CN107349414A - Purposes of the protein function inhibitor DAPT in the medicine for preparing treatment tumour - Google Patents
Purposes of the protein function inhibitor DAPT in the medicine for preparing treatment tumour Download PDFInfo
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- CN107349414A CN107349414A CN201610306026.8A CN201610306026A CN107349414A CN 107349414 A CN107349414 A CN 107349414A CN 201610306026 A CN201610306026 A CN 201610306026A CN 107349414 A CN107349414 A CN 107349414A
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- dapt
- adenoma
- medicine
- pituitary adenoma
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
Abstract
The invention provides purposes of the protein function inhibitor DAPT in the medicine for preparing treatment pituitary adenoma.Pass through above-mentioned technical proposal, the present invention can effectively improve the prognosis of pituitary adenoma patients.
Description
Technical field
The present invention relates to biochemistry and field of medicaments, in particular it relates to protein function inhibitor DAPT
Purposes in the medicine for preparing treatment tumour.
Background technology
Pituitary adenoma therapeutic modality mainly includes drug therapy, operative treatment, radiation treatment, at present
Mainly based on operation, quite a few corrective surgery is ineffective for treatment, postoperative often to occur remaining and answer
Hair, is the problem that current neurosurgery is difficult to break through.Drug therapy be solve this problem it is effective
Approach.SMS 201-995 and dopamine-receptor stimulant be used to control a part of hypersecretion GH types
With PRL type adenoma patients, height and the drug susceptibility of SSTR2 expressions are proportionate.But
Clinically still suffer from a large amount of surgery excision residuals, postoperative recurrence, the patient to Drug-resistant, treatment method
Improper and over-treatment is simultaneously deposited, and makes its therapeutic efficiency low, and disability rate is high, and overall recurrence rate is more than 30%.
Current still lack of targeted, effective class of medications.
It is therefore desirable to develop that pituitary adenoma differentiation, propagation, the method for apoptosis and invasive procedure can be influenceed
And medicine, so as to provide effective way to improve the treatment of pituitary adenoma and outcome.
The content of the invention
First purpose of the present invention is to provide protein function inhibitor DAPT and is preparing treatment pituitary gland
Purposes in the medicine of knurl.
Second object of the present invention is to provide protein function inhibitor DAPT function fragment, derivative
And its purposes of salt or solvate in the medicine for preparing treatment pituitary adenoma.
Wherein, DAPT refers to CAS accession number 208255-80-5 compound, Chinese name：(3,5-
Difluoro phenylacetyl group)-L- alanyl-L-2- phenylglycine t-butyl esters；Molecular formula：C23H26F2N2O4；
It is a kind of gamma-secretase (γ-secretase) inhibitor, gamma-secretase substrate Notch can be suppressed indirectly
Activity, and then influence cellular signal transduction and cell differentiation procedure.
Wherein, the derivative of the DAPT is DAPT halo, sulfonation, nitrification, hydroxylation, alcoxyl
Change or esterification products.
DAPT derivatives can be into salt or solvate, wherein described salt includes sodium salt, sylvite etc., institute
The solvate stated refers to hydrate, alcoholate etc..The derivative can be used at least part of suppression
Differentiation, propagation and the invasion and attack of pituitary adenoma processed.Those skilled in the art will envision that DAPT derivative
Thing and functionalization fragment possess and DAPT identical core textures.Therefore, its function fragment, derivative
And its salt or solvate are likewise supplied with preferably should in the medicine for treating or preventing pituitary adenoma is prepared
Use effect.
Pituitary adenoma of the present invention covers known a variety of pituitary adenomas, including functional pituitary adenoma
And/or non-functional pituitary adenoma, wherein, the functional pituitary adenoma include GH types pituitary adenoma,
At least one of PRL types pituitary adenoma, ACTH types pituitary adenoma and TSH type pituitary adenomas；Institute
State non-functional pituitary adenoma include ghost adenoma, oncocytoma, gonadotroph adenoma,
At least one of static corticotropin adenoma and glycoprotein secretory adenoma.
In addition to the active ingredient (s, medicine of the present invention also includes pharmaceutically acceptable at least one tax
Shape agent.Described excipient is understood by those skilled in the art, is including but not limited to disintegrated
Agent, lubricant, dispersant etc., those skilled in the art can be selected according to the actual demand of preparation
Select, the present invention is not particularly limited to this.
Medicine of the present invention, pharmaceutically various common dosage forms can be prepared into via conventional method, such as
Tablet, capsule, pill, powder, granule, supensoid agent, oral administration solution, powder pin or injection
Deng.Optional oral, the sublingual, vein of administering mode, subcutaneous, transdermal or part administration etc., with unit
Form of medication gives animal or people.
The suitable unit dosage fonn of medicine of the present invention includes peroral dosage form (such as tablet, glue
Capsule, pill, powder, granule, oral administration solution or suspension), it is sublingual or buccal administration formulation, quiet
Arteries and veins, subcutaneously, transdermal or intramuscular dosage form (such as parenteral solution, powder pin etc.).In addition, the medicine
Can be ordinary preparation, sustained release preparation, quick releasing formulation and controlled release preparation.
Preferably, medicine of the present invention is peroral dosage form, intravenously administrable formulation or intramuscular administration agent
Type.
The present invention simultaneously for the function fragment containing DAPT, DAPT, DAPT derivatives and its salt or
The pharmaceutical preparation of solvate provides preferable embodiment, specifically, when preparing tablet or capsule
During the solid composite medicament of form, the excipient that can be added in active component, including diluent,
Such as lactose, dextrin, starch, pregelatinized starch, sucrose, mannitol, microcrystalline cellulose；Bonding
Agent, such as polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose；Disintegrant, such as carboxylic first
Base sodium starch, crosslinked carboxy methylcellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose,
PVPP etc.；Lubricant, such as silica, magnesium stearate, stearate, jade
Rice starch, talcum powder etc., flavouring, such as mannitol, Aspartame, saccharin sodium and stevioside,
In addition, can also add surfactant, as dodecyl sodium sulfate, sodium dioctyl sulfosuccinate,
Sucrose ester and poloxamer etc.., can in active component when preparing the pharmaceutical composition of pill
The excipient of addition, including diluent and absorbent, such as lactose, glucose, dextrin, starch, sugarcane
Sugar, cocoa butter etc.；Binder, such as Arabic gum, tragacanth, gelatin, honey；Disintegrant,
Such as methylcellulose, ethyl cellulose, dry starch, agar powder, alginate.Oral administration solution
Or the figuration that suspension can add, including sweetener, such as saccharin sodium, sucrose, honey element, A Siba
Sweet tea and stevioside etc.；Suspending agent, such as polyvinylpyrrolidone, microcrystalline cellulose, sucrose, hydroxypropyl
Methylcellulose etc.；Preservative, such as parabens, sodium benzoate, methyl p-hydroxybenzoate, right
Nipasol etc..The excipient that granule can add, including filler, binder, coloring
Agent and flavouring etc..Injection preparation, such as parenteral solution, emulsion, freeze drying powder injection, it can use
Various diluents commonly used in the art, such as water, ethanol, polyethylene glycol, propane diols, the different tristearin of oxidation
Alcohol etc., cosolvent, buffer or pH adjusting agent etc..In addition, in order to prepare isotonic parenteral solution, can add
Enter sodium chloride, glucose or glycerine etc..Tablet of the present invention can be pure tablet, can also be by piece
Coating tablet, such as film-coating, sugar-coat etc. is further made in agent.By preparing polymer substrate or in film
Specific polymer is used in coating, tablet can be made to quick-release, sustained release or controlled release form.Capsule
Can be soft capsule or hard shell capsules, without film or with film, so as to quick-release, sustained release or controlled capability
Energy.
In the pharmaceutical composition of the present invention, DAPT is generally prepared with dosage unit.Contain per dosage unit
There are 5 to 10 milligrams of DAPT, give daily 1 time or multiple.It can also be used under particular case higher
Or relatively low-dose, the suitable dose of each patient by doctor according to mode of administration, the age of the patient,
Body weight and reaction finally determine.
The medicine can with available treatment means (such as chemotherapy, surgical operation therapy or
Radiotherapy) combination.
In addition to using medicine in any means summarized, medicine of the invention can be used as other treatments
The additive of method.The treatment of the present invention, which should be understood, to be combined with any other known treatment method.
Pass through above-mentioned technical proposal, DAPT can substantially suppress the growth of pituitary adenoma cells and transplantable tumor.
The DAPT of various dose is applied in Primary Growth hormone adenoma tumour cell and GH3 cells, can
The obvious propagation for suppressing primary pituitary adenoma cell and GH3 cells.Particularly at 5-20ng/mL place
Manage under dosage, optimal Inhibit proliferaton effect can be obtained.Transwell experiments display that DAPT exists
The invasive ability of tumour cell can be suppressed under 2-20ng/mL dosage.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Embodiment
The embodiment of the present invention is described in detail below.It should be appreciated that this place is retouched
The embodiment stated is merely to illustrate and explain the present invention, and is not intended to limit the invention.
DAPT is Gene Operation (US) commercial prod in following examples, and article No. is
IN01001-0005MG。
Embodiment 1
1.1 Specimen origin
Sample is derived from the tumor tissues of pituitary adenoma patients surgery excision.It is preoperative according to clinical manifestation, serum
Hormonal readiness and imageological examination make tentative diagnosis, further according to seen in art and postoperative pathological and immune
Histochemical stain is made a definite diagnosis, for the GH types pituitary adenoma with invasiveness, TSH types adenoma, PRL types
Each 10 of adenoma, nonfunctional adenoma.
1.2 main agents
Pancreatin, DMEM culture mediums, hyclone, dimethyl sulfoxide (DMSO), poly-D-lysine are commercially available
Product.
1.3 cell culture
The pituitary adenoma tissues of surgery excision are put under sterile working in serum-free DMEM nutrient solutions,
Sterile PBS is rinsed 2-3 times in super-clean bench, removes connective tissue, slough and clot, sample is used
Eye scissors shreds into 1mm3Size tissue is bad, adds trypsase piping and druming scattered, treat cell it is well dispersed with
Afterwards, DMEM nutrient solutions (including 10% hyclone) are added and terminates digestion, filtered through 100 mesh cells
After device filtering, 1000r/min centrifugation 10min, supernatant is abandoned, adding DMEM nutrient solutions makes cell weight
Outstanding scattered, microscopy counts, and adjustment cell density is 1 × 106/mL.Cell is counted with Trypan Blue to live
Property.It is inoculated in be coated with the blake bottle of poly-D-lysine in advance and cultivates.Treat that primary pituitary adenoma cell reaches
When being merged to 80%-90%, cell is collected with Trypsin Induced, is resuspended and passed on DMEM nutrient solutions.
1.4 observation index：
1.4.1 morphology and cell proliferation rate observation
Set 6 various doses treatment group, added respectively in DMEM nutrient solutions final concentration 0.5,
1st, 5,10,20 and 100ng/mL DAPT, control group add isometric DMSO, carry out thin
Born of the same parents cultivate.
The Morphological Features of cell are once cultivated in observation daily under inverted phase contrast microscope, record different disposal group
Pendant adenoma cell adherent time and the time for covering with individual layer, as a result as shown in table 1.
Table 1
1.4.2 flow cytomery Apoptosis
The treatment group of 6 various doses is set, add final concentration of 0.5 respectively in DMEM nutrient solutions,
1st, 5,10,20 and 100ng/mL DAPT, control group add isometric DMSO, carry out thin
Born of the same parents cultivate.
It is all to be harvested after the primary pituitary adenoma cell Secondary Culture 3d of 3 weeks to take incubation time, and
Single cell suspension is made, centrifuges 5min through 1000r/m (r=15cm), abandons supernatant, cell directly suspends
In PI hypotonic mediums, FCM is analyzed cell DNA, the fluorescence warp that PI-DNA compounds are sent
FCM quantitative analyses, Apoptosis are represented with the percentage of cells less than 2 times of body peaks.As a result such as table 2
It is shown.
Table 2
1.4.3 MTS methods detection cell propagation
The treatment group of 6 various doses is set, add final concentration of 0.5 respectively in DMEM nutrient solutions,
1st, 5,10,20 and 100ng/mL DAPT, control group add isometric DMSO, and culture is former
For pituitary adenoma cells and GH3 cells to exponential phase, 96 porocyte culture plates are taken, are added per hole
DMEM nutrient solutions (adding 10% calf serum) are in 37 DEG C of 5%CO2Saturation vapour carbon dioxide training
Support and cultivated 24 hours in case.Add 20 μ l MTS/PMS mixed liquors per hole, continue culture 3-4 hours and develop the color.
Culture plate is rocked before detection 10 seconds, mix color in enzyme detector, detected at wavelength 570nm
The absorbance value (OD) in each hole.Curve is drawn to OD values (OD570) with sample dilution.System
It is as shown in table 3 to count cell proliferative conditions.
Table 3
1.4.4 tumor cell invasion ability detects
According to the ECM550 series specification requirement of Chemicon companies, cell is put into culture plate,
The serum free medium of 300 μ l pre-temperatures is added in upper chamber, 15-30min is stood at room temperature, makes matrigel
Rehydration.Remaining culture liq is sucked again.
Prepare cell suspension：Cell can be first allowed to remove serum starvation 12-24h before preparing cell suspension, further
Remove the influence of serum.Vitellophag, terminate centrifugation after digesting and discard nutrient solution, 1-2 is washed with PBS
Time, it is resuspended with the serum free medium containing BSA.Add the DAPT of various dose and to adjust cell close
Spend to 1-10 × 105。
Inoculating cell：The μ L of cell suspension 200 are taken to add Transwell cells；Room adds under 24 orifice plates
Culture mediums of the 500 μ L containing FBS or chemotactic factor (CF).
Cultivate cell：Cellar culture 24h.
Mtt assay carries out result count：Matrigel and upper indoor cell are wiped with cotton swab；In 24 orifice plates
500 μ l MTT containing 0.5mg/mL complete medium is added, cell is placed in one, submerges film
In the medium, taken out after 37 DEG C of 4h.500 μ l DMSO are added in 24 orifice plates, cell is placed in
Wherein, film is immersed in DMSO, vibrate 10min, fully dissolving.Take out cell, 24 orifice plates
In surveying OD values (OD570) on ELIASA, processing data result is as shown in table 4.
Table 4
| Treatment group (ng/mL) | 0.5 | 1 | 5 | 10 | 20 | 100 | 0 |
| Primary pituitary adenoma cell | 0.379 | 0.334 | 0.296 | 0.223 | 0.178 | 0.142 | 0.457 |
| GH3 cells | 0.391 | 0.345 | 0.277 | 0.207 | 0.165 | 0.134 | 0.672 |
Result above shows to apply different doses in Primary Growth hormone adenoma tumour cell and GH3 cells
The DAPT of amount, it can substantially suppress the propagation of primary tumor cell and GH3 cells.Particularly exist
Under 5-20ng/mL treatment dosage, optimal Inhibit proliferaton effect can be obtained.Transwell experiments are aobvious
Show that DAPT can suppress the invasive ability of tumour cell.
1.4.5 transplanted tumor in nude mice is tested
SPF level BALB/c-nu mouse (kind), female, 5-7 week old, body weight (18 ± 2) g (purchases
Beijing Vital River Experimental Animals Technology Co., Ltd., experimental animal credit number：SCXK (capital)
2012-0001) through forelimb oxter subcutaneous vaccination mouse source Growth Hormone Pituitary Adenoma GH3 cells (in being purchased from
Academy of Medical Sciences basic research institute of state cell centre), treat knurl length to about 120mm3Therefrom filter out body weight
And the uniform mice with tumor of knurl body 30, it is standby.
By mice with tumor, 30 are uniformly divided into 3 groups at random, and every group 10, every group respectively through tail intravenous administration
Various dose DAPT, the administration per bu 1 time, each dosage be respectively 1mg/kg, 5mg/kg,
10mg/kg.Administration puts to death animal after 15 days, strips tumor tissue and calculates tumour inhibiting rate TVI, as a result such as table 5
It is shown.
TVI%=(gross tumor volume on the day of gross tumor volume-administration group on the day of blank group)/(swollen on the day of blank group
Knurl volume) × 100%.
Table 5
| Each dosage (mg/kg) | Tumour inhibiting rate (%) after being administered 15 days |
| 1 | 10.71 |
| 5 | 28.97 |
| 10 | 49.81 |
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited to above-mentioned reality
The detail in mode is applied, can be to the technical side of the present invention in the range of the technology design of the present invention
Case carries out a variety of simple variants, and these simple variants belong to protection scope of the present invention.
It is further to note that each particular technique described in above-mentioned embodiment is special
Sign, in the case of reconcilable, can be combined by any suitable means, in order to avoid need not
The repetition wanted, the present invention no longer separately illustrate to various combinations of possible ways.
In addition, various embodiments of the present invention can be combined randomly, as long as its
Without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (8)
1. purposes of the protein function inhibitor DAPT in the medicine for preparing treatment pituitary adenoma.
2. protein function inhibitor DAPT function fragment, derivative and its salt or solvate are being made
Purposes in the medicine of standby treatment pituitary adenoma.
3. purposes according to claim 2, it is characterised in that the derivative of the DAPT is
DAPT halo, sulfonation, nitrification, hydroxylation, alkoxide or esterification products.
4. purposes according to claim 1 or 2, it is characterised in that the pituitary adenoma is work(
Energy property pituitary adenoma and/or non-functional pituitary adenoma, wherein, the functional pituitary adenoma includes GH
In type pituitary adenoma, PRL types pituitary adenoma, ACTH types pituitary adenoma and TSH type pituitary adenomas
It is at least one；The non-functional pituitary adenoma includes ghost adenoma, oncocytoma, rush property
At least one of glandular hormone adenoma, static corticotropin adenoma and glycoprotein secretory adenoma.
5. according to the purposes described in any one in claim 1-4, it is characterised in that the medicine
Using DAPT, DAPT function fragment, DAPT derivative and its salt or solvate as single work
Property composition or one of as active component.
6. purposes according to claim 5, it is characterised in that the medicine is also included pharmaceutically
At least one of acceptable excipient, carrier and diluent.
7. according to the purposes described in any one in claim 1-6, it is characterised in that the medicine
For tablet, capsule, pill, powder, granule, supensoid agent, oral administration solution, powder pin or injection.
8. purposes according to claim 7, it is characterised in that the medicine be peroral dosage form,
Sublingual or buccal administration formulation, vein, subcutaneous, transdermal or intramuscular dosage form.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610306026.8A CN107349414A (en) | 2016-05-10 | 2016-05-10 | Purposes of the protein function inhibitor DAPT in the medicine for preparing treatment tumour |
| PCT/CN2017/088125 WO2017194031A1 (en) | 2016-05-10 | 2017-06-13 | Use for protein function inhibitor dapt in preparing medicine for treating adenoma |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610306026.8A CN107349414A (en) | 2016-05-10 | 2016-05-10 | Purposes of the protein function inhibitor DAPT in the medicine for preparing treatment tumour |
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| Publication Number | Publication Date |
|---|---|
| CN107349414A true CN107349414A (en) | 2017-11-17 |
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|---|---|---|---|
| CN201610306026.8A Pending CN107349414A (en) | 2016-05-10 | 2016-05-10 | Purposes of the protein function inhibitor DAPT in the medicine for preparing treatment tumour |
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| WO (1) | WO2017194031A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1777436A (en) * | 2003-02-18 | 2006-05-24 | 罗斯坎普研究有限责任公司 | Anti-angiogenic and anti-tumoral properties of beta and gamma secretase inhibitors |
| CN101098708A (en) * | 2004-11-10 | 2008-01-02 | 胡布雷希特实验室 | Treatment of an intestinal adenoma and/or adenocarcinoma by inhibition of Notch pathway activation |
| CN102085372A (en) * | 2009-12-04 | 2011-06-08 | 中国医学科学院基础医学研究所 | Application of Notch pathway inhibitor in treatment of tumors caused by activation of mTOR |
| WO2016013669A1 (en) * | 2014-07-25 | 2016-01-28 | 国立研究開発法人理化学研究所 | Method for producing adenohypophysis or precursor tissue thereof |
-
2016
- 2016-05-10 CN CN201610306026.8A patent/CN107349414A/en active Pending
-
2017
- 2017-06-13 WO PCT/CN2017/088125 patent/WO2017194031A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1777436A (en) * | 2003-02-18 | 2006-05-24 | 罗斯坎普研究有限责任公司 | Anti-angiogenic and anti-tumoral properties of beta and gamma secretase inhibitors |
| CN101098708A (en) * | 2004-11-10 | 2008-01-02 | 胡布雷希特实验室 | Treatment of an intestinal adenoma and/or adenocarcinoma by inhibition of Notch pathway activation |
| CN102085372A (en) * | 2009-12-04 | 2011-06-08 | 中国医学科学院基础医学研究所 | Application of Notch pathway inhibitor in treatment of tumors caused by activation of mTOR |
| WO2016013669A1 (en) * | 2014-07-25 | 2016-01-28 | 国立研究開発法人理化学研究所 | Method for producing adenohypophysis or precursor tissue thereof |
Non-Patent Citations (4)
| Title |
|---|
| LEE M ET AL.: "Targeting PI3K/mTOR Signaling Displays Potent Antitumor Efficacy against Nonfunctioning Pituitary Adenomas", 《CLIN CANCER RES》 * |
| MONSALVES E ET AL.: "The PI3K/AKT/mTOR pathway in the pathophysiology and treatment of pituitary adenomas", 《ENDOCR RELAT CANCER》 * |
| XIE R ET AL.: "Specific inhibition of mTOR pathway induces anti-proliferative effect and decreases the hormone secretion in cultured pituitary adenoma cells", 《J NEUROONCOL》 * |
| 杨永凯等: "DAPT抑制人胶质瘤细胞增殖的体内外实验研究", 《福建医药杂志》 * |
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| WO2017194031A1 (en) | 2017-11-16 |
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Application publication date: 20171117 |