CN107714719A - Application of the rapamycin in the medicine for preparing treatment IL-27 low expression carcinoma of endometrium - Google Patents
Application of the rapamycin in the medicine for preparing treatment IL-27 low expression carcinoma of endometrium Download PDFInfo
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- CN107714719A CN107714719A CN201711087886.8A CN201711087886A CN107714719A CN 107714719 A CN107714719 A CN 107714719A CN 201711087886 A CN201711087886 A CN 201711087886A CN 107714719 A CN107714719 A CN 107714719A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Abstract
The invention belongs to pharmaceutical technology field, it is related to the purposes of rapamycin, and in particular to application of the rapamycin in the medicine for preparing the treatment low expression carcinomas of endometrium of IL 27.Shown through experiment in vitro and internal animal experiment, 27 more normal endometrials of carcinoma of endometrium cancer stove IL are significantly reduced, and rapamycin treatment can increase endometrial carcinoma cell IL 27 and generate, and enhancing NK cells are acted on the tumor-killing of carcinoma of endometrium.Rapamycin chemotherapy can significantly inhibit the carcinoma of endometrium progress caused by NK dysfunctions, can be further used for the treatment of the low expression carcinomas of endometrium of IL 27.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to rapamycin is low in preparation treatment interleukins (IL) -27
Express the application in the medicine of carcinoma of endometrium.
Background technology
Carcinoma of endometrium is the malignant tumour of one group of endometrial epithelium source type, is that female reproductive system is most common pernicious
One of tumour, the 20%~30% of female genital tract malignant tumour is accounted for, in recent years in worldwide, uterus carcinoma of endometrium
The incidence of disease risen and had the trend of rejuvenation.In China, the incidence of disease of uterus carcinoma of endometrium is only second to cervical carcinoma, occupies
Second.And it is in the first place of female genital tract malignant tumour in the developed countries such as America and Europe, its incidence of disease.Carcinoma of endometrium at present
Pathogenesis be still not clear, think more morbidity with high estrogen stimulation and it is relevant without progestational hormone antagonism.According to the cause of disease, histology
And the difference of biological characteristics, carcinoma of endometrium can be divided into following two subclass：I types carcinoma of endometrium is estrogen-dependent type,
It is clinical most common type, accounts for the 80%-90% of carcinoma of endometrium.Its organization type is mostly adenocarcinoma of endometrium (75%-
80%), II types carcinoma of endometrium is non-estrogen-dependent type, accounts for the 10%-15% of endometrial carcinoma, and its organization type is more
For serous papillary adenocarcinoma, small part is clear cell carcinoma, and cell differentiation is poor, and grade of malignancy is high, poor prognosis.Carcinoma of endometrium
Preferred operative treatment, on the basis of case is performed the operation by stages, aid in Radiotherapy chemotherapy and hormone therapy, but therapeutic effect is undesirable.
With the intensification to signal path, tumor cells targeted therapy and tumor cells Mechanism Study, molecular targeted agents
Treatment turns into study hotspot.It is the newcomer of IL-12 families by EBI-3 and the p28 IL-27 formed, is mainly derived from dendron shape
The secretion of cell.IL-27 acceptors are made up of two subunits of WSX-1 and gp130, are expressed in panimmunity cell and nonimmune cell
Surface.Development, differentiation and functions of the IL-27 to these cells all play indispensable effect.IL-27 is combined with its acceptor
Afterwards, induced by activating the STAT1/STAT3 approach in downstreamT cell to Th1 directions break up, while suppress its to Th2,
Th17 and Foxp3+Treg directions break up.In addition, IL-27 can also induce the surface expression MHC molecule of some nonimmune cells,
Make it have the function of antigen presentation.With more clinical meaning, IL-27 many infectious diseases, autoimmunity disease and
Important function has all been played in tumour, has been the potential action target spot of relevant disease.
Rapamycin is a kind of macrolide antibiotics molecular formula extracted from water imbibition streptomycete fermentation liquid
(31H79NO15).Initial rapamycin is studied as the antifungal drug of hypotoxicity, and it is immune to find within 1977 that rapamycin has
Inhibitory action, find that it has antitumor action again in recent years.The rapamycin antineoplastic action mechanism reported includes：
(1) S6 ribosomes (P70s6k) dephosphorylation is caused so that it is inactivated in vivo；(2) by the function inhibitio to mTOR and
Prevent 4E-BPS from phosphorylation, the translation initiation of blocking oncoprotein matter；(3) suppress STAT3 phosphorylation by mTOR, make
It can not play a part of activated gene transcription；(4) cell cycle dependent kinase (cdk) and cyclin can be suppressed
(cyclin) activity of complex kinase, the cellular processes after causing are suppressed；(5) blood vessel formation against function；(6) induce
The apoptosis of tumour cell non-dependent P53；(7) synthesis and utilization of tumour cell energy are prevented.At present, rapamycin is in tumour
Immunoregulation effect in treatment waits to study at present.
Chinese patent 200680051034.7, which discloses, to be targeted the rapamycin inhibitor of mammal by administration and controls
The method for the treatment of, the inhibitor or sirolimus, temsirolimu, everolimus or forms of rapamycin analogs etc., available for extensive
Cancer, including prostate cancer, cancer of pancreas, oophoroma, lung cancer, breast cancer, carcinoma of urinary bladder, colon cancer, the cancer of the brain, head and neck cancer, uterus
Endometrial carcinomas, leukaemia, lymthoma and sarcoma.Chinese periodical《Guangdong medical science》In January, 2009 discloses paper《SB203580 and thunder
Pa mycin combines the extracorporeal anti-tumor function to people's carcinoma of endometrium Ishikawa cells》, disclose under the same conditions
It is alone that SB203580 with the united antitumor action of rapamycin will be substantially better than SB203580.But in the prior art, on
Application of the rapamycin in IL-27 low expression carcinomas of endometrium are treated, yet there are no report.
The content of the invention
First purpose of the present invention is to be directed to deficiency of the prior art, there is provided the new pharmaceutical applications of rapamycin.
Second object of the present invention is to be directed to deficiency of the prior art, there is provided one kind suppresses carcinoma of endometrium and suppressed
Agent.
Third object of the present invention is to be directed to deficiency of the prior art, a kind of medicine of synergistic treatment carcinoma of endometrium
Composition
To realize above-mentioned first purpose, the present invention adopts the technical scheme that：
Application of the rapamycin in the medicine for preparing treatment IL-27 low expression carcinomas of endometrium.
The rapamycin improves endometrial carcinoma cell IL-27 level, and the killing for strengthening tumor-infiltrated NK cells is lived
Property, limitation carcinoma of endometrium progress.
The present invention studies rapamycin to endometrial carcinoma cell IL-27 expressions by experiment in vitro, by internal
Test assessment crosses value of the rapamycin in treatment carcinoma of endometrium.
As a result show：(1) IL-27 significantly reduces compared with cancer beside organism's IL-27 levels in endometrial carcinoma cancer stove tissue,
Prompting, endometrial carcinoma cell IL-27 generations are reduced；(2) rapamycin treatment promotes endometrial carcinoma cell IL-27 generations；
(3) rapamycin is lived by promoting endometrial carcinoma cell IL-27 generation to further enhance the killing of tumor-infiltrated NK cells
Property, so as to limit carcinoma of endometrium progress,
To realize above-mentioned second purpose, the present invention adopts the technical scheme that：
One kind suppresses carcinoma of endometrium inhibitor, and the inhibitor is overexpressed plasmid by rapamycin and IL-27 and formed.
Using the Endometrium cancerous cell line of rapamycin treatment 3, while it is overexpressed with plasmid the IL- of these three cell lines
27 is horizontal, it is found that rapamycin can effectively strengthen the killing activity of NK cells, and being overexpressed IL-27 can cooperate with enhancing thunder pa mould
Rapamycin and IL-27 are overexpressed plasmid combinations use and can effectively strengthened pair by element to the inhibitory action of carcinoma of endometrium
The lethal effect of endometrial carcinoma cell.
To realize above-mentioned 3rd purpose, the present invention adopts the technical scheme that：
A kind of pharmaceutical composition of synergistic treatment carcinoma of endometrium, described pharmaceutical composition is by rapamycin and cis-platinum group
Into IL-27 levels significantly reduce compared with normal structure in the carcinoma of endometrium lesion tissue.
Rapamycin and cisplatin combined application can significantly improve the life span of carcinoma of endometrium tumor-bearing mice, reduce cancer stove
Tissue volume, limitation carcinoma of endometrium progress, there were significant differences compared with rapamycin or cis-platinum is used alone, therefore by cis-platinum
The treatment of IL-27 low-level carcinomas of endometrium can be further used for by being applied in combination with rapamycin.
The present invention collects the cancer stove tissue and normal endometrial tissue of different pathological endometrial carcinoma by stages, as a result
Show endometrial carcinoma cancer stove tissue obvious reduction (as shown in Figure 1) horizontal compared with normal control internal film tissue IL-27.In vivo
Outer experiment confirms that rapamycin treatment endometrial carcinoma cell can promote its IL-27 to generate (as shown in Figure 2).Further research hair
Existing rapamycin strengthens NK cellkilling capacities (such as Fig. 3 institutes by improving endometrial carcinoma cell itself IL-27 levels
Show).Inside and outside is it is demonstrated experimentally that rapamycin can limit carcinoma of endometrium progress with cisplatin combined application, by improving IL-27
Level can effectively improve the life span (as shown in Figure 4) of carcinoma of endometrium tumor-bearing mice.
The invention provides the purposes and method that rapamycin enhancing NK cellular immunities are limited Treatment of Endometrial Neoplasms；Especially
It is that can be remarkably reinforced endometrial carcinoma cell IL-27 through experiment in vitro and zoopery confirmation, the medication of rapamycin combination with cisplatin
Generation, killing ability of the enhancing NK cells to carcinoma of endometrium, and then limit carcinoma of endometrium progress.Therefore rapamycin can
Chemotherapy for IL-27 low expression carcinomas of endometrium.
Brief description of the drawings
Accompanying drawing 1 is in IL-27 Endometrial Carcinomas stove (differentiated, middle differentiation and low differentiation) and normal control internal film tissue
Level.In figure, normal endometrium：IL-27 expression, highly- in normal endometrial tissue
Differentiated group (differentiated), moderately-differentiated group (middle differentiation), poorly-
Differentiated group (low differentiation)：IL-27 expression in endometrial.
Accompanying drawing 2 is that rapamycin treatment endometrial carcinoma cell improves its IL-27 levels, and then strengthens NK cells to uterus
The killing activity of inner membrance cancer cell.Wherein, Rapamycin：Rapamycin, ishikawa, RL95-2 and KLE：People's endometrium
Cancerous cell line.CK7：Keratin 7, isotype：Isotype control.*P<0.05, * * P<0.01and***P<0.001.
Accompanying drawing 3 is that rapamycin is horizontal and then enhancing NK cell killings by improving endometrial carcinoma cell itself IL-27
Ability.In figure, mock：Blank control group, IL-27+：IL-27 overexpression groups.*P<0.05, * * P<0.01, * * * P<0.001and
****P<0.0001。
Accompanying drawing 4 is that rapamycin limits carcinoma of endometrium development with cisplatin combined application, and then effectively improves endometrium
The life span of cancer tumor-bearing mice.In figure, NC：Compare slow-virus transfection group, IL-27over：IL-27 is overexpressed slow virus processing
Group, Cisplatin：Cisplatin treated group.NS:It is not statistically significant, * P<0.05, * * P<0.01, * * * P<0.001and****P<
0.0001。
Embodiment
The invention will be further elucidated with reference to specific embodiments.It should be understood that these embodiments are merely to illustrate this hair
Bright rather than limitation the scope of the present invention.In addition, it is to be understood that after the content of the invention recorded has been read, art technology
Personnel can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims and limited
Fixed scope.
The IL-27 of the carcinoma of endometrium cancerous tissue of embodiment 1 and normal endometrial tissue is horizontal
IL-27 is horizontal in carcinoma of endometrium cancer stove tissue reduces：
Carcinoma of endometrium cancerous tissue and the normal endometrial tissue related check data that the court preserves are collected, find uterus
IL-27 is horizontal in endometrial carcinomas patient's cancer stove tissue reduces (as shown in Figure 1)；It is probably carcinoma of endometrium to illustrate low-level IL-27
One of the reason for grade malignancy is high.
The experiment of the inside and outside of embodiment 2 confirms that rapamycin treatment improves endometrial carcinoma cell IL-27 level
Rapamycin (100nM, purchased from MedChem Express companies) handles Endometrial carcinoma cell line ishikawa,
RL95-2 and KLE (cell line is purchased from Chinese Academy of Sciences's cell bank), IL-27 application Elisa methods detect IL-27 after 48 hours
Protein level (Elisa reagents are purchased from BioLegend companies).People's Endometrial carcinoma cell line ishikwa (107Cell/only)
Knurl (4-5 week old nude mice is purchased from Si Laike Experimental Animal Centers) is subcutaneously injected into, starts daily intraperitoneal injection rapamycin after 1 week
(2mg/kg), control group injection PBS, injection in every 24 hours once, continue 21 days.Tumour cell is analyzed with Flow Cytometry
IL-27 levels (IL-27 streamings antibody is purchased from BioLegend companies), and compared with control group.It was found that 100nM thunder pas
The IL-27 that mycin concentration can effectively improve three Endometrium cancer cells is horizontal, and results from vivo experiments also meets (as schemed therewith
Shown in 2A-C).
The experiment of the inside and outside of embodiment 3 confirms that rapamycin can be by promoting tumour cell IL-27 generation limitation endometriums
Cancer is in progress
Using the Endometrium cancerous cell line of 100nM rapamycin treatments 3, while these three cell lines are overexpressed with plasmid
The horizontal 48h of IL-27 after, it is then thin with the Peripheral NK Cell of magnetic bead sorting (NK cell sortings magnetic bead is purchased from German Mei Tian Ni companies)
Born of the same parents co-culture 48 hours, and apply flow cytometer detection NK cell surface molecules and intracellular cytokine.It was found that rapamycin can be effective
Strengthen the killing activity of NK cells, the tumor inhibition effect of enhancing rapamycin can be cooperateed with by being overexpressed IL-27 (as shown in Fig. 3).
People's Endometrial carcinoma cell line ishikwa (107Cell/only) into knurl, (4-5 week old nude mice comes from this Lay for hypodermic injection
Gram Experimental Animal Center), start daily intraperitoneal injection rapamycin (2mg/kg) and/or cis-platinum (10 μM), control group note after 1 week
Physiological saline is penetrated, injection in every 24 hours once, continues 21 days, and every 7 days tail vein injections are once with PKH67 marks through magnetic
The 2 × 10 of pearl sorting6Peripheral blood NK cell (NK cell sortings magnetic bead is purchased from German Mei Tian Ni companies).It is simultaneously sick slowly with IL-27
After malicious transfected with human ishikawa endometrial carcinoma cells, (107Cell/only) in mouse bare subcutaneous injection into after knurl 1 week, it is same to use
Rapamycin and/or Intraperitoneal Cisplatin injection, end of line vein NK cells of going forward side by side, which are adopted, to be transferred, and method is the same, into knurl after 2 weeks it is every 3 days
A gross tumor volume is measured, calculation formula is：Volume=(long * is wide2)/2.As a result show, IL-27 and rapamycin synergy
Cancer cell multiplication can effectively be suppressed, cis-platinum and rapamycin synergy can extend mouse survival time (such as Fig. 3 A-C and Fig. 4 A-
Shown in D).
The present invention confirms that rapamycin has stronger anti-tumor activity, in addition, thunder through in vitro and in vivo result of the test
The IL-27 that pa mycin can be improved in carcinoma of endometrium cancerous tissue is horizontal, is entered by the level for improving endometrial carcinoma cell IL-27
One step suppresses carcinoma of endometrium cancer cell process.Experiment in vivo is shown：IL-27 and rapamycin synergy can effectively suppress cancer
Cell is bred, and rapamycin and cisplatin combined application can significantly improve the life span of carcinoma of endometrium tumor-bearing mice, is prompted
Rapamycin and cisplatin combined application can be further used for the treatment of IL-27 low-level carcinomas of endometrium.
The present invention is confirmed through in vitro and in vivo result of the test, and carcinoma of endometrium endogenous IL- can be improved using rapamycin
27 level, strengthen the lethal effect to endometrial carcinoma cell, have for IL-27 low expressions carcinoma of endometrium more notable
The effect of.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (5)
1. application of the rapamycin in the medicine for preparing treatment IL-27 low expression carcinomas of endometrium.
2. application according to claim 1, it is characterised in that the rapamycin improves endometrial carcinoma cell IL-27
Level, strengthen the killing activities of tumor-infiltrated NK cells, limitation carcinoma of endometrium progress.
3. one kind suppresses carcinoma of endometrium inhibitor, it is characterised in that the inhibitor is overexpressed matter by rapamycin and IL-27
Grain composition.
4. a kind of pharmaceutical composition of synergistic treatment carcinoma of endometrium, it is characterised in that described pharmaceutical composition is by rapamycin
Formed with cis-platinum.
5. pharmaceutical composition according to claim 4, it is characterised in that IL-27 in the carcinoma of endometrium lesion tissue
Level significantly reduces compared with normal structure.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114681609A (en) * | 2022-05-05 | 2022-07-01 | 浙江大学 | Application of anti-IL-6 antibody composition in preparation of drugs for treating hepatocellular carcinoma |
Citations (2)
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| CN101360495A (en) * | 2005-11-14 | 2009-02-04 | 阿里亚德基因治疗公司 | Administration of mntor inhibitor to treat patients with cancer |
| WO2009079587A2 (en) * | 2007-12-18 | 2009-06-25 | Schering Corporation | Biomarkers for sensitivity to anti-igf1r therapy |
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2017
- 2017-11-08 CN CN201711087886.8A patent/CN107714719A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101360495A (en) * | 2005-11-14 | 2009-02-04 | 阿里亚德基因治疗公司 | Administration of mntor inhibitor to treat patients with cancer |
| WO2009079587A2 (en) * | 2007-12-18 | 2009-06-25 | Schering Corporation | Biomarkers for sensitivity to anti-igf1r therapy |
Non-Patent Citations (3)
| Title |
|---|
| BAE-JUMP VL.ET AL.: "Synergistic effect of rapamycin and cisplatin in endometrial cancer cells", 《CANCER》 * |
| MACEDO C.ET AL.: "Rapamycin augments human DC IL-12p70 and IL-27 secretion to promote allogeneic Type 1 polarization modulated by NK cells", 《AM J TRANSPLANT》 * |
| 邓守恒等: "雷帕霉素增强Ishikawa细胞化疗敏感性实验研究", 《武汉大学学报(医学版)》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114681609A (en) * | 2022-05-05 | 2022-07-01 | 浙江大学 | Application of anti-IL-6 antibody composition in preparation of drugs for treating hepatocellular carcinoma |
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