CN101732338A - Application of chitohexaose in preparation of medicines for preventing angiogensis - Google Patents
Application of chitohexaose in preparation of medicines for preventing angiogensis Download PDFInfo
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- CN101732338A CN101732338A CN200810229067A CN200810229067A CN101732338A CN 101732338 A CN101732338 A CN 101732338A CN 200810229067 A CN200810229067 A CN 200810229067A CN 200810229067 A CN200810229067 A CN 200810229067A CN 101732338 A CN101732338 A CN 101732338A
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Abstract
The invention relates to biomedicines, in particular to application of chitohexaose in preparation of medicines for preventing angiogensis. The chitohexaose can inhibit the angiogensis of tumors through inhibiting the migration of vascular endothelial cells, i.e. the chitohexaose can be further used for preparing the medicines for treating the tumor and inhibiting the tumor migration. By using a tumor cell culture solution as an induction factor and using the endothelial cells of human umbilical veins as research objects, the chitohexaose is found to be capable of remarkably inhibiting the proliferation and the migration of the endothelial cells of the human umbilical veins induced by the tumor cell culture solution.
Description
Technical field
The present invention relates to treat the medicine of tumor, the application of shell six sugar in the medicine of preparation prevention angiogenesis specifically is that shell six sugar are in preparation treatment tumor and medicine that suppresses neoplasm metastasis or the application in the health food furtherly.
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 meets or exceeds 1-2mm
3The time, 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 shell six sugar in the medicine of preparation prevention angiogenesis, further shell six sugar can be in the application in preparing the medicine for the treatment of tumor and suppressing neoplasm metastasis; Shell six sugar can suppress tumor-blood-vessel growth: by acting on Human umbilical vein endothelial cells, suppress the propagation and the migration of the inductive Human umbilical vein endothelial cells of tumor cell culture liquid, thereby suppress the angiogenesis of tumor.
For achieving the above object, the technical solution used in the present invention is:
The application of shell six sugar in the medicine of preparation prevention angiogenesis.
Described shell six sugar can suppress the angiogenesis of tumor by the migration that suppresses vascular endothelial cell, and promptly shell six sugar can be further used for preparing the treatment tumor and suppress in the medicine of neoplasm metastasis; The medicine of described treatment tumor and inhibition neoplasm metastasis is treatment solid tumor and the medicine that suppresses the solid tumor transfer.
Described shell six sugar are shell six sugar of purity 〉=80wt%; The useful effect concentration of described shell six sugar in cells survival environment or cultivating system is 50-100 μ g/mL, as: during experimental applications, the useful effect concentration of shell six sugar in the body fluid of affected part is 50-100 μ g/mL.
Described shell six sugar mix the various forms of powders of formation, unguentum, powder, injection, water preparation or injection with acceptable drug adjuvant on the materia medica; Described excipient substance is polyvinylpyrrolidone, little silica white etc.
Can take subcutaneous, intravenous injection or anorectal administration in use; The use of injection can be selected normal saline, glucose, stabilizing agent, antiseptic, suspending agent or emulsifying agent etc. arbitrarily for use.
Advantage of the present invention is:
1. according to embodiment 1: experimental results show that shell six sugar can obviously suppress the propagation by the inductive Human umbilical vein endothelial cells of tumor cell culture liquid, suppression ratio reaches 33.3% in shell six sugared concentration during at 50-100 μ g/mL.Therefore, shell six sugar have the latent effect that suppresses tumor-blood-vessel growth, are 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. according to embodiment 2: experimental results show that shell six sugar can obviously suppress the migration by the inductive Human umbilical vein endothelial cells of tumor cell culture liquid, suppression ratio reaches 78% in shell six sugared concentration during at 50 μ g/mL.The experiment conclusion according to the present invention can further be inquired into shell six sugar inhibition tumor-blood-vessel growths and be cut into branch really.Thereby develop antitumor and the medicine that suppresses neoplasm metastasis more efficiently.
3. according to embodiment 3: experimental results show that shell six sugar under 50 μ g/mL concentration to suppressing by the migration effect of the inductive Human umbilical vein endothelial cells of tumor cell culture liquid chitooligose monomer significantly better than oligochitosan or other degree of polymerization.The experiment conclusion according to the present invention can further be studied the mechanism of shell six sugar inhibition 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 variable concentrations shell six sugar are to the effect of huve cell growth.A is the effects (24 hour) of variable concentrations shell six sugar to normal huve cell; B is the effects (24 hour) of variable concentrations shell six sugar to the inductive huve cell of tumor cell culture liquid.
Fig. 2 variable concentrations shell six sugar are to suppressing the effect of the inductive Human umbilical vein endothelial cells migration of tumor cell culture liquid.Wherein: a1-a6 is the MCF-7 human breast cancer cell culture fluid of 10% (v/v) and induces;
The oligochitosan of Figure 35 0 μ g/mL and five kinds of chitooligose monomers are to suppressing the effect of the inductive Human umbilical vein endothelial cells migration of tumor cell culture liquid.Wherein: a1-a6 is the MCF-7 human breast cancer cell culture fluid of 10% (v/v) and induces;
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, 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 shell six sugar (other content are shell pentasaccharides and shell seven sugar) of mass content 〉=80%, finds that by cell biology method shell six sugar can obviously suppress the propagation and the migration of the inductive Human umbilical vein endothelial cells of tumor cell culture liquid.Illustrate that shell six sugar can suppress the angiogenesis of tumor by the migration that suppresses vascular endothelial cell.
Reference literature (Anti-angiogenic activities of chitooligosaccharides, Haige Wu, Ziang Yao, Xuefang Bai, Yuguang Du, Bingcheng Lin, CarbohydratePolymers, Volume 73, Issue 1,4July 2008, Pages 105-110), the condition of culture of Human umbilical vein endothelial cells is: add 10% calf serum, 100U/ml penicillin, 100ug/ml streptomycin in complete medium 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, breast cancer cells as inducible factor; The condition of culture of human colon cancer cell, hepatoma carcinoma cell, ovarian cancer, breast cancer cell is: add 10% calf serum, 100U/ml penicillin, 100ug/ml streptomycin in complete medium RPMI1640 culture fluid; 37 ℃, feed CO
2Volume content is 5% air cultivation.
Embodiment 1
Reference literature (Anti-angiogenic activities ofchitooligosaccharides, Haige Wu, Ziang Yao, Xuefang Bai, Yuguang Du, Bingcheng Lin, CarbohydratePolymers, Volume 73, Issue 1, and 4July 2008, and Pages 10
5-1
10), 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 20 μ L MTT (5mg/mL) reagent and 200 μ L DMSO, 1-5h (this example adopts 3h) the back inhibitory action of microplate reader detection of drugs on cell proliferation.
As seen from Figure 1, shell six sugar can suppress the promotion of tumor cell culture liquid to the huve cell growth in the concentration range of 50-100 μ g/mL, and are proportionate with concentration, but this inhibitory action was not obvious after concentration surpassed 200 μ g/mL.
Embodiment 2
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, cultivate 10-24h (this example adopts 24h), Human umbilical vein endothelial cells grows up to monolayer in 6 well culture plates after, use the cell scraper cut, with PBS (pH 7.4) flushing 3 times, then shell six sugar are joined in the culture fluid, final concentration is respectively 6.25 μ g/mL, 12.5 μ g/mL, 25 μ g/mL, 50 μ g/mL, 100 μ g/mL and 200 μ g/mL, be inducible factor with tumor cell culture liquid simultaneously, continue to cultivate 10-24h (this example adopts 24h) back and be inverted observed result under the optical microscope.
As seen from Figure 2, tumor cell culture liquid can obviously promote the migration of Human umbilical vein endothelial cells.
As seen from Figure 2, the facilitation that shell six sugar of 50 μ g/mL and 100 μ g/mL all can significantly suppress or antagonism tumor cell culture liquid moves Human umbilical vein endothelial cells.
Embodiment 3
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, cultivate 10-24h (this example adopts 24h), Human umbilical vein endothelial cells grows up to monolayer in 6 well culture plates after, use the cell scraper cut, with PBS (pH 7.4) flushing 3 times, the chitooligose monomer with oligochitosan and different polymerization degree joins in the culture fluid then, and final concentration is 50 μ g/mL, be inducible factor with tumor cell culture liquid simultaneously, continue to cultivate 10-24h (this example adopts 24h) back and be inverted observed result under the optical microscope.
As seen from Figure 3, tumor cell culture liquid can obviously promote the migration of Human umbilical vein endothelial cells.
As seen from Figure 3, shell six sugar of 50 μ g/mL are more obvious to the inhibitory action of Human umbilical vein endothelial cells migration to tumor cell culture liquid than the chitooligose monomer of oligochitosan or other degree of polymerization.
Claims (7)
1. the application of shell six sugar in the medicine of preparation prevention angiogenesis.
2. according to the described application of claim 1, it is characterized in that: described shell six sugar can suppress the angiogenesis of tumor by the migration that suppresses vascular endothelial cell, and promptly shell six sugar can be further used for preparing the treatment tumor and suppress in the medicine of neoplasm metastasis.
3. according to the described application of claim 2, 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 claim 1 or 2 described application, it is characterized in that: described shell six sugar are shell six sugar of purity 〉=80wt%.
5. according to claim 1 or 2 described application, it is characterized in that: the useful effect concentration of described shell six sugar in cells survival environment or cultivating system is 50-100 μ g/mL.
6. according to claim 1 or 2 described application, it is characterized in that:
Described shell six sugar mix the various forms of powders of formation, unguentum, powder, injection, water preparation or injection with acceptable drug adjuvant on the materia medica.
7. according to the described application of claim 6, it is characterized in that: described excipient substance is polyvinylpyrrolidone or little silica white.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11207343B2 (en) | 2016-03-30 | 2021-12-28 | Ayuvis Research, Inc. | Compositions and therapeutic methods |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11207343B2 (en) | 2016-03-30 | 2021-12-28 | Ayuvis Research, Inc. | Compositions and therapeutic methods |
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Open date: 20100616 |