CN109387630A - For predicting the biomarker and application thereof of gemcitabine drug susceptibility - Google Patents
For predicting the biomarker and application thereof of gemcitabine drug susceptibility Download PDFInfo
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- CN109387630A CN109387630A CN201710689553.6A CN201710689553A CN109387630A CN 109387630 A CN109387630 A CN 109387630A CN 201710689553 A CN201710689553 A CN 201710689553A CN 109387630 A CN109387630 A CN 109387630A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
Abstract
The application of the biomarker of drug susceptibility when the present invention provides AKR1C1, AKR1C2 or AKR1C3 as prediction gemcitabine or its pharmaceutically acceptable salt treating cancer.The cancer is colon cancer, lung cancer, gastric cancer, cancer of pancreas, oophoroma, melanoma, liver cancer, breast cancer, cervical carcinoma.Clinical application is instructed using technical solution of the present invention, it not only can be to avoid the blindness of medicament selection, it avoids being delayed patient's state of an illness since medicament selection is improper, and medication effect can also be monitored over the course for the treatment of, realize the reasonability of medication and the purpose of individualized treatment.
Description
Technical field
The invention belongs to molecular biology and medical domains, and in particular to for predicting the life of gemcitabine drug susceptibility
Substance markers object and application thereof.
Background technique
Gemcitabine is current clinically common antineoplastic chemotherapy medicine.Gemcitabine hydrochloride is suitable for treatment not expert
The advanced stage of art or metastatic cancer of pancreas and treatment Local advancement or Metastatic Nsclc are applicable in paclitaxel plus
It is recurred after auxiliary/new adjuvant chemotherapy in treatment, unresectable, local recurrence or metastatic breast cancer.Even if in current target
In the case where continuing to bring out to drug and novel immune therapeutic agent, gemcitabine still has extensive clinical application, especially
It is in cancer of pancreas field, gemcitabine is standard care drug.But in treatment clinical course, different patients are to gemcitabine
Sensibility or effective gender gap it is larger, there are problems that primary and acquired resistance.Therefore, effective gemcitabine medicine is found
The marker of object sensibility carrys out direction of medication usage, not only can be to avoid due to medicament selection undue delay Case treatment, and can also
Medication effect is monitored over the course for the treatment of, realizes the purpose of medication reasonability and individualized treatment.
Research at present thinks that gemcitabine drug resistance mainly absorbs that transport process obstacle, activation, catabolic enzyme are different in endochylema with it
Often and DNA reparation is related, and research contents includes hENT1 (people's balanced type nucleoside transporter 1), RRM1 (ribonucleotide reduction
Enzyme M1), RRM2 (ribonucleotide reductase M2), genes or the albumen such as dCK (deoxycytidine kinase).
Research for these genes or albumen is also very much, but the result of study between different researchs is variant.Such as
Roland Andersson(World J Gastroenterol.2014；20:8482-8490) etc. researchers 10 clinics are ground
Study carefully and carried out system review, be related to 855 patients, is divided into high and low hENT1 group, high expression patient hENT of result of study display
Overall survival be considerably longer than low expression person.But in a random III phase clinical research --- CONKO-001 clinical test
(Eur J Cancer.2015；51:1546-1554) in receive auxiliary gemcitabine chemotherapy patient tissue samples in use
SP120 rabbit monoclonal antibody detects hENT1 expression by immunohistochemistry, as a result confirms that hENT1 does not have any predicting function.And another
Clinical research (NCT01124786, J Clin Oncol.2013；Equally show that hENT1 is not previously predicted Ji in 31:4453-4461)
The effect of his western shore sensibility.Fujit et al. (Neoplasia.2010；12:807-817) in patient PDAC of 70 excisions
The mRNA of hENT1, dCK, RRM1, RRM2 are had detected, wherein 40 patients receive the adjuvant chemotherapy based on gemcitabine.It grinds
Study carefully as the result is shown it is high expression dCK and low patient RRM2 it is longer without progression of disease life cycle.Mar é chal et al.
(Gastroenterology.2012；143:664-674.e1-6) carry out another researches show that height express hENT1 and dCK
Patient receive gemcitabine adjuvant treatment when can predict longer life cycle.The reason of these results of study differ greatly
Including researcher use detection method difference, patient's medicining condition complexity, Tumor Heterogeneity, sample size lack etc..Except this it
It is likely to be outside and does not find more accurate prediction index.
Summary of the invention
Larger to the sensibility of gemcitabine or effective gender gap for current different patients, there are primary and acquired
The uncertain problem of resistance problems and gemcitabine sensitivity prediction index, the present invention attempt to look for new more accurate
Gemcitabine sensitivity prediction index.
Aldehyde ketone reductase (aldo.keto reductase, AKR) superfamily shares 15 families, wherein source of people AKR member
Share 15.Most of AKR members can be catalyzed simple oxidation by co-factor of nicotinamide adenine dinucleoside phosphate NADP
Reduction reaction.Their substrate specificities are in extensive range, including carbohydrate, fatty aldehyde, steroid hormone, prostaglandin and carcinogenic substance etc..
Therefore, AKR superfamily member may be to send out in the vital movements such as hormone sensitive lipase gene, drug metabolism, inflammatory reaction, carcinogenic substance removing toxic substances
Wave the enzyme of important function.Studies have shown that source of people AKR superfamily member has correlation with kinds of tumors occurrence and development, live
Property height it is closely related with the progress and therapeutic effect of tumour.More and more evidences show (international oncology .2013；40
(1): 43-46), AKR superfamily few members are related to tumour drug resistance.AKRlB10 becomes related non-small cell lung cancer of smoking,
The especially early diagnosis marker of lung squamous cancer, and function Characteristics of AKR1C1~3 in lung cancer Treated with Chemotherapeutic Drugs object tolerance course
The important factor of prognosis prediction is become, also provides effective action target spot to improve lung-cancer medicament sensibility.But it closes
Never there are research or report in the relationship of AKR family and gemcitabine drug resistance.
Present invention firstly discovers that aldehyde ketone reductase (aldo.keto reductase, AKR) family member AKR1C1,
AKR1C2, AKR1C3 family and gemcitabine drug resistance are related.The present invention has studied in 29 nude mouse tumor Transplanted tumor models
The correlation that gemcitabine drug susceptibility is expressed with AKR1C1~C3.Result of study shows in 11 AKR1C1~C3 high expression
Model in, 9 model results show that gemcitabine drug effects are poor, show insensitivity；In 18 AKR1C1~C3 low expressions
In model, 17 model results show gemcitabine good drug efficacy, show sensibility.
Therefore, the purpose of the present invention is to provide for predicting gemcitabine or its pharmaceutically acceptable salt treating cancer
When biomarker AKR1C1, AKR1C2, AKR1C3 of drug susceptibility and application thereof.
Specifically, the present invention provides AKR1C1, AKR1C2 or AKR1C3 as prediction gemcitabine or its pharmaceutically may be used
The application of the biomarker of drug susceptibility when the salts for treating cancer of receiving.
Further, the cancer is colon cancer, lung cancer, gastric cancer, cancer of pancreas, oophoroma, melanoma, liver cancer, cream
Gland cancer, cervical carcinoma.
Beneficial effects of the present invention: aldehyde ketone reductase (aldo.keto reductase, AKR) family member is utilized
AKR1C1, AKR1C2 or AKR1C3 are instructed as the biomarker of drug susceptibility when gemcitabine treating cancer is predicted
Clinical application not only can avoid being delayed patient's state of an illness since medicament selection is improper to avoid the blindness of medicament selection, and
Medication effect can also be monitored over the course for the treatment of, realize the reasonability of medication and the purpose of individualized treatment.
Detailed description of the invention
Expression analysis of Figure 1A KR1C1~C3 in different cells.GAPDH or β-tubulin is used as internal reference.Band ash
Angle value is higher, and the expression quantity for indicating corresponding albumen is higher.
Antitumor action of Fig. 2 gemcitabine in different Transplanted Colon Cancer in Nude Mice models
Antitumor action of Fig. 3 gemcitabine in different Pulmonary carcinoma nude mice Transplanted tumor models
Antitumor action of Fig. 4 gemcitabine in different Gastric Cancer Xenograft of Nude Mice models
Antitumor action of Fig. 5 gemcitabine in different cancer of pancreas Nude Mouse Models
Antitumor action of Fig. 6 gemcitabine in different oophoroma Nude Mouse Models
Antitumor action of Fig. 7 gemcitabine in MDA-MB-435 melanoma Nude Mouse Model
Specific embodiment
The present invention will be further illustrated in the following contents, but is understood not to limit purport and protection scope of the invention.
Experiment one: protein immunoblotting (Western blot, WB)
Experimental principle:
By polyacrylamide gel electrophoresis (polyacryamide gel electrophoresis, PAGE) separation
Protein example shifts and is integrated on solid phase carrier (such as nitrocellulose filter, bifluoride resin film etc.), on solid phase carrier
Protein or polypeptide as antigen, corresponding antibody can identify and in combination, then second with enzyme or isotope labelling
Antibody reacts, by substrate colour developing or autoradiograph with the expression quantity of testing goal albumen.
Experiment purpose:
Detect expression of AKR1C1~C3 albumen in different cells.
Experimental material:
Cell: human colon cancer cell CW-2, LoVo, HCT116, SW620, COLO 205, HT-29, RKO, DLD-1, NCI-
H716, SW1116, SW948；Human lung carcinoma cell NCI-H292, A549, NCI-H460, NCI-H1650, HCC827, NCI-
H1299, NCI-H1975, SK-MES-1, NCI-H1437, NCI-H1944；Human gastric cancer cells BGC-823, HGC-27, SGC-
7901, KATO III, NCI-N87, SNU-1；Human pancreatic cancer cell AsPC-1, BxPC-3, PANC-1, Capan-2, CFPAC-1,
MIA PaCa-2, HPAF-II；Human breast cancer cell BT-474, SK-BR-3, MCF-7, T-47D, MDA-MB-231, MDA-MB-
468；Proliferation of Human Ovarian Cell SK-OV-3, NIH:OVCAR-3, A2780；Human liver cancer cell BEL-7402, Hep G2；Human cervical carcinoma
Cell HeLa；Human melanoma cell MDA-MB-435 is purchased from the American Type Culture Collection committee, Chinese Academy of Sciences cell
Library, and cultivated by the cell culture condition that the website provides.
Primary antibody: AKR1C1 mouse monoclonal antibody (MAB6529) is bought from R&D Systems, AKR1C2 rabbit polyclonal antibody
(13035) purchase is bought from Cell Signaling Technology, AKR1C3 mouse monoclonal antibody (MAB7678) from R&D,
GAPDH rabbit monoclonal antibodies (2118) are bought from Cell Signaling Technology, HRP- β-tubulin murine monoclonal
Antibody (ab012) purchase is biological from connection section.
Secondary antibody: the goat anti-rabbit igg of HRP label and the anti-mouse IgG of horse of HRP label are purchased from Cell Signaling
Technology。
Experimental method:
Cell is in 25cm2Cultivated in culture bottle, collect cell when 80~90% coverage rate, according to cell quantity plus
Enter (50mM TrisHCl, 150mM NaCl, 1%NP-40,1%SDS, 1 × the protease suppression of 200-300 μ l RIPA lysate
Formulation C ocktail), be vortexed to mix to be placed on cracks 30min on ice.Supernatant is taken after 14000rpm, 4 DEG C of centrifugation 10min, uses BSA
Protein quantification detection kit is quantified.And 5 × loading buffer is added, it boils.
After 10%SDS-PAGE is separated by electrophoresis, 250mA electricity is gone on pvdf membrane each 30 μ g total protein of sample, uses TBST
The 5% skimmed milk power room temperature prepared closes 1h, is then incubated overnight at 4 DEG C with primary antibody, AKR1C1 antibody is dilute with 5% skimmed milk power
1000 times are released, AKR1C2 antibody dilutes 500 times, and AKR1C3 antibody dilutes 2000 times, the dilution of GAPDH or β-tubulin antibody
10000 times.Through secondary antibody (5%BSA dilutes 5000 times) incubation at room temperature 1h after thoroughly being washed with TBST, thoroughly washed with TBST again
The colour developing of ECL chemiluminescent substrate, exposure are added afterwards.The film of β-tubulin is detected after primary antibody is incubated for, is incubated for, washes without secondary antibody
ECL chemiluminescent substrate is directly added into after washing to be exposed.Experiment is using GAPDH or β-tubulin as internal reference.
Experimental result:
Expression quantity of tri- albumen of AKR1C1~C3 in different cells is specific as shown in Figure 1, as can be seen from Figure 1:
In human colon cancer cell, the high expression of AKR1C1~C3 in 205 cell of COLO；AKR1C1 in NCI-H716 cell
With AKR1C2 be in until high expression, AKR1C3 is high expression；The low table of three albumen in HCT 116, RKO, DLD-1 cell
It reaches；AKR1C1 and AKR1C2 low expression in CW-2, LoVo, SW620, HT-29, SW1116 and SW948 cell, AKR1C3 it is medium or
Height expression.
In human lung carcinoma cell, AKR1C1 in A549, NCI-H460, SK-MES-1, NCI-H1437, NCI-H1944 cell~
The high expression of C3；The equal low expression of AKR1C1~C3 in NCI-H292, NCI-H1650, NCI-H1299 and NCI-H1975 cell；
In HCC827 cell, AKR1C1 and AKR1C2 low expression, AKR1C3 low expression.
In gastric carcinoma cells, AKR1C1~C3 high expression in SGC-7901 cell；AKR1C1~C3 in HGC-27 and SNU-1
Equal low expression；The medium expression of AKR1C1 in BGC-823 cell, AKR1C2 are as low as medium, AKR1C3 high expression；KATO III and
In NCI-N87 cell, AKR1C1 and AKR1C2 albumen low expression, the medium expression of AKR1C3.
In human pancreatic cancer cell, the high expression of AKR1C1~C3 in AsPC-1 and BxPC-3 cell；PANC-1 and Capan-2
The middle equal low expression of AKR1C1~C3；In CFPAC-1 cell, AKR1C1 and AKR1C2 are as low as medium expression, AKR1C3 high expression；
In MIA PaCa-2 cell, high expression, AKR1C2 and AKR1C3 low expression are arrived in AKR1C1；In HPAF-II cell, AKR1C1
Low expression, AKR1C2 is as low as medium expression, AKR1C3 high expression.
In human breast cancer cell, AKR1C1~C3 is equal in BT-474, MCF-7, T-47D, MDA-MB-231 and MCF7 cell
Low expression；AKR1C1 and AKR1C2 is low expression in SK-BR-3 cell, and AKR1C3 is medium expression；In MDA-MB-468 cell
AKR1C1 and AKR1C2 high expression, the medium expression of AKR1C3.
In Proliferation of Human Ovarian Cell, the equal low expression of AKR1C1~C3 in NIH:OVCAR-3 and A2780 cell；SK-OV-3 cell
The high expression of middle AKR1C1~C3.
In human liver cancer cell, the equal low expression of AKR1C1~C3 in BEL-7402 cell；In Hep G2 cell AKR1C1 and
AKR1C2 low expression, AKR1C3 high expression.
In human cervical carcinoma cell HeLa, AKR1C1 and the equal low expression of AKR1C2, AKR1C3 high expression.
In human melanoma cell MDA-MB-435, the equal low expression of AKR1C1~C3.
Experiment two: transplantable tumor pharmacodynamic test in nude mouse
Experiment purpose: drug effect of the research gemcitabine to different tumour transplanted tumor in nude mice.
Experimental material:
Gemcitabine hydrochloride purchase from U.S. logical sequence biology, matrigel purchase from Corning company, the U.S. (article No.:
354262), BALB/c nude mouse is bought from Shanghai western Poole-Bi Kai experimental animal Co., Ltd.
Experimental method:
By colon cancer cell CW-2, LoVo, HCT116, SW620, COLO 205, HT-29, RKO, DLD-1, NCI-H716；
Human lung cancer cell A549, NCI-H460, NCI-H1650, NCI-H1299, NCI-H1975, NCI-H1944, NCI-H1437；People
Stomach cancer cell BGC-823, HGC-27, SGC-7901, NCI-N87, SNU-1；Human pancreatic cancer cell AsPC-1, BxPC-3, PANC-
1,Capan-2,CPFAC-1；Proliferation of Human Ovarian Cell SK-OV-3, A2780；Human melanoma cell MDA-MB-435 is trained in vitro
Support after, collect exponential phase of growth cell suspension mix to suitable concentration and with matrigel 1:1 after be used for BALB/c nude mouse
Subcutaneous tumor inoculation, establishes various Transplanted tumor models, to tumour growth to 100~200mm3After be divided into 2 groups, i.e. control group
With gemcitabine administration group, every group of 6 animals.Gemcitabine hydrochloride dosage be 120mg/kg, intraperitoneal injection, weekly
It is administered within 1st day and the 4th day.Tumour major diameter a (mm), minor axis b (mm) are measured 2 times a week, calculate gross tumor volume according to the following formula
(tumor volume, V): V=1/2 × a × b2(mm3)；Relative tumour volume is calculated according to gross tumor volume result
(relative tumor volume, RTV), calculation formula are as follows: RTV=Vt/V0.Wherein V0(d0) is measured when for sub-cage administration
Gained gross tumor volume, Vt are gross tumor volume when measuring each time.The evaluation index of anti-tumor activity is Relative tumor proliferation rate
T/C (%), calculation formula is as follows: T/C%=TRTV/CRTV* 100%；Wherein TRTV: treatment group is averaged RTV；CRTV: Vehicle controls
The average RTV of group.It is counted using Excel table, T.Test is examined.
Experimental result:
Gemcitabine its drug effect in different Transplanted tumor models shows otherness.
Under identical dosage and dosage regimen, antitumor action of the gemcitabine in different Nude Mouse Models
Performance differs greatly.(see Fig. 2) in 9 colon cancer Transplanted tumor models, gemcitabine to HCT-116, HT-29, CW-2,
LoVo, RKO, DLD-1 growth of transplanted human, which have, significantly inhibits effect, T/C% < 20%；But in COLO205, SW620 transplantable tumor mould
In type, the inhibiting effect of gemcitabine is poor, T/C% > 40%；In NCI-H716 model, the inhibiting effect of gemcitabine is situated between
In centre, T/C% is about 38%.
Similarly, (see Fig. 3) in transplantable lung cancer model, gemcitabine is to NCI-H1650, NCI-H1975 and NCI-
H1299 transplanted tumor in nude mice, which has, significantly inhibits effect, T/C < 20%；And to A549, NCI-H460, NCI-H1437 and NCI-
H1944 transplantable tumor inhibitory effect is poor (see Fig. 3), T/C > 40%.
(see Fig. 4) in model of gastric carcinoma, gemcitabine has NCI-N87, HGC-27 and SNU-1 growth of transplanted human significant
Inhibiting effect, T/C < 20%；But, T/C > 50% poor to BGC-823 and SGC-7901 transplantable tumor inhibiting effect.
(see Fig. 5) in pancreatic cancer models, gemcitabine has Capan-2, PANC-1, CFPAC-1 transplantable tumor significant
Inhibiting effect, T/C < 20%；It is poor to BxPC-3 and AsPC-1 transplantable tumor inhibiting effect, T/C > 40%.
It is also observed in Ovarian Cancer Model similar phenomenon (see Fig. 6), gemcitabine transplants A2780 and SK-OV-3
Tumor inhibiting effect differs greatly, obvious to A2780 inhibiting effect, and acts on SK-OV-3 model poor.
Gemcitabine also shows stronger anti-tumor activity (see Fig. 7), T/C in MDA-MB-435 melanoma tumor model
< 20%.
The result of study of experiment one and experiment two shows: existing between gemcitabine sensibility and AKR1C1~C3 expression
Strong correlation shows insensitivity specifically, gemcitabine drug effect is poor in the highly expressed model of AKR1C1~C3；
In the model of AKR1C1~C3 low expression, gemcitabine good drug efficacy shows sensibility.Therefore, AKR1C1~C3 can be used as life
Substance markers object is used to predict drug susceptibility when gemcitabine or its pharmaceutically acceptable salt treating cancer.
Claims (2)
- Medicine when 1.AKR1C1, AKR1C2 or AKR1C3 are as prediction gemcitabine or its pharmaceutically acceptable salt treating cancer The application of the biomarker of object sensibility.
- 2. application as described in claim 1, wherein the cancer is colon cancer, lung cancer, gastric cancer, cancer of pancreas, oophoroma, black Plain tumor, liver cancer, breast cancer, cervical carcinoma.
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| PCT/CN2018/100371 WO2019034042A1 (en) | 2017-08-14 | 2018-08-14 | Biomarker for predicting drug sensitivity to gemcitabine and use thereof |
| CN201880045621.8A CN110914688A (en) | 2017-08-14 | 2018-08-14 | Biomarker for predicting gemcitabine drug sensitivity and application thereof |
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| WO2022048492A1 (en) * | 2020-09-02 | 2022-03-10 | 深圳艾欣达伟医药科技有限公司 | Akr1c3 detection method, and diagnostic kit for detecting akr1c3 and use thereof |
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| WO2022048492A1 (en) * | 2020-09-02 | 2022-03-10 | 深圳艾欣达伟医药科技有限公司 | Akr1c3 detection method, and diagnostic kit for detecting akr1c3 and use thereof |
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