CN101416979A - Use of oligosaccharide in preparing medicine for treating tumor and inhibiting tumor metastasis - Google Patents
Use of oligosaccharide in preparing medicine for treating tumor and inhibiting tumor metastasis Download PDFInfo
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- CN101416979A CN101416979A CNA2007101576687A CN200710157668A CN101416979A CN 101416979 A CN101416979 A CN 101416979A CN A2007101576687 A CNA2007101576687 A CN A2007101576687A CN 200710157668 A CN200710157668 A CN 200710157668A CN 101416979 A CN101416979 A CN 101416979A
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Abstract
The invention relates to the biological medicine, in particular to the application of chitosan oligosaccharide in preparing medicines used for treating tumors and restraining tumor metastasis, wherein, by taking a nutrient solution for tumor cells as an inducing factor and taking a human umbilical vein endothelial cell as an study object, the chitosan oligosaccharide can significantly restrain the human umbilical vein endothelial cell metastasis induced by the nutrient solution for tumor cells and the formation of tubular structure caused by the endothelial cell metastasis, but have no obvious restraining effect on the proliferation of the human umbilical vein endothelial cells metastasis induced by the nutrient solution for tumor cells.
Description
Technical field
The present invention treats the medicine of tumor, and specifically oligochitosan is in preparation treatment tumor and the medicine of inhibition neoplasm metastasis or the application in the health food.
Background technology
Along with development of human society, the aggravation of environmental pollution, the change of life style, tumor is malignant tumor-cancer especially, has become one of principal disease that threatens the human life.Malignant tumor has become human dead first or second reason according to statistics, and the annual whole world has 7,000,000 people to die from cancer approximately.Although compare with some developed countries, as the U.S., Britain, France, Russia, Japan etc., China's mortality of malignant tumors and to account for the ratio of total death relatively low, but malignant tumor also is discharged to second in the various causes of the death in China, then ranks the first in the big city.
Tumor is no matter be optimum or pernicious, all show as the out of control abnormality proliferation of cell in essence, this excrescent ability is except the lasting growth that shows as tumor itself, in malignant tumor, also show as infringement and intravascular, lymphatic vessel and the body cavity of normal adjacent tissue are transferred to other position of health, i.e. neoplasm metastasis.Neoplasm metastasis is the basic biological property of malignant tumor, is most patients' lethal factor clinically.Primary tumo(u)r can undergo surgery and excise or radiotherapy, but the cancer of having sent out often is difficult to not damage normal structure with above-mentioned means treatment.Therefore, neoplasm metastasis is a kind of serious challenge to treatment of cancer.
Early stage in the primary tumo(u)r growth, the required nutriment of growth of tumour cell is to provide by the infiltration of adjacent tissue organ microcirculation, and this is enough to make primary tumo(u)r growth and diffusion.When diameter of tumor met or exceeded 1-2mm, the nutrient substance that relies on the environment infiltration to provide can not guarantee the growth of tumor cell.At this moment, the blood vessel that supplies nutrients to tumor progressively forms.The capillary network that tumor inducing forms is not only relevant with primary tumo(u)r, and provides primary condition for the free tumor cell of invading substrate enters blood circulation.The new capillary vessel basement membrane itself exists damaged, and the venular wall of thin-walled also has the slit, adds that vascular structures such as small lymph pipeline provide the convenience that enters blood circulation for tumor cell.Therefore, the formation of new capillary vessel is absolutely necessary to the propagation and the growth of primary tumo(u)r cell itself, also is simultaneously the necessary condition that tumor invasion shifts.Most results of study show that tumor vessel forms parameter and can be used as the better index of judging kinds of tumors recurrence, transfer and prognosis.
Document 1 has been set forth molecular mechanism (the document 1.Patrick A of tumor-blood-vessel growth, Sylvie L, Fr ' ederic LL, Andreas B.Molecular mechanisms of tumor vascularization.Critical Reviews in Oncology/Hematology 2005; 54:53-61.).Angiogenesis needs migration, propagation and the formation tubular structure of vascular endothelial cell.Tumor cell can produce a large amount of somatomedin, comprises VEGF, FGF, TGF etc.These somatomedin can promote migration, propagation and the formation tubular structure of vascular endothelial cell by a series of signal conduction, finally form new blood vessel.
As seen, the migration of vascular endothelial cell, propagation and formation tubular structure are to form cardiovascular essential condition.
Summary of the invention
The object of the present invention is to provide the application of oligochitosan in the medicine of preparation treatment tumor and inhibition neoplasm metastasis; Oligochitosan can suppress tumor-blood-vessel growth: by acting on Human umbilical vein endothelial cells, suppress the migration of the inductive Human umbilical vein endothelial cells of tumor cell culture liquid and form tubular structure, thereby suppress the angiogenesis of tumor.
For achieving the above object, the technical solution used in the present invention is:
The application of oligochitosan in the medicine of preparation treatment tumor and inhibition neoplasm metastasis.
Described oligochitosan mixes the various forms of pills of formation, powder, tablet, unguentum, powder, injection, water preparation, granule, capsule or injection etc. with adjuvant.Can take through the oral cavity in use or non-administering mode through the oral cavity; That non-mode through the oral cavity can be taked is subcutaneous, intravenous injection or anorectal administration; The use of injection can be selected normal saline, glucose, stabilizing agent, antiseptic, suspending agent or emulsifying agent etc. arbitrarily for use.
The medicine of described treatment tumor and inhibition neoplasm metastasis is treatment solid tumor and the medicine that suppresses the solid tumor transfer, and oligochitosan can suppress the angiogenesis of tumor by the migration that suppresses vascular endothelial cell.
The degree of polymerization of described oligochitosan is preferably 2-8, degree of acetylation＜5%.
Described oligochitosan also can be used as antitumor and suppresses the health food or the additive of neoplasm metastasis, the health food form can be liquid such as picture refreshment drink, lactic acid beverage, flavoring agent, as additive, such as joining wheaten food class, fruit jelly, ice cream, curing food, Petaso, point is in the heart.
Advantage of the present invention is:
1. the present invention is with the oligochitosan of the method for enzymolysis preparation, experimental results show that oligochitosan can obviously suppress the migration of Human umbilical vein endothelial cells and form tubular structure, have the latent effect that suppresses tumor-blood-vessel growth, be expected to the medicine and and antitumor relevant health care food and the food additive etc. that are developed to antitumor and suppress neoplasm metastasis.
2. the experiment conclusion according to the present invention can further be inquired into oligochitosan inhibition tumor-blood-vessel growth and be cut into branch really.Thereby develop antitumor and the medicine that suppresses neoplasm metastasis more efficiently.
3. the experiment conclusion according to the present invention can further be studied the mechanism that oligochitosan suppresses angiogenesis, determines its mechanism of action, can be developed into the medicine of the treatment disease relevant with angiogenesis etc.
Description of drawings
Fig. 1 is the influence of tumor cell culture liquid to the Human umbilical vein endothelial cells migration, and wherein: A is 0h, and B is not for adding tumor cell culture liquid 24h, and C induces 24h for tumor cell culture liquid;
Fig. 2 is the influence of variable concentrations oligochitosan (COS) to the inductive Human umbilical vein endothelial cells migration of tumor cell culture liquid, wherein: A is tumor cell culture liquid+5ug/mlCOS24h, B is tumor cell culture liquid+50ug/mlCOS24h, and C is tumor cell culture liquid+500ug/mlCOS24h;
To be oligochitosan (COS) become the influence of pipe effect to the inductive Human umbilical vein endothelial cells of tumor cell culture liquid to Fig. 3, and wherein: A induces 24h for tumor cell culture liquid, and B is tumor cell culture liquid+50ug/mlCOS effect 24h;
Fig. 4 is the influence of oligochitosan (COS) to the inductive huve cell growth of tumor cell culture liquid.
The specific embodiment
The angiogenesis of tumor is the process of a complexity, and the mechanical stimulus in weary oxygen, inflammation and the external world etc. all is the inducement of tumor-blood-vessel growth.And the somatomedin, the cytokine that participate in tumor-blood-vessel growth are also a lot.The inhibition tumor-blood-vessel growth is the hot issue in the antitumor research at present, oligochitosan has good biocompatibility and biodegradability, is expected to be developed as a kind of effective, the safe inhibition tumor growth and medicine, health food or the food additive of transfer.
The present invention adopts conventional enzyme solution to prepare the oligochitosan that the degree of polymerization is 2-8, find that by cell biology method oligochitosan can obviously suppress the migration of the inductive Human umbilical vein endothelial cells of tumor cell culture liquid and form tubular structure, but can not suppress the propagation of the inductive Human umbilical vein endothelial cells of tumor cell culture liquid.Illustrate that oligochitosan can suppress the angiogenesis of tumor by the migration that suppresses vascular endothelial cell.
The condition of culture of Human umbilical vein endothelial cells is: add volumetric concentration 10% calf serum, 100U/ml penicillin, 100ug/ml streptomycin in the RPMI1640 culture fluid; 37 ℃, feed CO
2Volume content is 5% air cultivation.
With culture fluid such as human colon cancer cell, hepatoma carcinoma cell, ovarian cancer cells as inducible factor; The condition of culture of human colon cancer cell, hepatoma carcinoma cell, ovarian cancer cell is: add volumetric concentration 10% calf serum, 100U/ml penicillin, 100ug/ml streptomycin in the DMEM culture fluid; 37 ℃, feed CO
2Volume content is 5% air cultivation.
Embodiment 1 migration experiment
Human umbilical vein endothelial cells is pressed 0.1-10 * 10
6It is individual/ml that (this example adopts 1-2 * 10
6Individual/ml) density is inoculated in 6 orifice plates, cultivates 10-24h (this example adopts 24h), and Human umbilical vein endothelial cells is used the cell scraper cut grow up to monolayer in 6 well culture plates after, usefulness PBS (120mMNacl, 5mMKcl, 1.7mMKH
2PO
4, 8.3mMNaHPO
4.12H
2O) flushing is 3 times, the oligochitosan that with the degree of polymerization is 2-8 then joins in the culture fluid, final concentration is respectively 5ug/ml, 50ug/ml and 500ug/ml, is inducible factor with tumor cell culture liquid simultaneously, continues to cultivate 10-24h (this example adopts 24h) back observed result under phase contrast microscope.
As seen from Figure 1, tumor cell culture liquid can obviously promote the migration of Human umbilical vein endothelial cells.
As seen from Figure 2, the facilitation that the oligochitosan of 50ug/ml and 500ug/ml all can significantly suppress or antagonism tumor cell culture liquid moves Human umbilical vein endothelial cells.
Embodiment 2 forms the tubular structure experiment
Overlay 96 orifice plates with 10-100ul (this example adopts 50-100ul) Mus tail collagen, solidify the back with 0.1-10 * 10
5It is individual/ml that (this example adopts 1-2 * 10
5Individual/ml) density inoculation Human umbilical vein endothelial cells, cultivate behind the 10-24h (this example employing 24h) the degree of polymerization is that the oligochitosan of 2-8 joins in the culture fluid, final concentration is that 50ug/ml is an inducible factor with tumor cell culture liquid simultaneously, continues to cultivate 10-48h (this example adopts 24h) back observed result under phase contrast microscope.
As seen from Figure 3, oligochitosan can suppress tumor cell culture liquid forms tubular structure to Human umbilical vein endothelial cells inducing action.
Embodiment 3
Human umbilical vein endothelial cells is pressed 0.1-10 * 10
6It is individual/ml that (this example adopts 1-2 * 10
6Individual/ml) density is inoculated in 96 orifice plates, dosing behind the cultivation 10-24h, be inducible factor with tumor cell culture liquid simultaneously, continue to cultivate 10-24h (this example employing 24h) back and add MTT (tetrazole indigo plant) reagent and DMSO, 1-5h (this example adopts 3h) the back inhibitory action of microplate reader detection of drugs on cell proliferation.
As seen from Figure 4, oligochitosan can suppress the promotion of tumor cell culture liquid to the huve cell growth in the concentration range of 5-50ug/ml, and is proportionate with concentration, but this inhibitory action was not obvious after concentration surpassed 200ug/ml.
Claims (5)
1. the application of oligochitosan in the medicine of preparation treatment tumor and inhibition neoplasm metastasis.
2. according to the described application of claim 1, it is characterized in that: described oligochitosan mixes the various forms of pills of formation, powder, tablet, unguentum, powder, injection, water preparation, granule, capsule or injection with adjuvant.
3. according to the described application of claim 1, it is characterized in that: the medicine of described treatment tumor and inhibition neoplasm metastasis is treatment solid tumor and the medicine that suppresses the solid tumor transfer.
4. according to the described application of claim 1, it is characterized in that: the degree of polymerization of described oligochitosan is 2-8, degree of acetylation＜5%.
5. according to the described application of claim 1, it is characterized in that: described oligochitosan can suppress the angiogenesis of tumor by the migration that suppresses vascular endothelial cell.
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| CNA2007101576687A CN101416979A (en) | 2007-10-24 | 2007-10-24 | Use of oligosaccharide in preparing medicine for treating tumor and inhibiting tumor metastasis |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225198A (en) * | 2011-06-28 | 2011-10-26 | 南京农业大学 | Anti-tumour medicine composition and preparation method and application thereof |
| CN104586877A (en) * | 2015-02-10 | 2015-05-06 | 河北工业大学 | Chitosan oligosaccharide-containing pharmaceutical composition and applications thereof |
| WO2017107628A1 (en) * | 2015-12-24 | 2017-06-29 | 广东药科大学 | Chitosan oligosaccharide capsule and method for preparation thereof |
| CN110279862A (en) * | 2019-07-09 | 2019-09-27 | 上海市第六人民医院 | A kind of anti-cancer composition and its application in the drug of preparation treatment osteosarcoma |
| WO2021253545A1 (en) * | 2020-06-18 | 2021-12-23 | 广东药科大学 | Chitosan oligosaccharide composition, preparation method therefor, and application thereof |
-
2007
- 2007-10-24 CN CNA2007101576687A patent/CN101416979A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102225198A (en) * | 2011-06-28 | 2011-10-26 | 南京农业大学 | Anti-tumour medicine composition and preparation method and application thereof |
| CN104586877A (en) * | 2015-02-10 | 2015-05-06 | 河北工业大学 | Chitosan oligosaccharide-containing pharmaceutical composition and applications thereof |
| WO2017107628A1 (en) * | 2015-12-24 | 2017-06-29 | 广东药科大学 | Chitosan oligosaccharide capsule and method for preparation thereof |
| CN110279862A (en) * | 2019-07-09 | 2019-09-27 | 上海市第六人民医院 | A kind of anti-cancer composition and its application in the drug of preparation treatment osteosarcoma |
| WO2021253545A1 (en) * | 2020-06-18 | 2021-12-23 | 广东药科大学 | Chitosan oligosaccharide composition, preparation method therefor, and application thereof |
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