Application of 5-oxyproline in preparation of product for diagnosing chemotherapy-induced cardiomyopathy

Abstract

The 5-oxoproline disclosed by the invention can be used as a biomarker for diagnosing chemotherapy-induced cardiomyopathy, provides a blood metabolism marker for auxiliary prediction and early diagnosis of chemotherapy-induced cardiomyopathy for the first time, and has relatively high accuracy and diagnosis reference value; by accurately measuring the content of a small molecule metabolic marker 5-oxoproline in blood, the diagnosis of early myocardial injury induced by chemotherapeutics does not completely depend on conventional non-specific myocardial injury markers and imaging means, but is examined through an objective index, namely the content change of metabolites in the blood of a patient; a discovery time window of subclinical myocardial injury is advanced, the early diagnosis detection rate is remarkably improved, the diagnosis process is simplified, opportunity is provided for early intervention, further aggravation of chemotherapy-induced cardiomyopathy is prevented or reversed, and therefore the overall survival prognosis of tumor patients is improved.

Description

Technical Field

[0001] The present invention relates to a new application of 5-oxyproline as a biomarker, in particular to a new application of 5-oxyproline as a biomarker in the preparation of a biomarker for early diagnosis of cardiomyopathy induced by chemotherapy in tumor patients. Background Art

[0002] According to the global cancer burden data released by the World Health Organization's International Agency for Research on Cancer in 2020, breast cancer has surpassed lung cancer to become the world's largest tumor and the malignant tumor with the highest incidence in women. While various types of chemotherapy drugs (such as anthracyclines, new HER2 targeted drugs, etc.) bring survival benefits, there are also various adverse drug reactions, especially chemotherapy-induced cardiotoxicity, which may even exceed the benefits of tumor treatment. Anthracyclines, the most classic chemotherapy drug for tumor treatment, are widely used in clinical treatment due to their powerful therapeutic effects, but their clinical application is largely affected by cumulative and dose-dependent cardiotoxicity, which may eventually lead to irreversible structural changes in the myocardium and progressive heart failure. Autopsy studies have shown that cardiotoxicity develops from myocardial vacuolar changes to irreversible myocardial collagen accumulation. Therefore, anthracyclines, the most classic chemotherapy drug for breast cancer treatment, can cause different types and degrees of cardiotoxicity, including myocardial contractile dysfunction and arrhythmias. One-third of cancer patients die from cardiovascular disease rather than the tumor itself, which is currently the primary cause of non-cancer-related deaths in cancer patients. Cardiovascular complications have become the most common cause of death in breast cancer patients. Therefore, early detection of breast cancer chemotherapy cardiotoxicity is crucial, which can provide an opportunity for early intervention and help prevent or reverse further aggravation of myocardial damage, thereby improving the overall survival prognosis of breast cancer.

[0003] At present, the clinical means of evaluating myocardial injury after chemotherapy include conventional echocardiography, biomarkers such as BNP, cTnI, etc. Conventional echocardiography lacks sensitivity in detecting early subclinical cardiac injury. Changes in biomarkers such as BNP and cTnI often indicate that the patient already has obvious myocardial injury, rather than the early stage of myocardial injury caused by breast cancer chemotherapy. Metabolomics is the end of the gene, transcription, and proteome series pathways, reflecting the biological changes that are taking place. Unlike genomics and proteomics that reflect the differences in the organism, the research field of metabolomics has expanded to the mutual influence and interaction between the body and the environment. Small molecule metabolites are not only the material basis of the body's life activities and biochemical metabolism, but also reflect the changes in the metabolic environment in the body caused by certain external factors. Therefore, the differences in the concentration of certain unique metabolites between different individuals actually reflect the intrinsic manifestations and external causes of the disease. Therefore, metabolomics analysis based on biological samples (such as serum, urine, saliva, etc.) is helpful for the screening and early diagnosis of complex diseases.

[0004] At present, there is still a lack of simple and effective serum biomarkers for early myocardial injury after chemotherapy. Therefore, it is of great clinical application value to find specific, sensitive, economical and non-invasive serum metabolic markers for early diagnosis of myocardial injury after chemotherapy. Summary of the invention

[0005] The purpose of the present invention is to provide the use of 5-oxoproline as a biomarker in the preparation of a product for diagnosing chemotherapy-induced cardiomyopathy. The present invention also provides a product for diagnosing chemotherapy-induced cardiomyopathy in tumor patients.

[0006] To achieve the purpose of the present invention, on the one hand, the present invention provides the use of 5-oxoproline as a biomarker in the preparation of a product for diagnosing chemotherapy-induced cardiomyopathy.

[0007] In order to solve the problem that early diagnosis of chemotherapy-induced cardiomyopathy in cancer patients is difficult, the inventors of this application used LC-MS / MS to measure the content of major metabolites in the blood. The specific method is: further enrichment analysis of metabolites with significant differences between the two groups, screening and determining metabolites that may be involved in early myocardial injury and further verifying them. It was finally determined that 5-oxyproline can be used as an early diagnostic biomarker for chemotherapy-induced cardiomyopathy in cancer patients, and can assist the current clinical means of evaluating myocardial injury after chemotherapy in the early diagnosis of chemotherapy-induced cardiomyopathy in cancer patients. It not only has high accuracy, but also no longer relies entirely on conventional non-specific myocardial injury markers and imaging methods, significantly improving the early diagnosis detection rate and simplifying the diagnosis process.

[0008] The present invention aims at the shortcomings of the prior art in the diagnosis of chemotherapy-induced cardiomyopathy in tumor patients, such as non-specificity and low sensitivity, the myocardial damage detected is generally in the late stage, and the early diagnosis of myocardial damage after chemotherapy cannot be achieved. A biomarker suitable for the early diagnosis of myocardial damage after chemotherapy is provided. The diagnostic marker has good sensitivity and specificity for myocardial damage after chemotherapy, especially early myocardial damage, and can detect and intervene early, which is of great significance for improving the prognosis of heart failure caused by cardiomyopathy after chemotherapy and reducing mortality.

[0009] When the 5-oxoproline is used as a biomarker in the preparation of a product for diagnosing chemotherapy-induced cardiomyopathy, it is targeted at the diagnosis of chemotherapy-induced cardiomyopathy in cancer patients, wherein the cancer patients are preferably but not limited to breast cancer, and the chemotherapy drugs are generally anthracyclines, such as but not limited to doxorubicin.

[0010] When the 5-oxoproline is used as a biomarker in the preparation of products for diagnosing chemotherapy-induced cardiomyopathy, the prepared products include but are not limited to kits.

[0011] At present, most of the methods in this field use imaging or conventional myocardial injury markers to diagnose myocardial injury. The present invention proposes for the first time to use serum metabolomics technology to screen biomarkers of myocardial injury after chemotherapy, and discovers markers that are particularly suitable for the early diagnosis of myocardial injury after chemotherapy, providing a good diagnostic method for early myocardial injury that is difficult to detect.

[0012] On the other hand, the present invention also provides the use of a reagent for detecting 5-oxyproline in the preparation of a product for diagnosing chemotherapy-induced cardiomyopathy.

[0013] The present invention has found in research that 5-oxyproline can be used as a diagnostic biomarker for chemotherapy-induced cardiomyopathy in tumor patients, especially for the early diagnosis of chemotherapy-induced cardiomyopathy in tumor patients. Therefore, the reagent for detecting 5-oxyproline can be used to prepare a product for diagnosing chemotherapy-induced cardiomyopathy. The reagent for detecting 5-oxyproline in the product can be used to quickly determine the 5-oxyproline content in the blood of the patient to be diagnosed, and the 5-oxyproline content obtained by the detection can be used to diagnose the cardiomyopathy of the patient to be diagnosed.

[0014] When a reagent for detecting 5-oxoproline is used to prepare a product for diagnosing chemotherapy-induced cardiomyopathy, the diagnostic object is a tumor patient, especially a breast cancer patient. The cardiomyopathy refers to cardiomyopathy induced by chemotherapy in tumor patients, and the chemotherapy generally uses anthracyclines, such as but not limited to doxorubicin.

[0015] The reagent for detecting 5-oxoproline is used to prepare a product for diagnosing chemotherapy-induced cardiomyopathy. The product can be any type of product that can be used to diagnose chemotherapy-induced cardiomyopathy, for example including but not limited to a kit for diagnosing chemotherapy-induced cardiomyopathy.

[0016] Finally, the present invention also provides a product for diagnosing chemotherapy-induced cardiomyopathy, wherein the product contains a reagent for detecting 5-oxoproline.

[0017] The inventors of the present application discovered that 5-oxyproline can be used as a biomarker for chemotherapy-induced cardiomyopathy, and prepared a product for diagnosing chemotherapy-induced cardiomyopathy using a reagent for detecting 5-oxyproline, and the product can be, for example, a kit. The present invention uses a reagent for detecting 5-oxyproline to prepare a product for diagnosing chemotherapy-induced cardiomyopathy, and the product has a diagnostic effect on chemotherapy-induced cardiomyopathy in tumor patients, and can be particularly used for early diagnosis of chemotherapy-induced cardiomyopathy. By examining the objective indicator of changes in the content of 5-oxyproline in the blood of tumor patients, the time window for discovering subclinical myocardial damage is advanced, and the early diagnosis detection rate of chemotherapy-induced cardiomyopathy in tumor patients is significantly improved.

[0018] The product of the present invention is used to diagnose chemotherapy-induced cardiomyopathy in tumor patients, wherein the tumor patients include but are not limited to breast cancer patients, and the drugs used in the chemotherapy include but are not limited to anthracyclines, such as doxorubicin.

[0019] The present invention discovers for the first time that 5-oxyproline can be used as a biomarker for diagnosing chemotherapy-induced cardiomyopathy, and provides for the first time a blood metabolic marker for assisting in the prediction and early diagnosis of chemotherapy-induced cardiomyopathy, which has high accuracy and diagnostic reference value. By accurately measuring the content of the small molecule metabolic marker 5-oxyproline in the blood, the diagnosis of early myocardial injury induced by chemotherapy drugs will no longer rely entirely on conventional non-specific myocardial injury markers and imaging methods, but will instead be based on objective indicators such as changes in the content of metabolites in the patient's blood, thereby advancing the time window for discovering subclinical myocardial injury, significantly improving the early diagnosis detection rate, simplifying the diagnostic process, providing opportunities for early intervention, and helping to prevent or reverse the further aggravation of chemotherapy-induced cardiomyopathy, thereby improving the overall survival prognosis of cancer patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The flowchart of data analysis for screening metabolic markers of the present invention.

[0021] Figure 2 This is a classification statistical diagram of the screened metabolites based on their chemical classification information.

[0022] Figure 3 This is a diagram showing the fold analysis of significant metabolic differences in positive ion mode.

[0023] Figure 4 This is the analysis chart of the significant metabolic difference fold in negative ion mode.

[0024] Figure 5 The enriched pathways were jointly analyzed for significantly differential metabolites and differential genes in mouse myocardial tissue.

[0025] Figure 6 The figure shows the changes of 5-oxyproline in the serum and myocardial tissue of mice and its correlation with early cardiac function decline.

[0026] Figure 7 This is a graph showing the sensitivity and specificity of 5-oxoproline and cTNT in mouse serum for diagnosing early myocardial injury.

[0027] Figure 8 This is a comparison chart of the changes in serum 5-oxoproline, cTNI, and BNP in the early stages of doxorubicin chemotherapy in breast cancer patients.

[0028] Fig. 9This graph shows the significant changes in LVEDD and IVST in breast cancer patients after the completion of doxorubicin chemotherapy and their correlation with the early decrease in 5-oxoproline. DETAILED DESCRIPTION

[0029] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0030] Example 1

[0031] Screening of early blood metabolic markers for anthracycline-induced cardiomyopathy

[0032] 1. Experimental animals and groups

[0033] A total of 16 C57 mice aged 6-8 weeks were selected and randomly divided into an experimental group and a control group, with 8 mice in each group.

[0034] The mice in the experimental group were given a tumor heart disease model (doxorubicin, 5 mg / kg, once), and cardiac ultrasound was performed to evaluate cardiac function one week later.

[0035] 2. Extraction of metabolites from blood

[0036] (1) The experimental group mice and the control group mice were anesthetized after tumor heart disease modeling, and the hearts were removed. The hearts were washed with pre-cooled 4°C saline, the residual blood was drained, and part of the apex of the heart was quickly frozen with liquid nitrogen for myocardial tissue metabolome analysis;

[0037] (2) After myocardial tissue frozen in liquid nitrogen was slowly thawed at 4°C, an appropriate amount of sample was added to precooled methanol / acetonitrile / water solution (2:2:1, v / v), vortexed, low-temperature ultrasonicated for 30 min, allowed to stand at -20°C for 10 min, centrifuged at 14000g for 20 min at 4°C, the supernatant was vacuum dried, and for mass spectrometry analysis, 100 μL of acetonitrile aqueous solution (acetonitrile: water = 1:1, v / v) was added for re-dissolution, vortexed, and centrifuged at 14000g for 15 min at 4°C. The supernatant was obtained to obtain the metabolic extract.

[0038] 3. Targeted metabolomics analysis based on LC-MS / MS

[0039] The metabolites in the sample (metabolite extract) were separated by hydrophilic interaction chromatography, and the samples were separated using a VanquishLC ultra-high performance liquid chromatography system (UHPLC) HILIC column; column temperature 25°C; flow rate 0.3mL / min; injection volume 2μL; mobile phase composition A: water + 25mM ammonium acetate + 25mM ammonia B: acetonitrile; gradient elution program as follows: 0-1.5min, 98% B; 1.5-12min, B linearly changed from 98% to 2%; 12-14min, B maintained at 2%; 14-14.1min, B linearly changed from 2% to 98%; 14.1--17min, B maintained at 98%; the sample was placed in an automatic sampler at 4°C during the entire analysis process.

[0040] After separation by Vanquish LC ultra-high performance liquid chromatography system (UHPLC), the samples were analyzed by mass spectrometry using Q-Exactive series mass spectrometer (Thermo), and electrospray ionization (ESI) positive and negative ion modes were used for detection. The ESI source and mass spectrometer setting parameters are as follows: nebulizer gas auxiliary heating gas 1 (Gas1): 60, auxiliary heating gas 2 (Gas2): 60, curtain gas (CUR): 30psi, ion source temperature: 600℃, spray voltage (ISVF) ±5500V (positive and negative modes); primary mass-to-charge ratio detection range: 80-1200Da, resolution: 60000, scanning accumulation time: 100ms, secondary segmented acquisition method, scanning range is 70-1200Da, secondary resolution: 30000, scanning accumulation time: 50ms, dynamic exclusion time: 4s.

[0041] 4. Analyze and verify the possible metabolic markers screened

[0042] The raw data were converted into .mzXML format by ProteoWizard, and then peak alignment, retention time correction and peak area extraction were performed using XCMS software. The data extracted by XCMS were first subjected to metabolite structure identification and data preprocessing, then experimental data quality evaluation, and finally data analysis.

[0043] Data analysis includes univariate statistical analysis, multidimensional statistical analysis, differential metabolite screening, differential metabolite correlation analysis, KEGG pathway analysis, etc. The specific process is shown in the attached Figure 1 shown.

[0044] In this example, 1106 metabolites were identified after the positive and negative ion modes were combined, and the number of metabolites identified by the positive and negative ion modes is shown in Table 1.

[0045] Table 1 Statistics of metabolites identified in positive and negative ion modes

[0046] Detection Mode Number of metabolites identified Positive ion mode (Pos) 628 Negative ion mode (Neg) 478

[0047] All metabolites (metabolites identified by combining positive and negative ions) are classified and counted according to their chemical taxonomy. The proportion of each type of metabolite is shown in the attached figure. Figure 2 shown.

[0048] The differential metabolites were screened by univariate statistical analysis and multidimensional statistical analysis. The variable weight value (Variable Importance for the Projection, VIP) obtained by the OPLS-DA model can be used to measure the influence and explanatory power of the expression pattern of each metabolite on the classification and discrimination of each group of samples, and to mine differential metabolite molecules with biological significance. Generally, metabolites with VIP>1 are considered to have significant contributions in the model interpretation.

[0049] Metabolomics usually uses strict OPLS-DA VIP>1 and P value<0.05 as the screening criteria for significant differential metabolites. This experiment uses this as the screening criteria. The bar graph intuitively displays the fold changes of the significantly differential metabolic differences identified. The results are shown in the attached Figure 3 and attached Figure 4 shown.

[0050] Attached Figure 3 and 4 In the figure, the horizontal axis represents the log2 FC value of the differential metabolites, that is, the logarithm of the difference multiple of the differential metabolites with base 2, and the vertical axis represents the significant differential metabolites. Red represents up-regulated differential metabolites, and green represents down-regulated differential metabolites.

[0051] Metabolomics showed that there were 79 differentially expressed metabolites after doxorubicin-induced early myocardial injury. MetaboAnalyst online tool (https: / / www.metaboanalyst.ca) was used to jointly analyze transcriptome (differentially expressed genes, Benjamini-Hochberg corrected P < 0.05 and |log2[foldchange]| ≥ 1) and metabolomics (differential metabolites, using orthogonal partial least squares discriminant analysis, VIP> 2). The results are shown in the attached figure. Figure 5 shown.

[0052] By the attached Figure 5 It can be seen that the differential metabolites and differential genes are co-enriched in the glutathione metabolic pathway. Among them, the metabolite with significant changes in the glutathione metabolic pathway is 5-oxyproline.

[0053] The detection methods for the metabolites screened as potential biomarkers are:

[0054] (1) Sample pretreatment

[0055] Synthesis of 5-oxoproline internal standard: Prepare 1 mg / mL glutamic acid-d5 solution with 0.1N hydrochloric acid, heat at 80°C for 15 hours to synthesize 5-oxoproline-d5 internal standard solution, and adjust the pH back to neutral with ammonia water to prepare 5-oxoproline internal standard;

[0056] Preparation of internal standard working solution: dilute the 5-oxoproline internal standard 200 times with 75% acetonitrile aqueous solution containing 0.2% formic acid to prepare 5-oxoproline internal standard working solution;

[0057] Sample processing: Take 50 μL of the standard curve, quality control product and sample to be tested respectively and add them into a 1.5 mL centrifuge tube, add 400 μL of internal standard working solution, vortex for 60 seconds, centrifuge at 13000 rpm and 4 degrees for 10 minutes, aspirate 200 μL of the supernatant and transfer it to a 2.2 mL 96-well plate, and wait for loading on the machine.

[0058] (2) Liquid phase method

[0059] The metabolites in the sample were separated by a chromatographic column Phenomenex Kinetex F5 (2.6um, 2.1×100mm). The specific chromatographic conditions were as follows:

[0060] Mobile phase A was 0.1% formic acid in water;

[0061] Mobile phase B was 0.1% formic acid acetonitrile;

[0062] Flow rate: 0.25 ml / min;

[0063] The column temperature was 25°C;

[0064] The gradient elution conditions are shown in Table 2 below.

[0065] Table 2 Gradient elution conditions

[0066] Time(min) A(％) B(％) 0 99 1 1.2 99 1 2 1 99 3 1 99 3.01 99 1 4 99 1

[0067] (3) Mass spectrometry

[0068] AB SCIEX Triple Quad TM 4500MD liquid chromatography tandem mass spectrometry detection system, using ESI+, multiple reaction monitoring (MRM) mode for mass spectrometry scanning; Curtain Gas (CUR) is 35psi; Collision Gas (CAD) is 9psi; Voltage is +5500V; Desolvation gas temperature is 500℃; Heating gas (GS1) is 50psi; Auxiliary gas (GS2) is 50psi. The mass spectrometry channel parameters are shown in Table 3 below.

[0069] Table 3 Mass spectrometry channel parameters

[0070] Analyte Q1 Q3 Dwell Time(msec) DP EP CE CXP P-Glu 130.1 84.0 100 60 10 18 9 P-Glu-d5 135.2 89.2 50 60 10 20 9

[0071] (4) Calibration products and quality control products

[0072] The 5-oxoproline standard was prepared with water to form a 50 mM primary stock solution, which was diluted with water to form a 4 mM secondary stock solution, which was then diluted with water and mixed to obtain standard curves and quality control products of different concentrations, as shown in Table 4 below.

[0073] Table 4 Standard curves and quality control products of different concentrations

[0074]

[0075] The developed targeted LC / MS method was further used to detect the content of 5-oxoproline in the serum and myocardial tissue of mice with early myocardial injury induced by doxorubicin. The results are shown in the attached figure. Figure 6 shown.

[0076] By the attached Figure 6 It can be seen that 5-oxyproline decreased significantly and was negatively correlated with the global longitudinal strain (GLS), an indicator of early cardiac function decline.

[0077] At the same time, ROC analysis was performed based on the GLS decrease of more than 15% as the diagnostic criterion for early myocardial injury. The results are shown in the attached figure. Figure 7 shown.

[0078] By the attached Figure 7 It can be seen that 5-oxoproline has high diagnostic sensitivity and specificity and can be used as a biomarker for chemotherapy-induced cardiomyopathy in cancer patients.

[0079] Example 2

[0080] Validation of 5-oxoproline as a biomarker in the early diagnosis of chemotherapy-induced cardiomyopathy

[0081] This example was conducted under the guidance of the Good Clinical Practice Guidelines for Drugs, using a protocol approved by the Ethics Committee and was reviewed and approved by the Ethics Committee.

[0082] This example uses breast cancer patients as research subjects, and the patients are female patients aged between 18 and 70 years old who have been pathologically confirmed to have breast cancer, have no heart discomfort symptoms, no history of structural heart disease, and have not been treated with anthracyclines in the past.

[0083] Sample size calculation: According to previous CMR studies, extracellular matrix content (ECV) is one of the most valuable and sensitive indicators reflecting myocardial changes. In our pilot study, which included 10 patients (early myocardial injury) and 10 controls, the average ECV was 30% and 24%, respectively. The standard deviation of ECV in the entire group was 0.3. The difference between the chemotherapy group and the control group in the pilot study was 4%. According to the sample ratio (n CMP / n Control = 1), the type I error (two-sided) was 5%, and the power was 0.8. It is estimated that the sample size of each group will require at least 42 subjects. Each subject in this project has three sample collections (baseline, first follow-up, and last follow-up). The baseline and first follow-up are similar to the control group and chemotherapy group in the pilot study. Therefore, it is estimated that the final sample size will require at least 42 subjects; considering the loss of follow-up and dropout during the follow-up process, the sample size of this example adopts 60 subjects.

[0084] Experimental methods: Follow-up was conducted according to the research plan of the ethics application. Blood was collected from subjects at baseline (before chemotherapy), after the first course of anthracycline treatment (at the second dose), and after all courses of anthracycline treatment, and serum samples were centrifuged and stored for subsequent detection of metabolites and cTNI and BNP. Cardiac ultrasound was performed to evaluate cardiac function at baseline and after chemotherapy, and data were collected for analysis. The specific collection method is:

[0085] Baseline serological data collection of subjects: Serological data of subjects who meet the inclusion criteria are collected as baseline indicators before starting doxorubicin treatment.

[0086] Initial follow-up serological collection: At the end of the first course of doxorubicin treatment (at the second dose), 4-5 ml of blood was collected from the subjects as the initial follow-up sample;

[0087] Serological collection at the last follow-up: After the end of all courses of doxorubicin treatment, 4-5 ml of blood was collected from the subjects as the last follow-up sample.

[0088] After all blood samples were collected, they were centrifuged to obtain serum samples for metabolite detection as well as cTNI and BNP detection. The test results are shown in the attached Figure 8 shown.

[0089] Attached Figure 8 The changes of 5-oxoproline, cTNI and BNP in serum of breast cancer patients in the early stage of adriamycin chemotherapy in this example are shown in the figure. Figure 8 It can be seen that compared with cTNI and BNP (conventional myocardial injury markers), 5-oxyproline changes more significantly in the early stages of myocardial injury in tumor heart disease.

[0090] At baseline and after chemotherapy, all subjects underwent cardiac ultrasound to assess cardiac function, and data were collected and analyzed. The results are shown in the attached Fig. 9 shown.

[0091] By the attached Fig. 9 It can be seen that the left ventricular end-diastolic diameter (LVEDD) and interventricular septum thickness (IVST) of breast cancer patients changed significantly after the end of doxorubicin chemotherapy and there was a certain correlation with the early decrease of 5-oxyproline.

[0092] It can be seen from the above experimental results that 5-oxyproline changes significantly in the early stage of chemotherapy-induced cardiomyopathy in tumor patients, and its content decreases significantly. It is negatively correlated with the global longitudinal strain (GLS), an indicator of early cardiac function decline, and compared with cTNI and BNP (conventional myocardial injury markers), 5-oxyproline changes more significantly in the early stage of myocardial injury in tumor heart disease. Clinical trials have further confirmed that LVEDD and IVST change significantly after the end of doxorubicin chemotherapy in breast cancer patients and have a certain correlation with the early decline of 5-oxyproline. Therefore, 5-oxyproline can be used as a biomarker for the early diagnosis of tumor chemotherapy-induced cardiomyopathy, and can be diagnosed through the objective indicator of changes in the 5-oxyproline content in the patient's blood, which overcomes the defect that the diagnosis of chemotherapy-induced cardiomyopathy in tumor patients in the prior art needs to rely entirely on conventional non-specific myocardial injury markers and imaging methods. The present invention uses 5-oxoproline as a diagnostic marker for tumor chemotherapy-induced cardiomyopathy, which can be combined with imaging and other means. It not only has high accuracy and diagnostic reference value, but also can effectively improve the early diagnosis detection rate, provide opportunities for early intervention, and help prevent or reverse the further aggravation of chemotherapy-induced myocardial damage, which has great clinical significance.

[0093] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the essence and scope of the technical solution of the present invention.

Claims

Use of 1.5-oxoproline as a biomarker in the preparation of products for the diagnosis of chemotherapy-induced cardiomyopathy.

2. The use according to claim 1, characterized in that The chemotherapy drug used is anthracycline; and / or, the concentration of 5-oxoproline is decreased in chemotherapy-induced cardiomyopathy; And / or, the product is a kit.

3. The use according to claim 2, characterized in that The anthracycline drug is doxorubicin.

4. Use of reagents for detecting 5-oxoproline in the preparation of products for diagnosing chemotherapy-induced cardiomyopathy.

5. The use according to claim 4, characterized in that The chemotherapy drug used is anthracycline; and / or, the concentration of 5-oxoproline is decreased in chemotherapy-induced cardiomyopathy; And / or, the product is a kit.

6. The use according to claim 5, characterized in that The anthracycline drug is doxorubicin.

7. A product for diagnosing chemotherapy-induced cardiomyopathy, characterized in that: The product contains a reagent for detecting 5-oxoproline.

8. The product for diagnosing chemotherapy-induced cardiomyopathy according to claim 7, characterized in that: The product is a test kit.

9. The product for diagnosing chemotherapy-induced cardiomyopathy according to claim 6 or 7, characterized in that: The chemotherapy drug used is anthracycline drugs.

10. The product for diagnosing chemotherapy-induced cardiomyopathy according to claim 8, characterized in that: The anthracycline drug is doxorubicin.

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