CN1709264A - Use of ganoderic acid T and ganoderic and Me in tumour growth or proliferation inhibitor - Google Patents
Use of ganoderic acid T and ganoderic and Me in tumour growth or proliferation inhibitor Download PDFInfo
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- CN1709264A CN1709264A CN 200510026378 CN200510026378A CN1709264A CN 1709264 A CN1709264 A CN 1709264A CN 200510026378 CN200510026378 CN 200510026378 CN 200510026378 A CN200510026378 A CN 200510026378A CN 1709264 A CN1709264 A CN 1709264A
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Abstract
The present invention discloses application of ganoderic acid T and ganoderic acid Me in preparation of inhibitor of tumor growth or proliferation. The internal and external tests show that ganoderic acid T and ganoderic acid Me have obvious action for inhibiting human tumor cell growth or proliferation, at the same time its toxicity for normal cell is low.
Description
Technical field
The present invention relates to the purposes of Ganoderic acid T GA-T Ganoderic acid T. (Ganoderic acid T) and Ganoderic acid Me GA-Me (+)-Ganoderic acid Me (Ganoderic acid Me).
Background technology
Ganoderma is a kind of medicinal fungi of preciousness, the applicating history in existing several thousand.The Shennong's Herbal of the Eastern Han Dynasty is classified Ganoderma as medicine-feeding.Later on the medicine scholar also has many treatises about Ganoderma the successive dynasties, and as " The Master of Preserving Simplicity " of the Ge Hong of the Eastern Jin Dynasty, " Newly Revised Canon of Materia Medica " of the Su Jing Tang Dynasty, beam be for " Mingyi Bielu " of TAO Hong-Jing, and the Compendium of Material Medica of Ming Dynasty's Li Shizhen (1518-1593 A.D.) etc.The ancient medicine scholar fully realizes the medical value of Ganoderma is existing, thinks that Ganoderma has " strengthening the body resistance " effect, can be used for treating multiple disease.
The modern study of Ganoderma starts from the 1950's, along with the success of artificial culture and submerged fermentation biotechnology, for medical research and the product development of Ganoderma provides competent raw material.The Pharmacopoeia of the People's Republic of China (2000) has recorded Ganoderma as legal Chinese crude drug, and U.S.'s " medical herbs pharmacopeia and treatment summary " has also recorded Ganoderma, and this series monograph has only recorded 10 kinds of Chinese medicines so far.The medical value that Ganoderma is described has obtained many-sidedly admitting.
The chemical research of Ganoderma proves that it contains polysaccharide, triterpenes, main effective ingredient such as peptide class.Pharmacological research proves that it has pharmacological action widely, as antitumor, and anti HIV-1 virus, immunomodulating resists myocardial ischemia, blood lipid regulation, blood sugar lowering, sedation, hepatoprotective effect, anti-radiation and anti-chemotherapy, anti-hypoxia and anti-aging effects etc.
Triterpenoid compound is one of main chemical compositions of Ganoderma class, a lot of triterpenoid compound have the important physical activity, such as, ganodriol F, ganodermanontriol, lucidumol A and lucidumol B have the anti HIV-1 virus activity, and ganodericacid F has the activity of very strong inhibition hypertensinase etc.Separate to obtain after this compounds from nineteen eighty-two T Kubota people such as (Helv.Chim.Acta, 65 (2), 611-619,1982) first, separated obtaining more than 100 kind of similar compound up to now.
About the disclosed patent of Ganodenic acid and the document of delivering are broadly divided into three classes:
The first kind is about the fermenting and producing Ganodenic acid, these patents and document mainly are optimization of fermentation conditions, increase Ganodenic acid output: Japan Patent: openly specially permit the communique spy and open flat 4-304890, disclose the fermentation manufacturing technique of Ganodenic acid, but the content of Ganodenic acid only is 0.46-1.0 milligram/100 milligram dry weight in the product of gained.Among the patent CN1264743A, clock Kien Giang and Fang Qinghua provide a kind of " solution fermentation is produced ganoderan and Ganodenic acid technology simultaneously ", relate to the static culture method of a kind of liquid aerobic fermentation-liquid, investigated vibration and the static influence that Ganodenic acid is produced in the second stage incubation.Wang Shuhua, Sun Cuihuan, Zhu Wanqin, Wang Hengxin, Feng Jian. ganoderma lucidum liquid deep layer fermenting process research preliminary study, JOURNAL OF MICROBIOLOGY 1994,14 (5): 29-32 has reported that Ganoderma G3-1 criticizes cultured method.Also have some patents and document also to disclose and reported various fermentation process, such as, the clock Kien Giang discloses relevant fermentation method with Tang Yajie and has produced the patent of ganoderan and Ganodenic acid (patent publication No. CN1375557, CN1316519) simultaneously, can the high efficiency production Ganodenic acid, the total content of thick Ganodenic acid can reach 5 milligrams/100 milligrams, and total output is up to 1 grams per liter.
Second class is about Ganoderma antineoplastic patent and document, after mainly being Ganoderma sporophore or spore powder and other drug compatibility, be used for treatment for cancer: patent CN1483423 has reported a kind of Chinese medicine preparation for the treatment of malignant tumor and preparation method thereof, this Chinese medicine preparation is to be primary raw material with Herba Scutellariae Barbatae, Ganoderma, Caulis Spatholobi, the Radix Rehmanniae, Fructus Lycii etc., and various tumors are all had better curative effect.Patent CN 1480208 has reported a kind of pharmaceutical composition that is used for the chemicotherapy attenuation synergistic and preparation method thereof, and this medicine is made by weight ratio by the Radix Astragali, Fructus Lycii, Ganoderma.Patent CN 1421227 has reported and has comprised being used for the treatment of and the medicine that prevents radiation injury of Ganoderma.Patent CN 1286119 has reported a kind of Ganoderma lucidum and preparation method thereof, and Ganodenic acid purity is 15%, and the suppression ratio of tumor is reached on 30%.But do not see the report of relevant ganodenic acid monomer in the pertinent literature.
The 3rd class is about isolating patent of Ganodenic acid and document, has introduced the crude separation technology of Ganodenic acid, such as, patent CN1282611 has reported the isolation technics of antineoplastic component in the Ganoderma spore, raw material obtains a series of pastes behind lixiviate, extraction, chromatography.Patent CN 1181271 has reported the preparation method of a kind of high activity Ganodenic acid polysaccharide and high-load Ganodenic acid, and the yield of extract improves 40%.
Current, chemotherapy of tumors treatment field urgent problem is to seek the low toxicity that makes new advances, the efficient and difficult cancer therapy drug resource that produces multidrug resistance, and this invention just is consistent with it, therefore, has important economic benefit and social benefit.
Summary of the invention
Tumor growth provided by the invention and inhibition of proliferation agent, it is Ganoderic acid T GA-T Ganoderic acid T. (Ganoderic acid T, or it goes up the combined dosage form that forms of adding ingredient of permission with the pharmacology abbreviation GA-T) or Ganoderic acid Me GA-Me (+)-Ganoderic acid Me (Ganoderic acid Me, abbreviation GA-Me).
Wherein said Ganoderic acid T GA-T Ganoderic acid T. (GA-T) or Ganoderic acid Me GA-Me (+)-Ganoderic acid Me (GA-Me) are respectively by extracting (Chem.Pharm.Bull., 34 (5), 2282-2285,1986 in the glossy ganoderma mycelium fermentation; Agric.Biol.Chem., 51 (2), 619-622,1987), purity is greater than 99%, its separated at first evaluation in nineteen eighty-three (Tetrahedron Lett., 24 (10), 1081-1084,1983) and 1987 (Agric.Biol.Chem., 51 (2), 619-622,1987).Said tumor is medically affiliated all kinds of tumors, comprises benign tumor and malignant tumor.And said malignant tumor comprises: malignant melanoma, malignant lymphoma, Alimentary tumor (gastric cancer, intestinal cancer, hepatocarcinoma, carcinoma of gallbladder, cancer of bile ducts, cancer of pancreas), pulmonary carcinoma, breast carcinoma, carcinoma of testis, ovarian cancer, uterus carcinoma, carcinoma of prostate, maxillary cancer, carcinoma of tongue, oral cancer, laryngocarcinoma, thyroid carcinoma, brain tumor, each sarcoid, osteosarcoma, leukemia, nervous system neoplasms, tumor of bladder, skin carcinoma, skin accessory organ's cancer and metastatic carcinoma of skin.
Tumor growth provided by the invention and inhibition of proliferation agent, low dose of i.e. generation suppresses the effect of kinds of tumor cells growth and has dose dependent, they medicines as the treatment tumor can be applied in the chemotherapy of tumor.
Tumor growth provided by the invention and inhibition of proliferation agent, under the situation of low concentration, has the effect that suppresses tumor cell proliferation, illustrate not only have the effect of killing tumor cell but also the unlimited multiplication capacity that can contain tumor cell, thereby can bring into play the effect of further treating tumor more.
Tumor growth provided by the invention and inhibition of proliferation agent have different cytotoxicities to different human cancer cells with human normal cell, especially to the IC of cancerous cell
50Than Normocellular IC
50Much lower, and both significant differences (p＜0.05).
Tumor growth of the present invention and inhibition of proliferation agent, low toxicity is suitable for people and mammal per os or non-oral administration.
Tumor growth provided by the invention and inhibition of proliferation agent do not have specific restriction aspect dosage form, can be used as peroral administration powder, pill, and tablet, solid type preparation such as capsule also can be used as para-oral external agent, and ointment sticks agent, injection.
Tumor growth provided by the invention and inhibition of proliferation agent can cooperate with the auxiliary material that does not influence pharmacotoxicological effect usually and make per os or para-oral preparation.
Tumor growth provided by the invention and inhibition of proliferation agent can be through aqueous solvent (as distilled water), water soluble preparation (as normal saline), and fatsolvent (as siritch) equal solvent is modulated with conventional method.
Tumor growth provided by the invention and inhibition of proliferation agent can be gone up adding ingredient (diluent, coloring agent, the tranquilizer that allows with the pharmacology usually, interfacial agent, cosolvent, buffer agent, correctives, spice, preservative agent, sugar-coat agent) combined, be used for per os or non-per os dosage form.
Tumor growth provided by the invention and inhibition of proliferation agent usually can with the diluted composition that allows on the pharmacology and to be molded into branch combined on the dosage form, be used for per os or non-per os dosage form.
Tumor growth provided by the invention and inhibition of proliferation agent per os dosage form are meant tablet, pill, granule, powder or capsule.Non-per os dosage form is meant intravenous injection, intramuscular dose, and agent, rectum, anus or vagina administration are bathed in the subcutaneous injection agent.Significant advantage of the present invention and technical progress:
Two kinds of native compounds with the multiple human growth of tumour cell of inhibition and proliferation function provided by the invention, overcome traditionally 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, reduced the probability that principal component not causes negative interaction.These two kinds of chemical compounds have significant inhibition human tumor cell growth and proliferation function (the interior and experiment in vitro of body), and are less to the Normocellular cytotoxicity of the mankind simultaneously, have a good application prospect.
Description of drawings
Fig. 1 is that the GA-T of variable concentrations and GA-Me are to the effect of HeLa cell inhibiting.
Fig. 2 is that the GA-T of variable concentrations and GA-Me are to the effect of 95-D cell inhibiting.
Fig. 3 is GA-T and the GA-Me IC to several tumor cells and normal cell L02
50Relatively.
Fig. 4 is the comparison that different pharmaceutical and concentration suppress the nude mice tumor growth in vivo.
The specific embodiment
Below by embodiment content of the present invention is described further.The cited case does not limit protection scope of the present invention:
GA-T and GA-Me are to the toxic action of HeLa cell:
GA-T is with GA-Me and separates the pure natural product that obtains from fermented mycelia, and purity is diluted to desired concn greater than 99% with the DMEM culture fluid.Adopt quick colorimetric method for determining GA-T of tetrazolium bromide (MTT) and GA-Me toxic action to the HeLa cell.With exponential phase cell (10
6Cellml
-1) being inoculated in 96 well culture plates, every hole 0.2ml adds certain density GA-T and GA-Me respectively and handles, parallel 4 holes of every concentration, matched group adds the culture fluid of equivalent volumes, puts 37 ℃, 5%CO
2And the incubator of saturated humidity was cultivated preceding 4 hours every hole adding 5mgml of experiment termination 1-4 days
-1MTT10 μ l, cultivate and finish the every hole adding in back 0.04N dimethyl sulfoxide (DMSO), every hole 150 μ l, vibration 10min treats that the MTT reduzate dissolves fully, with BioRad 550 type microplate reader, with 550nm is the experiment wavelength, and 655nm calculates the suppression ratio of tumor cell and the suppression ratio of medicine pair cell for to measure its trap with reference to wavelength, and, determine the half-inhibition concentration (IC of cell with the variable concentrations of medicine and the mapping of cell inhibiting rate
50).Experimental result is illustrated in fig. 1 shown below.
Above embodiment explanation, GA-T and GA-Me all have the good effect of killing the HeLa tumor cell, and this inhibition effect also has dose dependent.
GA-T and GA-Me are to the toxic action of 95-D cell:
GA-T is with GA-Me and separates the pure natural product that obtains from fermented mycelia, and purity is diluted to desired concn greater than 99% with the RPMI-1640 culture fluid.Adopt quick colorimetric method for determining GA-T of tetrazolium bromide (MTT) and GA-Me toxic action to the 95-D cell.With exponential phase cell (10
6Cellml
-1) being inoculated in 96 well culture plates, every hole 0.2ml adds certain density GA-T and GA-Me respectively and handles, parallel 4 holes of every concentration, matched group adds the culture fluid of equivalent volumes, puts 37 ℃, 5%C0
2And the incubator of saturated humidity was cultivated preceding 4 hours every hole adding 5mgml of experiment termination 1-4 days
-1MTT10 μ l, cultivate and finish the every hole adding in back 0.04N DMSO, every hole 150 μ l, vibration 10min treats that the MTT reduzate dissolves fully, with BioRad 550 type microplate reader, with 550nm is the experiment wavelength, and 655nm calculates the suppression ratio of tumor cell and the suppression ratio of medicine pair cell for to measure its trap with reference to wavelength, and, determine IC with the variable concentrations of medicine and the mapping of cell inhibiting rate
50Experimental result is seen Fig. 2.
Above embodiment explanation, GA-T and GA-Me all have the good effect of killing the 95-D tumor cell, and this inhibition effect has dose dependent.
GA-T and GA-Me compare the cytotoxicity of several tumor cells and normal cell L02:
GA-T is with GA-Me and separates the pure natural product that obtains from fermented mycelia, and purity is diluted to desired concn greater than 99% with DMEM or RPMI-1640 culture fluid.Adopt quick colorimetric method for determining GA-T of tetrazolium bromide (MTT) and GA-Me toxic action to several cells.With exponential phase cell (10
6Cellml
-1) being inoculated in 96 well culture plates, every hole 0.2ml adds certain density GA-T and GA-Me respectively and handles, parallel 4 holes of every concentration, matched group adds the culture fluid of equivalent volumes, puts 37 ℃, 5%CO
2And the incubator of saturated humidity was cultivated preceding 4 hours every hole adding 5mgml of experiment termination 1-4 days
-1MTT 10 μ l, cultivate and finish the every hole adding in back 0.04N DMSO (dimethyl sulfoxide), every hole 150 μ l, vibration 10min treats that the MTT reduzate dissolves fully, with BioRad 550 type microplate reader, with 550nm is the experiment wavelength, 655nm calculates the suppression ratio of tumor cell and the suppression ratio of medicine pair cell for to measure its trap with reference to wavelength, determines IC
50And mapping, the results are shown in Figure 3.
Above embodiment explanation, GA-T and GA-Me are bigger to human tumor cell's cytotoxicity, to Normocellular cytotoxicity a little less than, promptly GA-T and GA-Me have certain targeting inhibitory action to some human tumor cell.
Embodiment 4
GA-T and GA-Me suppress the active comparison of nude mice tumor growth in vivo:
GA-T is with GA-Me and separates the pure natural product that obtains from fermented mycelia, and desired concn is prepared and be diluted to purity greater than 99% with PBS.Two of male nude mouses, forelimb oxter injection 95-D cell (1 * 10
6Individual/ml), put to death the back around feeding, and peels off the solid tumor of nude mice, shreds and grind with PBS (7.4), and 80 eye mesh screens filter.It is standby to be made into cell suspending liquid.Male nude mouse is by the body weight random packet, and 95-D cell suspending liquid (1 * 10 is injected in the forelimb oxter
6Individual/as ml), to feed a week, treat that solid tumor grows after, inject the next day of different medicine abdominal cavity, negative control is normal saline (PBS).With the positive contrast of cancer therapy drug, injection 2 week back drug withdrawal was raised 10 days again, put to death, and peeled off the solid tumor of nude mice and weighed.With compare the calculating suppression ratio.The variable concentrations of medicine to the experimental result of the influence of the suppression ratio of tumor as shown in Figure 4.
Above embodiment explanation, GA-T and GA-Me also can suppress growth of tumor in vivo, also have dose dependent simultaneously.
Claims (4)
1, the application of Ganoderic acid T GA-T Ganoderic acid T. in preparation tumor growth and inhibition of proliferation agent.
2, the application of Ganoderic acid Me GA-Me (+)-Ganoderic acid Me in preparation tumor growth and inhibition of proliferation agent.
As claim 1 or 2 said application, it is characterized in that 3, wherein said tumor comprises benign tumor and malignant tumor for medically affiliated all kinds of tumors.
4, the application said as claim 3 is characterized in that wherein said malignant tumor comprises: malignant melanoma, malignant lymphoma, Alimentary tumor, pulmonary carcinoma, breast carcinoma, carcinoma of testis, ovarian cancer, uterus carcinoma, carcinoma of prostate, maxillary cancer, carcinoma of tongue, oral cancer, laryngocarcinoma, thyroid carcinoma, brain tumor, each sarcoid, osteosarcoma, leukemia, nervous system neoplasms, tumor of bladder, skin carcinoma, skin accessory organ's cancer and metastatic carcinoma of skin.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510026378XA CN100408042C (en) | 2005-06-01 | 2005-06-01 | Use of ganoderic acid T and ganoderic and Me in tumour growth or proliferation inhibitor |
| PCT/CN2006/001171 WO2006128378A1 (en) | 2005-06-01 | 2006-05-31 | Use of ganoderic acid in treating tumour |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510026378XA CN100408042C (en) | 2005-06-01 | 2005-06-01 | Use of ganoderic acid T and ganoderic and Me in tumour growth or proliferation inhibitor |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007101278480A Division CN101084905B (en) | 2005-06-01 | 2005-06-01 | Application of ganoderic acid Me in tumoral growth or propagation inhibitor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219822A (en) * | 2011-03-24 | 2011-10-19 | 上海交通大学 | Ganoderic acid T amide derivative TLTO-A and synthetic method and application thereof |
| CN102440969A (en) * | 2010-10-09 | 2012-05-09 | 华东理工大学 | Ganoderic acid monomer T tablet and its preparation method |
| CN104188976A (en) * | 2014-08-25 | 2014-12-10 | 上海应用技术学院 | Inhibitor by virtue of interaction of P53-MDM2 and applications of inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1267563C (en) * | 2004-04-13 | 2006-08-02 | 徐志祥 | Technique for extracting triterpene substane of mycelium of ganoderma lucidum |
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- 2005-06-01 CN CNB200510026378XA patent/CN100408042C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102440969A (en) * | 2010-10-09 | 2012-05-09 | 华东理工大学 | Ganoderic acid monomer T tablet and its preparation method |
| CN102219822A (en) * | 2011-03-24 | 2011-10-19 | 上海交通大学 | Ganoderic acid T amide derivative TLTO-A and synthetic method and application thereof |
| CN102219822B (en) * | 2011-03-24 | 2013-01-09 | 上海交通大学 | Ganoderic acid T amide derivative TLTO-A and synthetic method and application thereof |
| CN104188976A (en) * | 2014-08-25 | 2014-12-10 | 上海应用技术学院 | Inhibitor by virtue of interaction of P53-MDM2 and applications of inhibitor |
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