CN102440994A - Application of ganoderic acid G as immune synergist and super-antigen dependent therapeutic medicine in tumour treatments - Google Patents
Application of ganoderic acid G as immune synergist and super-antigen dependent therapeutic medicine in tumour treatments Download PDFInfo
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- CN102440994A CN102440994A CN2011102916165A CN201110291616A CN102440994A CN 102440994 A CN102440994 A CN 102440994A CN 2011102916165 A CN2011102916165 A CN 2011102916165A CN 201110291616 A CN201110291616 A CN 201110291616A CN 102440994 A CN102440994 A CN 102440994A
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Abstract
The invention relates to a novel purpose of ganoderic acid, in particular to application of the ganoderic acid G in various tumour treatments. The ganoderic acid G disclosed by the invention comprises various preparations including solid type preparations of troches, capsules and the like, ointment, pasting agents, injections and the like, which can be prepared by adopting a conventional method in a pharmaceutical field. The tumour treatment medicine provided by the invention, namely the ganoderic acid G, has the function of directly inhibiting tumour cell proliferation under small dose; at this time, the ganoderic acid G has low toxic effect on normal tissue cells; and the effect of further treating tumours is realized after adding super-antigen. The application of the ganoderic acid G as the immune synergist and the super-antigen dependent therapeutic medicine in the tumour treatments disclosed by the invention has the obvious advantages and the technical progresses that: when the ganoderic acid G is united with the super-antigen, the function of killing and wounding a wide variety of tumour cells in extracorporeal and esoteric experiments can be effectively played.
Description
Technical field
The present invention relates to the new purposes of Ganodenic acid, relate in particular to the new purposes of Ganodenic acid G (Ganoderic acid G).
Background technology
Ganoderma is the treasure in the Chinese medicine and pharmacy treasure-house.Spreading many legends since ancient times,, Ganoderma is being regarded as " Herba mesonae chinensis ", " Ganoderma ", and regard it as the symbol of " having good luck " as these mythology and have in the legend of superstitious color about Ganoderma.In the Ancient Times in China document, " Newly Revised Canon of Materia Medica " of the Shennong's Herbal about a B.C. century, " The Master of Preserving Simplicity " of the Ge Hong of the Eastern Jin Dynasty, the Su Jing Tang Dynasty, beam have all further replenished, have revised the argumentation of relevant Ganoderma on the basis of Shennong's Herbal for " Variorum of Shennong " of TAO Hong-Jing and the works such as Compendium of Material Medica of " Mingyi Bielu " and Ming Dynasty's Li Shizhen (1518-1593 A.D.).In sum, Ancient Times in China scholar draws according to practical experience, and Ganoderma has " strengthening the body resistance effect ", can treat multiple disease.
Modern science and technology prove that the effective constituent that mainly contains of Ganoderma comprises ganoderan (Polysacchari de), Ganodenic acid (Ganoderma Acid) and adenosine (Adenosine) etc.In recent years, the antitumor of polysaccharide and immunoregulatory activity effect receive much attention, and there are some researches show, polysaccharide can make impaired DNA be restored.The Anticancer Effect and Mechanism that the professor of Beijing Medical University Lin Zhibin, Zhang Qunhao etc. have observed ganoderan from cell and molecular level.After 2002, effective ingredient research of Ganoderma is developed into the discussion to Ganoderma triterpenoids (Ganodenic acid) active component again.At present, from Ganoderma, separated the Ganodenic acid that obtains and reached kind more than 100, like Ganodenic acid A, B, C, D, E, F, G, I, L, MA, MB, MC, MD.Yet the research relevant to the Ganodenic acid immunity is very few, especially unclear to having the mechanism that protects the liver and kill functions such as tumor cell.Though have the scholar to report that Ganoderma can promote DC ripe, also do not see the role's relevant report at immunology in the domestic literature about T, B cell line.
Relevant Ganodenic acid antitumor patent has CN1483423, mainly and behind the other medicines compatibility is used for treatment for cancer; The purposes of patent CN1480208 is that conduct is put, the pharmaceutical composition of chemotherapy attenuation synergistic; Patent CN1286119 contains 15% the Ganodenic acid method for preparing as the health article.In addition, the patent of ganodenic acid monomer has CN1823788A, and main component is Ganoderic acid Me GA-Me (+)-Ganoderic acid Me and the T application as sensitizing and potentiating agent and inhibitor; Patent CN1823787A is Ganoderic acid Me GA-Me (+)-Ganoderic acid Me and the application of T in the preparation cancerometastasis suppresses.Ganodenic acid G is as the monomer in the Ganodenic acid, and its related neoplasms suppresses and aspect drug combination, do not appear in the newspapers as yet.
At present, maximum problem is the drug resistance that tumor forms in the chemotherapy of tumors.The reversal agent of drug resistance that has that can realize in the modern biotechnology pharmacy comprises antisensenucleic acids and ribozyme, cytokine (IL-2 or TNF-α), GSH depletor, antibody and small molecular antibody peptide etc.In view of ideal synergism medicine should be little to normal tissue cell toxicity, have anti-tumor activity, stable a, long half time etc.This invention just meets with it.Therefore, have direct economic benefit and social benefit.
Summary of the invention
The technical issues that need to address of the present invention are the application in preparation multidrug resistance cancer chemotherapy sensitizing and potentiating agent and inhibitor of open Ganodenic acid, to satisfy clinical medical needs.
The said Ganodenic acid of the present invention is Ganodenic acid G (Ganoderic acid G, abbreviation GA-G).
The inventor finds; The low dose of use of Ganodenic acid G can increase multidrug-resistant carcinoma to producing chemical sproof chemotherapy medicament sensitive; Heavy dose of use can suppress the effect of multiple multidrug-resistant carcinoma cell growth and have dose dependent; Can they medicine and sensitizing and potentiating agents as the treatment multidrug-resistant carcinoma be applied in the chemotherapeutic treatment of tumor.Said low dose refers to the dosage in 1～5mg/ (kg body weight sky), and said heavy dose refers to the dosage in 10～50mg/ (kg body weight sky).
The invention still further relates to a kind of compositions, comprise the Ganodenic acid G that treats effective dose and medically acceptable carrier.
Can put on the patient who needs treatment with Ganodenic acid G and medically acceptable carrier with the form of compositions, general dosage is the dosage in 1～50mg/ (kg body weight sky), and concrete dosage can increase and decrease according to the difference of patient age, the state of an illness etc.
Said carrier is meant the pharmaceutical carrier that pharmaceutical field is conventional, like diluent, excipient such as water etc., and filler such as starch, sucrose etc., binding agent such as cellulose derivative gelatin, polyvinylpyrrolidone etc., lubricant such as Pulvis Talci etc.
The compositions that Ganodenic acid G of the present invention and above-mentioned carrier constitute can administered through oral, apply ointment or plaster or multiple form of medication such as injection puts on the patient who needs this treatment.
Be used for when oral, can its preparation be become conventional tablet, capsule or oral liquid etc.;
When being used to inject, can it be adopted the conventional method in this area, preparation becomes injection;
The various preparations of Ganodenic acid G of the present invention comprise that oral formulations, applicator and injection etc. can adopt the conventional method of pharmaceutical field to prepare;
In the preparation, the weight content of Ganodenic acid G is 0.5～99.9%, and preferred content is 10～99.9%.
The various preparations of Ganodenic acid G provided by the invention have the effect of enhancing multidrug-resistant carcinoma cell to chemotherapy drug susceptibility under the situation of low dose.Said low dose refers to the dosage in 1～5mg/ (kg body weight sky).
The various preparations of Ganodenic acid G provided by the invention; Under the situation of heavy dose, has the effect that suppresses the multidrug-resistant carcinoma cell proliferation; Explanation can be contained the unlimited multiplication capacity of tumor cell, thereby has and can further bring into play the effect of treating tumor more.Said heavy dose refers to the dosage in 10～50mg/ (kg body weight sky).
Anticarcinogen and sensitizing and potentiating agent in the multidrug-resistant carcinoma chemotherapy provided by the invention have identical cytotoxicity to the multidrug resistance cancerous cell with non-multidrug resistance cancerous cell, and both differences not significantly (p＜0.05).
Said Ganodenic acid G is through fermentation is purified or the monomer that process Ganoderma entity direct separation is purified.Said superantigen is can be through commercially available acquisition.
Said multidrug-resistant carcinoma is medically affiliated all kinds of tumors, comprises each malignant tumor of benign tumor.And said malignant tumor comprises: malignant melanoma, malignant lymphoma, Alimentary tumor, hepatocarcinoma, hysteroma, leukemia, nervous system neoplasms, skin carcinoma.
Animal experiment proves, anticarcinogen of the present invention and sensitizing and potentiating agent, and low toxicity is suitable for people and mammal per os and non-oral administration.
Anticarcinogen and sensitizing and potentiating agent in the multidrug-resistant carcinoma chemotherapy provided by the invention can cooperate with the adjuvant that does not influence pharmacotoxicological effect usually and process per os or para-oral preparation.
Remarkable advantage of the present invention and technical progress:
Ganodenic acid G monomer with while antitumor and enhanced sensitivity potentiation provided by the invention; Overcome traditional with the defective of Ganoderma mixed extract as medicine; With the means of modern biotechnology as invention, clear and definite effective ingredient, the utilization pure compound is as antitumor drug and sensitizing and potentiating agent; Reduced the probability that principal component not causes side effect; This chemical compound has significant while antitumor and the synergic effect of enhanced sensitivity (the interior experiment of external and body), and is less to human normal cell's cytotoxicity simultaneously, has a good application prospect.
Description of drawings
Fig. 1 variable concentrations Ganodenic acid G is to the inhibitory action of various cancerous cell.
Secret note, Ganodenic acid G concentration are 0 μ g/ml black square, and Ganodenic acid G concentration is 100 μ g/ml
Stain, Ganodenic acid G concentration are 30 μ g/ml informal vouchers, and Ganodenic acid G concentration is 300 μ g/ml
Fig. 2 Ganodenic acid G increases the sensitivity of nude mice to cisplatin.
Figure 31 00 μ g/ml Ganodenic acid G is to various cancerous cell and normal CD4
+The toxic action of T cell.
The Ganodenic acid G that Fig. 4 superantigen relies on is to the lethal effect of tumor cell.
The Ganodenic acid G that Fig. 4 a superantigen relies on is to the lethal effect of A20 cell
The Ganodenic acid G that Fig. 4 b superantigen relies on is to the lethal effect of HeLa cell
The specific embodiment
Through embodiment content of the present invention is described further below.The example of being lifted does not limit protection scope of the present invention.
All tumor cell lines among the embodiment provide by Tokyo woman medical university microorganism immune Research chamber.All experimental datas are all from obtaining with laboratory experiment.
Utilize
3The H method is measured the inhibitory action of U-937, Ramos, K562, Raji, THP-1 tumor cell.The logarithmic (log) phase cell is by 10
4/ hole is inoculated in culture plate at the bottom of 96 hole circles, every hole 200 μ l, and parallel 3 holes, matched group adds the equivalent culture fluid, after the Ganodenic acid G that is respectively 0,30,100,300 μ g/ml with concentration adds, puts 37 ℃ of 5%CO
2Incubator was cultivated 72 hours, counted before preceding 6 hours to add
3H counts the growth population of tumor cell then and is figure.
Logarithmic (log) phase KB-A-1 cell 10
6/ ml concentration, every inoculation of 0.2ml/ nude mice oxter, nude mice SPF environment was grown 15 days down; The separate entities tumor; Oxter, the inoculation experiments nude mice left and right sides under the aseptic condition, medicine lumbar injection treatment after 5 days adds Ganodenic acid G group by cisplatin (Cisplatin DDP) group and cisplatin and treats.5 days is a course of treatment, treats 2 courses of treatment altogether.Drug withdrawal was put to death nude mice after 6 days, got the solid tumor calculating tumor control rate of weighing.
Tumor control rate (%)=[(matched group solid tumor average weight number-administration group object tumor average weight number)/matched group solid tumor average weight number] * 100
Embodiment 3
Utilize
3The H method is measured KB-A-1, U-937, Ramos, K562, Raji, THP-1, A20, Hela and CD4
+Normal human T-cell's toxic action, the logarithmic (log) phase cell is by 10
4/ hole is inoculated in culture plate at the bottom of 96 hole circles, every hole 200 μ l, and parallel 3 holes, control wells is added the equivalent culture fluid, and using concentration is that the Ganodenic acid G of 100 μ g/ml stimulates, and puts 37 ℃ of 5%CO
2Incubator was cultivated 72 hours, counted before preceding 6 hours to add
3H calculates the suppression ratio of medicine pair cell then, and with the half-inhibition concentration mapping of cell.
Embodiment 4
With red fluorescence dyeing tumor cell A20, Hela RPMI-1640 washing in 30 seconds 3 times; Superantigen and superantigen add Ganodenic acid G stimulates tumor cell and T cell 1: 1 Mixed culture 2 hours in 96 well culture plates respectively; Collecting cell and washing are fixing; With the Caspase-3 dyeing tumor cell of green fluorescence labelling, with the dead tumor cell number mapping of flow cytometer counting.
Claims (6)
1. use as therapeutic agent during the synergist of Ganodenic acid G when the preparation chemotherapy of tumors, or associating superantigen, said Ganodenic acid G is monomer (the chemical name Lanost-8-en-26-oic acid in the Ganoderma; 3,7,12-trihydroxy-11; 15,23-trioxo-, (3 β; 7 β, 12 β)-, molecular formula C30H4408).
2. application according to claim 1 is characterized in that, all kinds of tumors under said tumor is meant medically comprise optimum and pernicious.
3. application according to claim 2 is characterized in that, said malignant tumor comprises: malignant melanoma, malignant lymphoma, Alimentary tumor, hepatocarcinoma, hysteroma, leukemia, nervous system neoplasms, skin carcinoma.
4. compositions comprises the Ganodenic acid G that treats effective dose and medically acceptable carrier.
5. superantigen relies on and is meant that variety of way comprises medically acceptable drug combination.
6. comprise that according to the superantigen of being carried in 5 all can induce the activatory superantigen of human T cell clone to comprise bacillary, virus and vegetalitas superantigen.
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| CN2011102916165A CN102440994A (en) | 2011-09-30 | 2011-09-30 | Application of ganoderic acid G as immune synergist and super-antigen dependent therapeutic medicine in tumour treatments |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020191845A1 (en) * | 2019-03-25 | 2020-10-01 | 广州白云山汉方现代药业有限公司 | Drug for reversing resistance of tumor cells to anti-tumor drugs |
| CN115463137A (en) * | 2022-09-02 | 2022-12-13 | 浙江寿仙谷植物药研究院有限公司 | Novel PD-1/PD-L1 small molecule inhibitor and application thereof |
-
2011
- 2011-09-30 CN CN2011102916165A patent/CN102440994A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 丁平等: "灵芝中6种主要三萜酸类成分的HPLC定量分析", 《中国药学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020191845A1 (en) * | 2019-03-25 | 2020-10-01 | 广州白云山汉方现代药业有限公司 | Drug for reversing resistance of tumor cells to anti-tumor drugs |
| CN115463137A (en) * | 2022-09-02 | 2022-12-13 | 浙江寿仙谷植物药研究院有限公司 | Novel PD-1/PD-L1 small molecule inhibitor and application thereof |
| CN115463137B (en) * | 2022-09-02 | 2024-01-26 | 浙江寿仙谷植物药研究院有限公司 | Novel PD-1/PD-L1 small molecule inhibitor and application thereof |
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Application publication date: 20120509 |