medicine being target spot prevention and therapy primary cutaneous T cell lymphatic cancer with CD8 lymphocyte prepared by chlorogenic acid.
4. the purposes according to any one of claim 1-3, is characterized in that: the purposes in the medicine being target spot prevention and therapy primary cutaneous T cell lymphatic cancer with CD4 and CD8 prepared by chlorogenic acid.
5. the purposes according to any one of claim 1-5, is characterized in that: take chlorogenic acid as effective ingredient, adds that pharmaceutically acceptable adjuvant or complementary composition make medicine.
6. purposes according to claim 5, is characterized in that: the dosage form of described medicine is ejection preparation or oral formulations.
7. the purposes according to claim 5-6, is characterized in that: every preparation unit contains chlorogenic acid 1-1000mg.
8. the purposes in the combination medicine for the treatment of primary cutaneous T cell lymphatic cancer prepared by chlorogenic acid and antitumor drug, it is characterized in that: described antitumor drug is one or more in cyclophosphamide, 5-fluorouracil, interleukin 12, interleukin-22, IFN-γ.
9. purposes according to claim 8, is characterized in that, the dosage ratio of described chlorogenic acid and antitumor drug is 1:5 ~ 5:1.
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|---|---|---|---|
| CN201510079639.8A CN104622864B (en) | 2015-02-13 | 2015-02-13 | Purposes of the chlorogenic acid in the drug that preparation prevents and treats primary cutaneous T cell lymph cancer |
| PCT/CN2016/073125 WO2016127848A1 (en) | 2015-02-13 | 2016-02-02 | Application of chlorogenic acid in preparing medicines for preventing and treating primary cutaneous t cell lymphoma |
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| CN201510079639.8A CN104622864B (en) | 2015-02-13 | 2015-02-13 | Purposes of the chlorogenic acid in the drug that preparation prevents and treats primary cutaneous T cell lymph cancer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016127848A1 (en) * | 2015-02-13 | 2016-08-18 | 四川九章生物科技有限公司 | Application of chlorogenic acid in preparing medicines for preventing and treating primary cutaneous t cell lymphoma |
| CN109420166A (en) * | 2017-08-28 | 2019-03-05 | 四川九章生物科技有限公司 | A kind of combination medicine for treating bone-marrow-derived lymphocyte related disease |
| CN113509439A (en) * | 2021-07-12 | 2021-10-19 | 博睿先锋(北京)生物科技有限公司 | Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391119A (en) * | 2011-11-14 | 2012-03-28 | 肖文辉 | Preparation of high purity chlorogenic acid preparation and clinical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104622864B (en) * | 2015-02-13 | 2019-04-26 | 四川九章生物科技有限公司 | Purposes of the chlorogenic acid in the drug that preparation prevents and treats primary cutaneous T cell lymph cancer |
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- 2015-02-13 CN CN201510079639.8A patent/CN104622864B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102391119A (en) * | 2011-11-14 | 2012-03-28 | 肖文辉 | Preparation of high purity chlorogenic acid preparation and clinical application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016127848A1 (en) * | 2015-02-13 | 2016-08-18 | 四川九章生物科技有限公司 | Application of chlorogenic acid in preparing medicines for preventing and treating primary cutaneous t cell lymphoma |
| CN109420166A (en) * | 2017-08-28 | 2019-03-05 | 四川九章生物科技有限公司 | A kind of combination medicine for treating bone-marrow-derived lymphocyte related disease |
| CN109420166B (en) * | 2017-08-28 | 2022-04-12 | 四川九章生物科技有限公司 | Combined medicine for treating B lymphocyte related diseases |
| CN113509439A (en) * | 2021-07-12 | 2021-10-19 | 博睿先锋(北京)生物科技有限公司 | Application of self-emulsifying delivery system in preparation of oral medicine for treating lymphatic metastasis tumor |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2016127848A1 (en) | 2016-08-18 |
| CN104622864B (en) | 2019-04-26 |
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