CN108310363A - Applications of the CRM197 in the drug for preparing treatment polycystic ovary syndrome - Google Patents
Applications of the CRM197 in the drug for preparing treatment polycystic ovary syndrome Download PDFInfo
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- CN108310363A CN108310363A CN201810250593.5A CN201810250593A CN108310363A CN 108310363 A CN108310363 A CN 108310363A CN 201810250593 A CN201810250593 A CN 201810250593A CN 108310363 A CN108310363 A CN 108310363A
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- crm197
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- polycystic ovary
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
The present invention relates to biomedicine fields, specifically, the application the invention discloses RM197 in the drug for preparing treatment polycystic ovary syndrome.The present invention blocks heparin-binding epidermal growth factor to be combined with EGF-R ELISA by CRM197, inhibits polycystic ovary syndrome granulosa cell proliferation, to reduce Antral follicles, improves the more capsule sample performances of ovary.
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of CRM197 treats the medicine of polycystic ovary syndrome in preparation
Application in object.
Background technology
Cross reacting material 197 (cross-reacting material197, CRM197) is a kind of nothing of diphtheria toxin
Virus mutants, can be with specific diptheria toxin receptor (diphtheria toxin receptor, DTR) on cell membrane, that is, liver
Element combine epidermal growth factor film combination precursor (pro heparin-binding epidermal growthfactor,
PROHB-EGF it) combines.
People have carried out a variety of researchs to the anticancer effect of CRM197 now.For example, Patent No.
200680022003.9 patent of invention《Anticancer therapeutic agent》In inform CRM197 be used to prepare treatment carcinoma of urinary bladder, colon cancer or
The application of the drug of the dispersivity peritonaeum metastatic cancer of person's gastric cancer and cancer of pancreas.In non-patent literature《Cross reacting material 197 exists
Progress in ovarian cancer drug-resistant》In it is also proposed that inhibiting HB-EGF using CRM197, so as to significantly inhibit external and body
The Tumor formation of interior drug-resistant ovarian carcinoma cell.
The cure mechanism of oophoroma is to inhibit the division of tumour cell and breeding or even killing tumor cell, taxol to be
The choice drug of recurrent and refractory ovarian is treated, specific action is in the G of cell cycle2Phase and M phases, micro-pipe is made to have
Spindle and chromosomal fibers cannot be formed when silk division, prevents the division of tumour cell, may also act on swollen on macrophage
Tumor necrosis factor (TNF) receptor promotes to discharge interleukins (IL) -1, TNF-2, IL-6, interferon (IFN) -1, IFN-2,
Killing or inhibiting effect are risen to tumour cell[1]；Platinum-containing anticancer drug is then acted on the DNA molecular of tumour cell, forms drug-
DNA molecular complex destroys and replicates template, to inhibit tumour cell division[2-3].And the cure mechanism of polycystic ovary syndrome
It is to improve the endocrine and metabolism index of patient, including correct hyperandrogenism, improves the raised clinical table of androgen levels
It is existing；The ratio of FSH and LH is adjusted, FSH low-levels are corrected, promotes follicular development ripe；Hyperinsulinemia is reduced for ovulation
Influence, reduce insulin level, improve insulin sensitivity etc.[4].Therefore, there is no the class same sexes between this 2 kinds of diseases.
In the prior art, treat polycystic ovary drug have clomiphene, dexamethasone, spirolactone, oral contraceptive,
Gonadotropin-releasing hormone (GRH) (GnRH) and the like (GnRHa), melbine, troglitazone and statins etc., but
It is that clomiphene, dexamethasone, spirolactone and statins etc. do not act on the treatment of oophoroma[5-11], clomiphene,
Dexamethasone, spirolactone even have reaction to the treatment of oophoroma[6-11]。
The drug for treating oophoroma is generally all toxic, and does not inform that the drug that can treat oophoroma also can in existing literature
For treating polycystic ovary syndrome.
[1], Wang Yan, Huang Rongli, application [J] China journal of obstetrics and gynecology of the yellow favour virtue taxols in treatment of ovarian cancer,
1999,34(7):439-441.
[2], Liu Yi, Yang Yufei, white jade wait the analytical technology of platinum-containing anticancer drugs and its mechanism of action progress [J]
Learn notification, 2013,76 (10):867-877.
[3], Chang Guanru, Hu Fengkai platinum-containing anticancer drug Study on mechanism progress [J] Huangshan University journals, 2007,9
(5):45-47.
[4], new development [J] Medical reviews of Zhou Lilan, Li Ying polycystic ovary syndrome Clinics and Practices, 2012,18
(8):1204-1207.
[5], Chen Hong appoints the happy of scape that conclusive evidence prompt statins there is no to increase risk of cancer [J] China cardiovascular
Sick magazine, 2011,39 (3):196-198.
[6], 1 report of the oophoroma syndrome of the green star normal sizes of Liu and clinical experience [J] drugs and people, 2014
(10):221-222.
[7], Hou Wenjing, Liu Yan, Zhao Rui wait .bcl-XL and survivin in the ovum of dexamethasone antagonism taxol induced
Expression [J] Chinese Medical Sciences University journal in nest cancer cell-apoptosis, 2009,38 (3):193-196.
[8], Jin Quanfang, Hu Ping, yellow light is flourish, and the antagonism of Dexamethasone on Cisplatin induction Ovarian Cancer Cells apoptosis is waited to make
With the mother and child care of [J] China, 2009,24 (23):3302-3304.
[9], Hou Wenjing, Liu Yan dexamethasone inhibit taxol on curative effect [J] in human ovarian cancer transplanted tumor in nude mice
Extra large medicine, 2008,31 (4):275-277.
[10], the use of Xu Yumei, Dong Yun tinkling of pieces of jade fertility drug objects and the worlds onset risk [J] the healthy reproduction of oophoroma/
Family planning magazine, 2002,21 (3):191-191.
[11], Tian Dongzhen Sterility patients induced ovulation treatment causes two gynemetrics of clinical analysis [J] China of oophoroma
Magazine, 2001,36 (9):565-566.
Invention content
Technical problem to be solved by the invention is to provide a kind of CRM197 in the medicine for preparing treatment polycystic ovary syndrome
Application in object.
In order to solve the above technical problem, the present invention provides CRM197 in the drug for preparing treatment polycystic ovary syndrome
Application.
During invention, inventor has found, by CRM197 intraperitoneal injection PCOS rat models, to be effectively improved
PCOS rat model serum E2, P, T it is horizontal, and the ovarian index of PCOS rat models can be significantly reduced.CRM197 can also make
The entovarial corpus luteum formation of PCOS rat models increases, and reduces cystic dilatation ovarian follicle, visible corolla mound, ovarian follicle in dominant follicle
Liquid, granular cell number of plies showed increased improve the more capsule sample performances of ovary.
Compared with prior art, the technical advantages of the present invention are that：
The present invention blocks heparin-binding epidermal growth factor to be combined with EGF-R ELISA by CRM197, inhibits
Polycystic ovary syndrome granulosa cell proliferation improves the more capsule sample performances of ovary to reduce Antral follicles.
Usages and dosage of the CRM197 when treating polycystic ovary syndrome be：Injection, about 20~80mg/kg (are, for example,
50mg/kg), once a week.
Description of the drawings
The specific implementation mode of the present invention is described in further detail below in conjunction with the accompanying drawings.
Ovarian index after Normal group, model control group and the administration of CRM197 treatment groups in Fig. 1, the embodiment of the present invention 1
Comparison schematic diagram.
Note：Tu1Zhong CRM197 treatment groups, Normal group compared with model control group,aP<0.05；CRM197 treatment groups
Compared between Normal group,bP<0.05。
Specific implementation mode
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This.
The application of embodiment 1, CRM197 in the drug for preparing treatment polycystic ovary syndrome.
Specific implementation mode is as follows：
1, material and method：
1.1, experimental animal：
70 age in days health cleaning grade female Spragu Dawley (SD) rats 45 are selected, by Zhejiang University experimental animal
Center provides, and 20 ± 2 DEG C of raising temperature, feed, water are added in time by special messenger to be changed, and adapts to environment 1 week, during adaptation all rats oneself
By ingesting and drinking water.
1.2, random grouping：
Normal group 15, model control group 15, CRM197 treatment groups 15.
1.3, prepared by animal model：
Model control group and CRM197 treatment groups establish polycystic ovary syndrome (PCOS) rat mould according to Poretsky methods
Human chorionic gonadtropin (HCG) 3.0U/d is subcutaneously injected in type 2 times a day, and the 1st day to the 10th day injection intermediate-acting insulins are certainly
0.5U/d starts, and is gradually incremented to 6.0U/d, presses this dosage daily later and injects, rat testosterone and insulin are detected after 22 days
Level increases and vaginal smear persistently occurs keratinocyte person meets PCOS models.Physiology is subcutaneously injected in the Normal group same period
Brine.
1.4, pharmaceutical intervention is tested：
Normal group and model control group rat physiological saline intraperitoneal injection are given respectively after modeling success, on every Mondays
It is secondary, CRM197 treatment groups rat CRM197 (solvent is physiological saline) intraperitoneal injection is given, once a week, dosage is
50mg/kg, after 6 weeks bloodletting each group rat is put to death.
1.5, collection of specimens and measurement：
1.5.1, serum estradiol (E2), progesterone (P) and testosterone (T) measure
Broken end takes blood after overnight fasting after the last administration, next day rat weight, centrifuges, and detaches serum, and -20 DEG C preserve,
Serum E is measured with enzyme linked immunosorbent assay (ELISA method)2, P and T contents.
1.5.2, the morphologic observation of ovary tissue：
Rat is breaked end take blood after, cut open the belly immediately take out rats with bilateral ovary, dry liquid, measured with precision electronic balance
The weight of ovary, record bilateral ovaries weight, calculating ovarian index, ovarian index=ovary weight in wet base (mg)/weight (g) ×
100%, after fixed preparation 48h in 10% formalin, it is put into automatic dehydrator and is dehydrated transparent and waxdip through row, 70 DEG C are often
Paraffin embedding is advised, is sliced after being put into refrigerator freezing 20min, piece is 4 μm thick, HE dyeing, neutral plastic cement mounting.It is seen under light microscope
Examine number, the ovarian morphology of Follicles.
1.6, statistical method：
Whole continuous datas mean ± standard deviationIt indicates, statistics credit is carried out using SPSS16.0 statistical softwares
Analysis.P<0.05 to represent difference significant, has statistical significance.
2 results：
2.1, serum E2, P and T situations of change：
Every group of rat is measured the serum E of gained by step 1.5.12, P and T contents according to the statistical method in step 1.6 into
Row statistical analysis obtains serum E2, the corresponding mean ± standard deviation of P and T contentsConcrete numerical value is as shown in table 1：
Serum E after being administered between 1 each group of table2, P, T level compares
| Group | E2(pg/mL) | P(ng/mL) | T(ng/mL) |
| Model control group | 15.18±8.55 | 13.35±7.43 | 1.41±0.47 |
| CRM197 treatment groups | 40.93±13.95ab | 24.98±10.13ab | 0.73±0.48a |
| Normal group | 72.82±12.87a | 40.47±12.68a | 0.42±0.20a |
Note：CRM197 treatment groups, Normal group compared with model control group,aP<0.05；CRM197 treatment groups with it is normal
Compare between control group,bP<0.05。
As shown in Table 1, the serum E of CRM197 treatment groups2And P levels are above model control group, and comparison in difference has system
Meter learns meaning (P<0.05).The serum T of CRM197 treatment groups is substantially less than model control group (P<0.05), although and normal control
Group is higher than Normal group, but no significant difference (P between the two compared to the level of serum T>0.05).Show
CRM197 can be effectively improved PCOS rat model serum E2, P and T it is horizontal.
2.2 ovarian index compare
Rat ovary weight is converted into ovarian index (ovary weight percentage of liveweight percentage).As shown in Figure 1, CRM197 is controlled
The ovarian index for the treatment of group is significantly lower than model control group, the statistically significant (P of comparing difference<0.05).Illustrate that CRM197 can be
The ovarian index of PCOS rat models is reduced to a certain extent.
The morphological change of 2.3 ovaries
The Follicles of the visible a large amount of corpus luteum of rats in normal control group ovary and different developmental phases, wherein dominant follicle can
See 8-9 layers of granular cell.Model control group Ovarian Volume increases, and seldom sees that corpus luteum is formed, it is seen that a large amount of ovarian follicle cystic dilatations, not
See the basic structures such as egg mother cell and corona radiata, rarely seen 1-2 layers of granular cell and a large amount of atretic follicles.CRM197 treatment groups ovary
It can be seen that Follicles and multiple corpus luteum, rare cystic dilatation ovarian follicle, visible corolla mound, liquor folliculi in dominant follicle, granular cell
Number of plies showed increased.Demonstrate CRM197 of the present invention has application value in terms of preparing treatment polycystic ovary syndrome.
Comparative example 1, ginsenoside are the nontoxicity generally acknowledged at present and can be used for treating the drug of oophoroma.
CRM197 in embodiment 1 is changed to ginsenoside, dosage is respectively set as 5mg/kg (routine dose ginsenosides
Treatment group), 10mg/kg (high dose ginsenoside treatment group)；Remaining is equal to embodiment 1；That is, setting ginsenoside is treated
Group, and according to the step described in above-described embodiment 1 it is horizontal to the blood serum E2, P and T of ginsenoside treatment group PCOS rat models and
Ovarian index is detected and statistical analysis.
Note：In practice, routine dose when CRM197 treatments oophoroma is 50mg/kg, and ginsenoside treats ovary
Routine dose when cancer is 5mg/kg, and the amount ratio of the two is 10:1.
Acquired results are：Blood serum E2, P and the T of routine dose ginsenoside treatment group and high dose ginsenoside treatment group
Horizontal and ovarian index and model control group there are no significant difference (P>0.05).And routine dose ginsenoside treatment group and height
The Ovarian Volume of dosage ginsenoside treatment group increases, and seldom sees that corpus luteum is formed, it is seen that a large amount of ovarian follicle cystic dilatations have no ovum mother
The basic structures such as cell and corona radiata, rarely seen 1-2 layers of granular cell and a large amount of atretic follicles, the ovarian morphology with model control group
Unanimously.Show that ginsenoside cannot generate therapeutic effect to polycystic ovary syndrome.
To sum up, CRM197 can be effectively improved PCOS rat model serum E2, P and T it is horizontal, and it is big to significantly reduce PCOS
The ovarian index of mouse model.CRM197 can also be such that the entovarial corpus luteum formation of PCOS rat models increases, and reduce cystic dilatation
Ovarian follicle, visible corolla mound, liquor folliculi in dominant follicle, granular cell number of plies showed increased improve the more capsule samples performances of ovary.And
It is same as the non-toxic drug ginsenoside that can treat oophoroma to polycystic ovary syndrome without therapeutic effect, thus prove
CRM197 has therapeutic effect to polycystic ovary syndrome, and it can not carry out simple association by the prior art and obtain easily
.
Finally, it should also be noted that it is listed above be only the present invention several specific embodiments.Obviously, this hair
Bright to be not limited to above example, acceptable there are many deformations.Those skilled in the art can be from present disclosure
All deformations for directly exporting or associating, are considered as protection scope of the present invention.
Claims (1)
- Applications of the 1.CRM197 in the drug for preparing treatment polycystic ovary syndrome.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810250593.5A CN108310363B (en) | 2018-03-26 | 2018-03-26 | Application of CRM197 in preparation of medicine for treating polycystic ovarian syndrome |
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| CN201810250593.5A CN108310363B (en) | 2018-03-26 | 2018-03-26 | Application of CRM197 in preparation of medicine for treating polycystic ovarian syndrome |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113855792A (en) * | 2021-12-01 | 2021-12-31 | 上海惠盾因泰生物科技有限公司 | Recombinant hEGF-CRM197 tumor therapeutic vaccine formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103285021B (en) * | 2013-01-05 | 2016-01-13 | 中国人民解放军第二军医大学 | The application of baicalin in preparation treatment polycystic ovarian syndrome medicine |
| CN103705501B (en) * | 2013-12-23 | 2017-06-06 | 中国人民解放军第二军医大学 | Application of the Quercetin in treatment Stein-Leventhal syndrome medicine is prepared |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113855792A (en) * | 2021-12-01 | 2021-12-31 | 上海惠盾因泰生物科技有限公司 | Recombinant hEGF-CRM197 tumor therapeutic vaccine formulation |
| CN113855792B (en) * | 2021-12-01 | 2022-03-01 | 上海惠盾因泰生物科技有限公司 | Recombinant hEGF-CRM197 tumor therapeutic vaccine formulation |
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