CN104744571A - VE-cadherin (Vascular Endothelium-Cadherin) antagonist polypeptide and application thereof - Google Patents
VE-cadherin (Vascular Endothelium-Cadherin) antagonist polypeptide and application thereof Download PDFInfo
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- CN104744571A CN104744571A CN201510157273.1A CN201510157273A CN104744571A CN 104744571 A CN104744571 A CN 104744571A CN 201510157273 A CN201510157273 A CN 201510157273A CN 104744571 A CN104744571 A CN 104744571A
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Abstract
The invention relates to a VE-cadherin (Vascular Endothelium-Cadherin) antagonist polypeptide and an application thereof, relates to the field of drugs, and in particular relates to a polypeptide for inhibiting generation of a tumor blood vessel and treating a malignant tumor. The polypeptide is characterized in that the polypeptide has a brand-new sequence, namely QARAKVCMQRTKKDAMQRSLRKQ. The polypeptide can specifically inhibit multiplication and migration of vascular endothelium cells of a tumor tissue in vitro, inhibits the generation of the tumor blood vessel, increases a survival rate of tumor loaded mice in a vivo test, and has a potential new drug development value.
Description
Technical field
The present invention relates to blood vessel endothelium calnexin antagonist polypeptide and application thereof, be specifically related to propagation and the migration of the vascular endothelial cell of specificity Tumor suppression tissue, Tumor suppression vasculogenesis, the polypeptide for the treatment of malignant tumour.
Background technology
Folkman in 1971 proposes growth and metastasis of tumours and relies on new vessel generation.And after thinking that solid tumor is formed, its development can be divided into without blood vessel phase and two stages of blood vessel phase.Without the blood vessel phase, the existence of minimal neoplastic relies on interstitial disperse blood supply around, and linearly, tumour is limited within 1mm ~ 2mm the speed of growth, and oncocyte number is less than 10
5~ 10
6individual, force tumour to be in " dormant state "; Intravasation after date, tumor tissues is the blood supply of perfusion property, and the exponentially property growth of knurl body, can increase 1. 6 ten thousand times after 2 weeks.New vessel not only provides nutrition required for tumour and oxygen, gets rid of meta-bolites, and is the approach of distant metastasis.Therefore, block tumor angiogenesis and just may stop growth and metastasis of tumours, anti-new vessel therapy also one of means becoming oncotherapy.
Blood vessel endothelium and the effect of stroma cell adhesion molecule to tumor-blood-vessel growth more and more receive publicity.Calnexin is the membranin that a class depends on calcium ion, is important cell adhesion albumen, is responsible for sticking of the identification of cell and cell and cell and tissue.The expression of calnexin has tissue specificity, and that express at vascular endothelial cell is blood vessel endothelium calnexin (VE-cadherin), and this is the target of a potential tumor-blood-vessel growth.Current report has one to be that the antibody E4G10 of target can specific recognition tumor vessel suppress it to generate with VE-cadherin, and the normal blood vessel of nonrecognition.This may be because the epitope of this antibody recognition VE-cadherin is covered in normal blood vessels, and on tumor vessel, this epi-position is exposed, and imply that potential clinical value.As can be seen here, suppress VE-cadherin can effective Tumor suppression vasculogenesis, thus Tumor suppression grow, and tumour is in " dormant state ".
At present, do not have the blood vessel endothelium calnexin antagonist polypeptide of ripe exploitation to come out, be used for the treatment of malignant tumour.
Blood vessel endothelium calnexin antagonist polypeptide in this patent has proved in treatment carcinoma of the pancreas effective, has the prospect developed in other tumor models.
Summary of the invention
goal of the invention
The invention provides brand-new sequence, this sequence is blood vessel endothelium calnexin antagonist polypeptide, and the propagation of the vascular endothelial cell of specificity Tumor suppression tissue and migration, have good curative effect to malignant tumour.
technical scheme
blood vessel endothelium calnexin antagonist polypeptide, is characterized in that its sequence is QARAKVCMQRTKKDAMQRSLRKQ.
Blood vessel endothelium calnexin antagonist polypeptide treatment malignant tumour, as the application in pancreatic cancer drug.
beneficial effect
Utilize solid-phase synthesis chemosynthesis blood vessel endothelium calnexin antagonist polypeptide, this polypeptide has brand-new sequence, and this polypeptide can targets identification tumor endothelial cell, and suppresses the propagation of vascular endothelial cell in vitro, and treatment malignant tumour, as carcinoma of the pancreas.The blood vessel endothelium calnexin antagonist polypeptide that we find can suppress migration of vascular endothelial cells vigor simultaneously, and improves tumor-bearing mice survival rate in testing in vivo, has potential new drug development value.
Embodiment
Embodiment 1
The effect of blood vessel endothelium calnexin antagonist polypeptide human vascular endothelial migration.
Adopt scratch experiment.First use marker pen at 24 orifice plates behind, compare with ruler, evenly must draw horizontal line, approximately every 0.5 ~ 1cm together, cross via hole.Every hole is through 3 lines; By becoming the HUVEC cell of logarithmic growth, with 1.0 × 10
5add in 24 well culture plates, cultivate 24h.Within second day, compare ruler with 10 μ l rifle heads, perpendicular to horizontal line cut behind, with the point of crossing of cut and horizontal line behind for Orientation observation site; Experimental port, positive drug control hole add Experimental agents blood vessel endothelium calnexin antagonist polypeptide (the raw work synthesis in Shanghai) and the positive control medicine vincristine(VCR) of different concns respectively; Blank group adds the solvent of same volume, and five multiple holes are established in every hole; Put into 37 DEG C, 5%CO
2incubator, cultivates.By 0,6,12,24,36 hours, take pictures; Measure 0,6,12,24,36h scratch width.With different time points, record the change of three fixed positions place, every hole scratch width, be cell migration distance.According to formulae discovery mobility (migration rate, MR): mobility (MR)=(testing scratch width-experiment scratch width of the 0th hour of n-th hour) × 100%/experiment scratch width of the 0th hour.As a result, increase with blood vessel endothelium calnexin antagonist polypeptide concentration, inhibition of metastasis rate declines gradually, and illustrate that blood vessel endothelium calnexin antagonist polypeptide can suppress human vascular endothelial to move, inhibiting rate is 78.2%.
Embodiment 2
Blood vessel endothelium calnexin antagonist polypeptide is to the growth of vitro culture human vascular endothelial and survival IC50.
Adopt MTT colorimetry.By the human vascular endothelial HUVEC of logarithmic growth, with 1.0 × 10
5add in 96 well culture plates, cultivate 24h, experimental port, positive drug control hole add Experimental agents blood vessel endothelium calnexin antagonist polypeptide (the raw work synthesis in Shanghai) and the positive control medicine taxol of different concns respectively; Blank group adds the solvent of same volume.Five multiple holes are established in every hole, cultivate 48h, respectively 0h, 2h, 8h, 14h, 20h, 24h, 36h, the every hole of 48h adds MTT, after effect 4h, add DMSO, hatch 30min, absorbance A value is measured, by formula HUVEC growth inhibition ratio=(1-experimental group light absorption value/control group light absorption value) × 100% at microplate reader 620nm place.The IC50 calculating Experimental agents is 2.32 μMs.
Embodiment 3
With vigor in the body of tumor model detection blood vessel endothelium calnexin antagonist polypeptide.
Set up pancreatic tumour model, positive control medicine taxol; 0. 5,1.0,2.0mg/Kg blank group adds the solvent of same volume, and experimental group polypeptide (the raw work synthesis in Shanghai) establishes 3 dosage:.After 21 days, observe mouse survival quantity, calculate survival rate.Result shows, and blood vessel endothelium calnexin antagonist polypeptide can protect small white mouse effectively, and improve the survival rate of tumor-bearing mice, survival rate reaches 87.2%.
SEQUENCE LISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120> is about blood vessel endothelium calnexin antagonist polypeptide and application thereof
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 23
<212> PRT
<213> artificial sequence
<400> 1
Gln Ala Arg Ala Lys Val Cys Met Gln Arg Thr Lys Lys Asp Ala Met
1 5 10 15
Gln Arg Ser Leu Arg Lys Gln
20
Claims (2)
1. blood vessel endothelium calnexin antagonist polypeptide, is characterized in that its sequence is QARAKVCMQRTKKDAMQRSLRKQ.
2. blood vessel endothelium calnexin antagonist polypeptide is in treatment malignant tumour, as the application in pancreatic cancer drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510157273.1A CN104744571A (en) | 2015-04-06 | 2015-04-06 | VE-cadherin (Vascular Endothelium-Cadherin) antagonist polypeptide and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510157273.1A CN104744571A (en) | 2015-04-06 | 2015-04-06 | VE-cadherin (Vascular Endothelium-Cadherin) antagonist polypeptide and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104744571A true CN104744571A (en) | 2015-07-01 |
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ID=53584893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510157273.1A Withdrawn CN104744571A (en) | 2015-04-06 | 2015-04-06 | VE-cadherin (Vascular Endothelium-Cadherin) antagonist polypeptide and application thereof |
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| CN (1) | CN104744571A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008021322A2 (en) * | 2006-08-14 | 2008-02-21 | Sloan-Kettering Institute For Cancer Research | Selective alpha particle-mediated depletion of tumor vasculature with vascular normalization |
-
2015
- 2015-04-06 CN CN201510157273.1A patent/CN104744571A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008021322A2 (en) * | 2006-08-14 | 2008-02-21 | Sloan-Kettering Institute For Cancer Research | Selective alpha particle-mediated depletion of tumor vasculature with vascular normalization |
Non-Patent Citations (1)
| Title |
|---|
| DEEPTI NAVARATNA等: "Retinal Neovascularization is Suppressed with a an Antagonist to VE-Cadherin", 《ARCH.OPHTHALMOL.》 * |
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20150701 |
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| WW01 | Invention patent application withdrawn after publication |