CN1511527A - Use of tetrandrine in inhibiting vascularization medicine - Google Patents
Use of tetrandrine in inhibiting vascularization medicine Download PDFInfo
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- CN1511527A CN1511527A CNA021594244A CN02159424A CN1511527A CN 1511527 A CN1511527 A CN 1511527A CN A021594244 A CNA021594244 A CN A021594244A CN 02159424 A CN02159424 A CN 02159424A CN 1511527 A CN1511527 A CN 1511527A
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Abstract
The present invention discloses the new use of tetrandrine in medicine for inhibiting vasculariztion, and the effective dosage is 4-15 mg/kg body weight/day. Owing to the effect of tetrandrine in inhibiting vasculariztion, it may be used in medicines for preventing and/or treating occurrence and metastasis of tumor and treating other vasculariztion relative diseases, such as senile dish plaque denaturation, psoriasis, angioma, atherosclerosiss, etc. The present invention uses the vasculariztion as the target of treating diseases and has the advantages of treatment specificity of pointing newly formed vessel; small dosage, high treating effect and less side effect owing to the direct action of medicine to vascular endothelial cell; and less medicine resistance owing to relatively stable endothelial cell gene expression.
Description
Technical field
The present invention relates to novel application of compound, particularly the new purposes of tetrandrine.
Background technology
Studies show that tumor self possesses and starts and promote the ability that new vessels generates, with the metabolism that satisfies self and the needs of nutrient substance supply.Tumor neovasculature generation (angiogenesis) is the process that begins to form new vessels from existing vascular bed.If there is not angiogenesis, the growth of primary tumo(u)r can not surpass 1-2mm, can not occur soaking into and shifting yet.Suppress tumor-blood-vessel growth, closely related with generation, development, infiltration and the transfer of blocking-up tumor.Suppress tumor-blood-vessel growth, also can stop the pernicious transformation of precancerous lesion to cancer.The not only growth of entity tumor, infiltration and transfer rely on new vessels and generate, and the growth of blood system malignant tumor (as malignant lymphoma, Lymphocytic leukemia etc.) and transfer are also closely related with angiogenesis.Growth of tumor, transfer, recurrence, more the back is closely related with angiogenesis, is target spot with the angiogenesis of tumor, and the exploitation angiogenesis inhibitor not only can be used for most of tumor treatment and also can be used for the prevention of cancer and the treatment of blood system malignant tumor.
Tetrandrine is to extract from Chinese crude drug Radix stephaniae tetrandrae root and the bisbenzylisoquinoline alkaloid that comes, and structural formula is suc as formula I:
Formula I
According to 1: 4000 diluent energy of reported in literature tetrandrine kill cancer cell, there is report to think that tetrandrine has obvious inhibitory action to the KB cell again, to Hela cell and Hela-S
3Cell has the obvious suppression effect.Wermel found once that tetrandrine had tumor killing effect to ehrlich carcinoma, rat liver cancer strain, the external existing report that tetrandrine is used for the treatment of tumor.Above-mentioned discovery does not all propose have the effect that suppresses angiogenesis relevant with tetrandrine with using.The existing medicinal relevant patent of this chemical compound of the U.S. and Japan, its content comprise that parasiticide is with multidrug resistance (US5025020,5332747,5466590), relevant ocular infection (US5627195), antiviral with resist and lure cancer agent (JP4099723) etc.Existing discovering, tetrandrine has certain therapeutical effect to tumor, mainly is by promoting apoptosis, reverse multidrug resistance, enhancing radiation sensitivity to produce.
Relevant tetrandrine is used for by angiogenesis inhibitor mechanism that treatment of diseases only is useful on diabetic retinopathy, there are report (Biol Pharm Bull 1999 Apr the chronic inflammatory disease aspect; 22 (4): 360-5, Biol Pharm Bull 1998Apr; 21 (4): 346-9).
Summary of the invention
A kind of new purposes that the purpose of this invention is to provide tetrandrine.
The inventor studies show that, tetrandrine has the effect that suppresses angiogenesis.
Technical solution of the present invention is: tetrandrine suppresses the application in the medicine for the treatment of and/or preventing of angiogenesis in preparation.Above-claimed cpd treats and/or prevents in the medicine the inhibition angiogenesis, and effective dose is generally the 4-15mg/kg body weight/day.
In said medicine, also can add one or more pharmaceutically acceptable carriers.Described carrier comprise the pharmaceutical field routine diluent, filler, excipient, binding agent, wetting agent, collapse and release agent, absorption enhancer, surfactant, absorption carrier, lubricant etc., add flavouring agent, sweeting agent etc. in case of necessity.
The medicine of the present invention's preparation can be made into multiple dosage forms such as injection, tablet, powder, granule, capsule, oral liquid, unguentum, cream.The medicine of above-mentioned various dosage forms all can be according to the conventional method preparation of pharmaceutical field.
Of the present invention studies show that, but be the medicine wide range of therapeutic of active component preparation and the disease of associated angiogenesis with above-mentioned formula 1 chemical compound.As reach the purpose that suppresses tumor by the angiogenesis that suppresses tumor, can develop antitumor drug, have definite treatment and preventive effect for diseases such as the disease of other and associated angiogenesis such as retinopathy of prematurity, retinal vein occlusion, the degeneration of old plate-like speckle, psoriasis, hemangioma, atherosclerosiss.
The present invention is that the target spot of treatment disease has the following advantages with the angiogenesis:
1, treats at the new vessels that has started, have specificity;
2, because vascular endothelial cell is exposed in the blood flow, and medicine can directly play a role, so dosage is little, the curative effect height, side effect is little;
3, because the endothelial cell gene expression is relatively stable, so be difficult for producing drug resistance.
Description of drawings
Fig. 1 is the dose-dependent inhibition effect curves of tetrandrine to human vascular endothelial cell proliferation.
Fig. 2 handles the optical microscope photograph that the human vascular endothelial cell pipe in back forms for the variable concentrations tetrandrine.
Fig. 3 handles the human migration of vascular endothelial cells result's in back optical microscope photograph for the variable concentrations tetrandrine.
The specific embodiment
Embodiment 1: tetrandrine is to the inhibitory action of human vascular endothelial cell proliferation.
(HUVEC available from Cascade Biologics company, Cot:C-003-5C) places the Medium 200 (available from Cascade Biologics company) that contains 10% hyclone (FBS) to cultivate (37 ℃, 5%CO with the human umbilical vein endothelial cell
2, 95% humidity), get the 4th generation cell be inoculated in 96 well culture plates by density 4000/250ul, set the medication group and the blank of matched group, each Concentraton gradient, all do 3 multiple holes for every group.Treat that the cell stand density reaches 80%, the tetrandrine (with the DMSO dissolving) that adds each Concentraton gradient of 5ul respectively, make final concentration be respectively 1000uM, 100uM, 10uM, 5uM and 1uM, matched group adds 5ulDMSO, continue to cultivate (M200 culture medium, 2%FBS) after 48 hours, Thiazolyl blue tetrazolium bromide salt (MTT) 20ul that adds 5mg/ml, 37 ℃ were continued to hatch 4 hours, stopped cultivating, and abandoned supernatant, every hole adds 150ulDMSO, vibration was measured each hole light absorption value at 490nm wavelength place with BIO-RAD Model 3500 microplate reader after 1 hour gently, represented the quantity of living cells in each hole with light absorption value.Above-mentioned experiment repeats 3 times.The result as shown in Figure 1, abscissa is a drug level among the figure, vertical coordinate is light absorption value (being directly proportional with living cells quantity).The result shows that tetrandrine is the dose-dependent inhibition effect to human umbilical vein endothelial cell's propagation, and its half amount of suppression is 50uM.
Embodiment 2: tetrandrine forms the inhibitory action of ability to human vascular endothelial cell pipe.
The every hole of 24 well culture plates adds BD Matrigel
TMMatrix virgin rubber 200ul, make it to aggregate into glue, the 4th generation human umbilical vein endothelial cell (HUVEC) suspension is seeded in 24 orifice plates that scribble Matrigel glue by 30000cell/500ul density, set the medication group of matched group, each Concentraton gradient, the medication group adds tetrandrine (10uM, 25uM, 50uM, the 100uM that 10ul has Concentraton gradient respectively, with the DMSO dissolving), matched group adds aseptic DMSO10ul, all does 3 multiple holes for every group.37 ℃, 5%CO
2, 95% humidity cultivated 24 hours, the formation of OLYMPUS CK40-RFL observation by light microscope vascular endothelial cell pipe, 4 low power fields countings are got in every hole, take pictures with OLYMPUS CK40 digital camera.The result shows that tetrandrine is dose-dependent inhibition to human vascular endothelial cell pipe formation ability as shown in Figure 2, and its half amount of suppression is 25uM.
Embodiment 3: tetrandrine is to the inhibitory action of human migration of vascular endothelial cells ability.
1, preparation chemotactic factor
Get the NIH3T3 cell that goes down to posterity and grew fine in back second day.The soft rinsing of serum-free DMEM 2 times.Serum-free DMEM, 5%CO
2, cultivate 24-48hours for 37 ℃.The collecting cell supernatant.Centrifugal (12000g, 4 ℃, 10min).Supernatant bacteriological filtration (0.22um filter membrane), (20 ℃) are preserved in packing.
2, Matrigel invasion and attack experiment
The Matrigel 25ul (virgin rubber is pressed 1: 2 dilution proportion with DMEM) that gets dilution adds chamber on the Transwell plate, covers whole polyester film surface, hatches 30min for 37 ℃, makes Matrigel aggregate into glue.The 4th generation human umbilical vein endothelial cell (HUVEC) suspension is seeded to the chamber by 30000/250ul density, PBS washing 3 digestion and harvestings from culture bottle.DMEM makes single cell suspension with serum-free, and 5 * 10
5Cells/ml, the medication group adds the medicine (10uM, 25uM, 50uM, 100uM are with the DMSO dissolving) of each Concentraton gradient, and matched group adds the DMSO with volume.The chamber adds the chemotactic factor of 500ul step 1 preparation under the Transwell plate.5%CO
2, cultivated 24 hours for 37 ℃.Wipe the cell of gel and polyester film upper surface gently with the wet cotton swab of DMEM.The careful taking-up gone up the chamber, and ice-cold methanol is fixed 30 minutes.Haematoxylin dyeing 1 minute.Gradient alcohol dehydration (80%, 95%, 100%, 100%), dimethylbenzene is transparent.Carefully polyester film is cut from last chamber, place resinene mounting on the microscope slide.The cell (400 *) under high power lens that is attached to the polyester film lower surface is got 6 visuals field countings at random and is averaged and take pictures.Repeated experiments 2 times.The result shows that tetrandrine is the dose-dependent inhibition effect to the transfer ability of human vascular endothelial cell as shown in Figure 3.
Embodiment 4: the tumor bearing nude mice in vivo test.
Results human colon cancerous cell line LoVo cell is made cell suspension with PBS, and the right side thigh portion that is seeded to big BALB/cAnN-nu/nu nude mice of 8 weeks with 2,000,000/200ul is subcutaneous.When treating the tumor bulk-growth, be divided into two groups at random, 5 every group to 5mm * 5mm size.Tetrandrine medication group dosage is 50mg/kg (medicine is to contain the PBS solution dissolving of 10%DMSO), and matched group is given the PBS solution 200ul that contains 10%DMSO, and successive administration 60 days is every the major diameter and the minor axis of record tumor body.During the medication, untoward reaction does not appear in mice.After putting to death mice, take out tumor, detect the microvessel density of tumor.The result shows that medication group tumor body dwindles than matched group, and growth is obviously slowed down, and microvessel density is starkly lower than matched group.Illustrate that this medical instrument has the effect that suppresses tumor in the body, and side effect is very little.
Claims (8)
1, tetrandrine suppresses the application in the medicine for the treatment of and/or preventing of angiogenesis in preparation.
2, application according to claim 1, the effective dose that it is characterized in that described tetrandrine is the 4-15mg/kg body weight/day.
3, application according to claim 1 and 2 is characterized in that also can adding one or more pharmaceutically acceptable carriers in the medicine of preparation angiogenesis.
4, application according to claim 1 is characterized in that described medicine is the medicine that treats and/or prevents tumor.
5, application according to claim 1 is characterized in that described medicine is the medicine that treats and/or prevents the degeneration of old plate-like speckle.
6, application according to claim 1 is characterized in that described medicine is for treating and/or preventing psoriatic medicine.
7, application according to claim 1 is characterized in that described medicine is for treating and/or preventing atherosclerotic medicine.
8, application according to claim 1 is characterized in that described medicine is the angiomatous medicine of treatment.
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| CNA021594244A CN1511527A (en) | 2002-12-31 | 2002-12-31 | Use of tetrandrine in inhibiting vascularization medicine |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100508979C (en) * | 2007-01-30 | 2009-07-08 | 南京大学医学院附属鼓楼医院 | Use of tetrandrine as chemotherapy pharmaceutical sensitivity agent for treating gastric cancer |
| CN101766619B (en) * | 2008-12-30 | 2011-08-24 | 武汉大学 | Pharmaceutical composition for malignancy treatment and application thereof |
| CN102669118A (en) * | 2012-03-14 | 2012-09-19 | 中国人民解放军第二军医大学 | New application of tetrandrine in fungal bio-film resistance |
| WO2013107428A1 (en) * | 2012-01-21 | 2013-07-25 | 杭州本生药业有限公司 | 7-substituted hanfangichin b derivative, and preparation method and use thereof |
| CN104039794A (en) * | 2012-01-21 | 2014-09-10 | 杭州本生药业有限公司 | 7-substituted hanfangichin B derivative, and preparation method and use thereof |
| CN104906098A (en) * | 2015-05-14 | 2015-09-16 | 天津中医药大学 | Applications of tetrandrine in preparation of medicines |
| CN110859842A (en) * | 2019-12-13 | 2020-03-06 | 澳门大学 | Tetrandrine composition, preparation method thereof, tetrandrine external preparation, preparation method and application thereof |
-
2002
- 2002-12-31 CN CNA021594244A patent/CN1511527A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100508979C (en) * | 2007-01-30 | 2009-07-08 | 南京大学医学院附属鼓楼医院 | Use of tetrandrine as chemotherapy pharmaceutical sensitivity agent for treating gastric cancer |
| CN101766619B (en) * | 2008-12-30 | 2011-08-24 | 武汉大学 | Pharmaceutical composition for malignancy treatment and application thereof |
| WO2013107428A1 (en) * | 2012-01-21 | 2013-07-25 | 杭州本生药业有限公司 | 7-substituted hanfangichin b derivative, and preparation method and use thereof |
| CN104039794A (en) * | 2012-01-21 | 2014-09-10 | 杭州本生药业有限公司 | 7-substituted hanfangichin B derivative, and preparation method and use thereof |
| JP2015504075A (en) * | 2012-01-21 | 2015-02-05 | ハンジョウ ベンシェン ファーマシューティカル シーオー．， エルティーディー．Ｈａｎｇｚｈｏｕ Ｂｅｎｓｈｅｎｇ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． | 7-Substituted Hanfungitin B Derivatives, Preparation Method and Use |
| US9328122B2 (en) | 2012-01-21 | 2016-05-03 | Hangzhou Bensheng Pharmaceuticals Co., Ltd. | 7-substituted Hanfangichin B derivative, and preparation method and use thereof |
| CN104039794B (en) * | 2012-01-21 | 2017-11-03 | 杭州本生药业有限公司 | The hanfangchin B derivative of 7 substitutions, and its preparation method and application |
| CN102669118A (en) * | 2012-03-14 | 2012-09-19 | 中国人民解放军第二军医大学 | New application of tetrandrine in fungal bio-film resistance |
| CN104906098A (en) * | 2015-05-14 | 2015-09-16 | 天津中医药大学 | Applications of tetrandrine in preparation of medicines |
| CN110859842A (en) * | 2019-12-13 | 2020-03-06 | 澳门大学 | Tetrandrine composition, preparation method thereof, tetrandrine external preparation, preparation method and application thereof |
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