WO2013033933A1 - Trousse, procédé et utilisation pour mesurer et évaluer la sensibilité du cancer de l'ovaire à une chimiothérapie primaire - Google Patents

Trousse, procédé et utilisation pour mesurer et évaluer la sensibilité du cancer de l'ovaire à une chimiothérapie primaire Download PDF

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Publication number
WO2013033933A1
WO2013033933A1 PCT/CN2011/079885 CN2011079885W WO2013033933A1 WO 2013033933 A1 WO2013033933 A1 WO 2013033933A1 CN 2011079885 W CN2011079885 W CN 2011079885W WO 2013033933 A1 WO2013033933 A1 WO 2013033933A1
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Prior art keywords
ovarian cancer
sample
primary
minutes
tissue
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PCT/CN2011/079885
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English (en)
Chinese (zh)
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崔世英
丁艳芳
赵瑾瑶
杨亮
毕丽华
姜继勇
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大连医科大学
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Publication of WO2013033933A1 publication Critical patent/WO2013033933A1/fr

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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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6875—Nucleoproteins
    • 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
    • G01N33/57407—Specifically defined cancers
    • G01N33/57449—Specifically defined cancers of ovaries
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4703—Regulators; Modulating activity

Definitions

  • Kit method and application for measuring primary chemotherapy sensitivity of ovarian cancer
  • the present invention relates to a kit for measuring chemosensitivity of ovarian cancer and its use in assessment of primary chemotherapy sensitivity/resistance, screening of tumor patients, and assessment of tolerance of primary chemotherapy drugs. Background technique
  • Epithelial Ovarian Cancer is one of the common tumors in female reproductive organs and the leading killer in female tumors.
  • serous carcinoma is the most common, accounting for 80-85% of all ovarian cancers in Western countries, divided into late and early stages, of which the late stage accounts for the vast majority, and early rare is about 5% of all ovaries.
  • early and late serous carcinomas are two different types of ovarian cancer, and their morphological differences actually reflect differences in tumor biology, which is ultimately the difference in gene levels. The disease is difficult to diagnose early, and the patient has missed the best treatment opportunity at the time of the late visit. Because patients with advanced ovarian cancer have varying degrees of spread, patients must be treated immediately after surgery.
  • the international chemotherapy regimens for postoperative patients with ovarian cancer are mainly divided into: first-stage adjuvant (adjuvant; platinum-based cisplatin or carboplatin/paclitaxel) and late salvage (salvage; multiple chemotherapy drugs) treatment .
  • first-stage adjuvant adjuvant
  • platinum-based first-stage adjuvant chemotherapy does not have any symptoms for 40 to 50% of patients.
  • Relief also known as primary resistance, is one of the reasons for the rapid death of patients because the treatment is not targeted and delays the optimal chemotherapy period. Therefore, predicting the sensitivity of patients to primary chemotherapy before chemotherapy is critical to prolonging the lives of patients with ovarian cancer.
  • epithelial ovarian cancer has long been classified into four different pathological types according to histomorphological classification, namely: serous, endometrial, mucinous and transparent cell, of which serousity is most common.
  • histomorphological classification namely: serous, endometrial, mucinous and transparent cell, of which serousity is most common.
  • clinical practice has found that ovarian cancer is classified only according to the traditional tissue morphological classification criteria. It is insufficient for further study of its pathological features and guiding clinical diagnosis and treatment. Therefore, there is an urgent need for a method for tumors under traditional taxonomy. Carry out further screening and classification.
  • the inventors of the present application found that the protein expression level of E CC2 is higher in sensitive cells than in resistant cells 2 More than this time, in combination with this finding, the inventors used the simple anatomical immunohistochemical method in our country to qualitatively confirm the biomarker effect of ERCC2 in ovarian cancer chemotherapy patients.
  • one of the objects of the present invention is to provide a kit for measuring the sensitivity of primary chemotherapy for ovarian cancer, the kit comprising: 5% goat serum, 1% BSA, 0.01% polyethylene Blocking solution consisting of diol octyl phenyl ether and phosphate buffer pH 7.4, antigen-antibody reaction system consisting of ERCC2 antibody (1: 1000), biotinylated secondary antibody working solution and blocking solution, by horseradish enzyme An avidin-oxidase reaction system consisting of a streptavidin working solution and a DAB reagent buffer, and a hematoxylin as a counterstain.
  • the kit further comprises an antigen retrieval system consisting of 0.01 M citrate buffer and phosphate buffer, and an endogenous peroxidation consisting of 3% hydrogen peroxide and phosphate buffer. Enzyme system.
  • the kit can be specifically adapted for use in paraffin-embedded ovarian cancer tissue samples.
  • a second object of the present invention is to provide a method for measuring sensitivity of a ovarian cancer tissue sample to a primary chemotherapeutic drug, characterized in that the kit of claim 1 is used, comprising the steps of: treating a sample to be tested with a blocking solution; , using ERCC2 antibody and biotinylated secondary antibody working solution for primary and secondary antibody reaction respectively, and then treating the sample with horseradish-labeled streptavidin working solution, and finally performing DAB color development and hematoxylin counterstaining; Sensitivity of the staining condition to the primary chemotherapeutic drug: The sample with a brown positive reaction was judged to be an ovarian cancer tissue sensitive to the primary chemotherapeutic drug; the sample with a blue negative reaction was determined to be ovarian cancer resistant to the primary chemotherapeutic drug. organization.
  • the above method for measuring the sensitivity of an ovarian cancer tissue sample to a primary chemotherapeutic drug more specifically includes the following steps:
  • a negative control group was used, and the same volume of blocking solution was used instead of ERCC2 antibody.
  • tissue sections were immersed in hematoxylin staining solution 2 times for 2 seconds each time; then treated with distilled water 3 times for 5 minutes each time; then 50% ethanol, 70% ethanol, 90% ethanol was treated once for 1 minute each time; then treated twice with absolute ethanol for 2 minutes, 1 :1 mixture of xylene and absolute ethanol, 2 minutes, 100% xylene treatment 2 Times, 2 minutes each time; finally seal with a gum, save;
  • the sensitivity to the primary chemotherapeutic drug was determined: the sample with a brown positive reaction was determined to be an ovarian cancer tissue sensitive to the primary chemotherapeutic drug; the sample with a blue negative reaction was judged to be resistant to the primary chemotherapeutic drug. Ovarian cancer tissue.
  • the pretreatment of the sample includes the following steps:
  • Dewaxing routine section of formalin-fixed paraffin-embedded tissue of ovarian cancer, paraffin section of thickness 4 ⁇ 5 ⁇ was dewaxed by 100% xylene three times for 5 minutes each time; dehydrated ethanol for 3 times , 2 minutes each time; 95% ethanol, 90% ethanol, 70% ethanol, 50% ethanol, each dewaxed once, 2 minutes;
  • Antigen retrieval antigen retrieval with 0.01 M citrate buffer, then washed 3 times with PBS for 5 minutes each time;
  • Tissue sections were placed in 3% hydrogen peroxide, incubated for 30 minutes at room temperature, and washed 3 times with PBS for 5 minutes each time.
  • the resulting sample was processed directly for testing.
  • the pretreatment of the sample includes the following steps:
  • Tissue fixation Fresh tumor tissue excised during ovarian cancer surgery is placed into 4% paraformaldehyde immediately after 2x2 cm 3 , 4 . C, fixed for 24 hours;
  • the pretreatment of the sample includes the following steps:
  • Freshly resected fresh tumor tissue from ovarian cancer patients is quickly placed in liquid nitrogen for use;
  • the tissue is first immersed in 4% paraformaldehyde at 4 ° C for 24 hours;
  • the treated sample is directly used for testing.
  • Another object of the present invention is to provide a method for screening an ovarian cancer patient susceptible to a primary chemotherapeutic drug, which method also requires the use of the ovarian cancer chemosensitivity assessment kit of the present invention described above, comprising the following steps: Taking the isolated tumor tissue of ovarian cancer patients as a test sample, after treating the sample to be tested with a blocking solution, the primary and secondary antibodies were reacted with E CC2 antibody and biotinylated secondary antibody working solution, respectively, and then labeled with horseradish-labeled streptococcus.
  • Samples were treated with avidin working solution, and finally DAB coloration and hematoxylin counterstaining were performed; susceptibility of primary chemotherapeutic drugs to sample-derived ovarian cancer patients was determined based on sample staining: Samples with brown positive reaction were judged as primary chemotherapy Drug-sensitive ovarian cancer tissue, sample-derived ovarian cancer patients are sensitive to primary chemotherapy drugs; samples that are blue-negative are judged to be ovarian cancer tissues that are resistant to primary chemotherapy drugs, and sample-derived ovarian cancer patients are primary Chemotherapy drugs are tolerated.
  • Another object of the present invention is to provide a method for guiding a first-stage chemotherapy drug for a patient after ovarian cancer surgery, including clinically collecting ovarian cancer tissue, performing immunohistochemical detection and judgment, and determining a medication plan according to the judgment result.
  • a negative control group was used, and the same volume of blocking solution was used instead of ERCC2 antibody.
  • tissue sections were immersed in hematoxylin staining solution 2 times for 2 seconds each time; then treated with distilled water 3 times for 5 minutes each time; then 50% ethanol, 70% ethanol, 90% ethanol was treated once for 1 minute each time; then treated with absolute ethanol for 2 times, 2 minutes each time, 1 :1 mixture of xylene and absolute ethanol was treated once, 2 minutes, 100% xylene treatment 2 Times, 2 minutes each time; finally seal with a gum, save;
  • the sensitivity to the primary chemotherapeutic drug was determined: the sample with a brown positive reaction was determined to be an ovarian cancer tissue sensitive to the primary chemotherapeutic drug; the sample with a blue negative reaction was judged to be resistant to the primary chemotherapeutic drug. Ovarian cancer tissue.
  • the source of the ovarian cancer tissue which can be positively judged positively is highly sensitive to the postoperative primary chemotherapy drug treatment; the source of the negative reaction ovarian cancer tissue is resistant to the postoperative primary chemotherapy drug treatment
  • the probability is high. For the latter, it is necessary to determine a suitable postoperative chemotherapy regimen based on the patient's physiopathological characteristics and clinical symptoms.
  • the primary chemotherapeutic agent described in all of the above methods of the present invention refers to a first-stage chemotherapeutic drug for performing chemotherapy in patients after ovarian cancer surgery, and such drugs include platinum, paclitaxel or a combination of the two in clinical practice.
  • the ovarian cancer or tumor described in the above technical solution of the present invention refers to the advanced stage of serous ovarian cancer.
  • the inventors of the present application have found a correlation between the expression level of ERCC2 in tumor cells, particularly serous ovarian cancer cells/tissues, and the sensitivity of cells, tissues or tumor patients as hosts to primary chemotherapeutic drugs.
  • ERCC2 immunohistochemical detection method in the prior art, the above-described determination relationship between the two is not disclosed in the prior art, and there has not been any technical suggestion.
  • the present application provides a series of methods for determining the tolerance of a primary chemotherapeutic drug, as well as related reagent combinations.
  • ERCC2 ERCC2 in patients with drug-resistant and sensitive first-stage chemotherapy after advanced serous ovarian cancer:
  • the cancerous epithelium of chemotherapy-sensitive patients showed a yellow-brown positive reaction (arrow); the cancer tissue epithelium of chemotherapy-resistant patients A blue negative reaction (shown by the arrow) appears.
  • Fig. 2 and Fig. 3 are gel electrophoresis patterns and statistical analysis results of protein expression levels of ERCC2 in ovarian cancer sensitive cell OV2008 and ovarian cancer resistant cell C13 in Example 2.
  • Fig. 4 is a graph showing the results of immunofluorescence detection (b, e) and immunohistochemistry (c, f) of ovarian cancer sensitive cell OV2008 and ovarian cancer resistant cell C13 in Example 2. detailed description
  • citrate buffer 0.01 M citrate buffer: 0.885 g of citrate was dissolved in 300 ml of distilled water, and 94.5 ⁇ l of glacial acetic acid was added to adjust the value to 6.0; wherein citrate was purchased from Tianjin Komi Chemical Reagent Co., Ltd., product batch number : 20070621;
  • Phosphate buffer (PBS) 8 g of sodium chloride, 0.2 g of potassium chloride, 3.62 g of disodium hydrogen phosphate (123 ⁇ 40) and 0.24 g of potassium dihydrogen phosphate were dissolved in 800 ml of distilled water, and the pH was adjusted to 7.4 with dilute hydrochloric acid. Constant volume 1L;
  • Blocking buffer 5% goat serum, 1% bovine serum albumin, pH 7.4 phosphate buffer, 0.01% polyethylene glycol octyl phenyl ether (tirton X-100);
  • 1% BSA was purchased from the US ROCHE, 10735078001;
  • polyethylene glycol octyl phenyl ether (tirtonX-100) was purchased from the United States ROCHE, 0694;
  • E CC2 primary antibody was purchased from Protein Tech Group, Inc., 10818-AP; Biotinylated secondary antibody working solution, horseradish-labeled streptavidin working solution, reagent A (concentration buffer 20x), reagent B (concentrated DAB buffer 20x) and reagent C (concentrated hydrogen peroxide buffer 20x) From the immunohistochemistry kit, purchased from ZYMED, USA, SP-9000;
  • Polyethylene glycol octylphenyl ether (Triton-X 100) was purchased from Amersco, Cat# 0694;
  • Bovine serum albumin was purchased from Roche, Cat# 10735078001;
  • drugs or reagents are of analytical grade.
  • Sample pretreatment including the following steps:
  • Antigen retrieval antigen retrieval with 0.01 M citrate buffer, then washed 3 times with PBS for 5 minutes each time;
  • Tissue sections were placed in 3% hydrogen peroxide, incubated for 30 minutes at room temperature, and washed 3 times with PBS for 5 minutes each time.
  • a negative control group was used, and the same volume of blocking solution was used instead of ERCC2 antibody.
  • tissue sections were immersed in hematoxylin staining solution 2 times for 2 seconds each time; then treated with distilled water 3 times for 5 minutes each time; then 50% ethanol, 70% ethanol, 90% ethanol was treated once for 1 minute each time; then treated with absolute ethanol for 2 times, 2 minutes each time, 1 :1 mixture of xylene and absolute ethanol was treated once, 2 minutes, 100% xylene treatment 2 Times, 2 minutes each time; finally seal with a gum, save;
  • results of the method according to the conventional clinical diagnosis and treatment index are compared with the IHC staining results, and the effectiveness of the method of the present invention is statistically analyzed, for example.
  • Chemotherapy-sensitive All predictable and assessed disease symptoms disappeared, or the patient's CA125 detection level was less than ⁇ 30 U/ml within 6 months of chemotherapy, and the new tumor was less than 3 cm 3 .
  • Chemotherapy-resistant type After 6 months of chemotherapy, the CA125 test is still higher than 30 U/ml, and is accompanied by clinical symptoms showing that the disease course is still progressing, and the new tumor is larger than 3 cm 3 .
  • OV2008 and ovarian cancer primary chemotherapy-resistant cells C13 were collected from the international gynecological oncology community.
  • OV2008 cells are derived from patients with epithelial serous ovarian cancer (Andrews et al, Cancer Res 1985, 45 (12 Pt l): 6250-6253; Andrews et al: Cancer Chemother Pharmacol 1987, 19(2): 149-154), and OV2008/C 13 Chemotherapy-sensitive and drug-resistant cells were cultured and screened in vitro for hundreds of luM cisplatins in OV2008 cells (Andrews et al, Cancer Res 1985, 45 (12 Pt l): 6250-6253) These cells were obtained from Dr. Chun Peng (Toronto, Canada) for routine in vitro cell processing before cell preservation: cell culture, protein purification, storage at -20 ° C.
  • Sample pretreatment including the following steps:
  • 1 cell culture (1) Take one bottle of cells changed the day before, digest with 0.25 trypsin, observe the rounding of the cells under microscope, add 1ml of 1640 medium containing 10% fetal bovine serum to stop the action of trypsin, and use capillary dropper Blowing, making the cells into suspension;
  • the protein concentration was determined by BCA kit and stored in Ep tubes at 30 ug, and stored at -70 °C.
  • BIO-RAD film transfer machine wet transfer 200 ⁇ 250mA 45min;
  • ECL chemiluminescence illuminating reagent VIII, B solution equal amount (0.125ml/cm 2 membrane), add to the membrane and incubate for 5min at room temperature. After 5min, absorb excess liquid, wrap it with plastic wrap, and put it into X-ray cassette. Exposure (exposure time depends on the strength of the strip after development), after the visible band appears in the developer, the tap water is cleaned, the fixer is fixed for 2 to 3 minutes, the tap water is rinsed, and the film is air-dried at room temperature.
  • Figure 2.B shows that the analysis results show that the protein content of ERCC2 is 2.49 times higher than that of ovarian cancer resistant cells (C13) in ovarian cancer sensitive cells (OV2008).
  • Fluorescent II antibody FITC-labeled goat anti-rabbit IgG (Zhongsu Jinqiao, Catalog No: ZF-0311)
  • OV2008 and C13 cells were digested with 0.25% trypsin, diluted to 2 x 104 cells/ml and inoculated into a six-well plate, 2 ml of cell suspension per well;
  • I antibody (ERCC2 1 : 150; ProteinTech, Catalog No: 101818-1-AP) prepared in the blocking solution was incubated at 4 degrees overnight;
  • the solvent preparation method described in the method is identical to the solvent described in Example 1 and the preparation method thereof.
  • OV2008 and C13 cells were digested with 0.25% trypsin, diluted to 2 x 104 cells/ml and inoculated into a six-well plate, 2 ml of cell suspension per well;
  • Figure 4-a d is an ovarian cancer cultured cell without any staining
  • Figure 4-b e is an immunohistochemical staining of ovarian cancer cultured cells, showing: expression of ERCC2 in primary chemotherapy-sensitive cells (OV2008) Significantly enhanced, strong green, and the expression of primary chemotherapy-resistant cells (C13) was weak and dark green
  • Figure 4-c, f is an immunohistochemical staining of ovarian cancer cultured cells, showing that ERCC2 expression in primary chemotherapy-sensitive cells (OV2008) is dark brown, significantly stronger than primary chemotherapy-resistant cells (C13) Expressed, light brown. This result is completely consistent with the results obtained by ERCC2 in chemosensitive and resistant patient sections.

Abstract

L'invention concerne une trousse, un procédé et une utilisation pour mesurer et évaluer la sensibilité du cancer de l'ovaire à une chimiothérapie primaire, la trousse comprenant un fluide de scellement étanche, un système de réaction antigène-anticorps, un système de réaction avidine-oxydase et un après colorant. La présente invention est basée sur le niveau d'expression d'ERCC2 dans des cellules/tissus du cancer de l'ovaire séreux en corrélation avec la sensibilité de cellules, tissus ou patients souffrant de tumeur en tant qu'hôte pour un médicament de chimiothérapie primaire. La détection d'ERCC2 peut être utilisée à des fins multiples de mesure et d'évaluation d'une sensibilité/résistance à une chimiothérapie, d'identification de patients souffrant de tumeur, et d'évaluation de la résistance à un médicament de chimiothérapie primaire.
PCT/CN2011/079885 2011-09-08 2011-09-20 Trousse, procédé et utilisation pour mesurer et évaluer la sensibilité du cancer de l'ovaire à une chimiothérapie primaire WO2013033933A1 (fr)

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