CN108459157B - Composition for predicting toxicity biomarker of irinotecan chemotherapy - Google Patents
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Abstract
The present invention relates to a biomarker panel for predicting the severity of delayed diarrhea and myelosuppression after drug administration. Compared with non-sensitive individuals with light delayed diarrhea degree after administration, sensitive individuals with severe delayed diarrhea degree have obviously higher content of cholic acid, deoxycholic acid and glycocholic acid in serum before administration, and the content of phenylalanine is obviously lower. Sensitive individuals with severe myelosuppression levels had significantly higher serum glycocholic acid levels, and significantly lower levels of phenylalanine, lysine and tryptophan, prior to administration, as compared to non-sensitive individuals with lesser myelosuppression levels following administration.
Description
Technical Field
The invention relates to the field of prediction biomarkers, in particular to a group of compositions of biomarkers for predicting the chemotherapeutic toxicity of irinotecan, which are derived from endogenous serum micromolecular metabolites and have important significance for rapidly predicting the sensitivity of individuals to the irinotecan and clinically individualized treatment.
Background
Irinotecan (CPT-11) is a DNA topoisomerase I inhibitor, primarily used for first-line treatment of metastatic colorectal cancer. Research shows that irinotecan has serious chemotherapy toxicity during clinical application, mainly comprises delayed diarrhea and myelosuppression, and becomes a main factor limiting the clinical application of the irinotecan.
The chemotherapy toxicity of irinotecan has obvious individual difference phenomenon, so that the prediction of the sensitivity of a patient to irinotecan before administration and the adjustment of the administration scheme are the basis for reducing the chemotherapy toxicity and realizing individual treatment. At present, the clinical common method is to predict the chemotherapy sensitivity of patients by detecting UGT1A1 gene polymorphism. However, this method is expensive, not very popular, and is complicated due to individual differences, and erroneous judgment is often caused by single genotype detection.
Therefore, the development of a multi-factor and convenient method for predicting the toxicity of irinotecan chemotherapy is particularly important. The metabolome is positioned at the end of the biological information flow, and the differences of genes, proteases, environmental factors and other factors are all reflected at the level of endogenous small molecule metabolites. Serum analysis is a commonly used research method in metabonomics research and clinical application, and is widely adopted due to its advantages of simplicity, economy and the like. There is currently no use of serum metabolite levels to predict individual differences in irinotecan chemotherapy toxicity.
Therefore, the research strategy of applying serum metabonomics to search biomarkers to predict the chemotherapeutic toxicity of irinotecan has important significance for the clinical application and the individual treatment of irinotecan.
Disclosure of Invention
The invention relates to a composition for predicting toxicity biomarkers of irinotecan chemotherapy, which comprises the following components in parts by weight:
detecting serum samples before administration of rats in a sensitive group and a non-sensitive group of irinotecan chemotherapy toxicity;
pre-dose serum samples of mammals from both the irinotecan chemotherapy toxicity-sensitive and non-sensitive groups were tested.
Pre-dose serum samples of subjects in the sensitive and non-sensitive groups of irinotecan chemotherapy toxicity were tested.
The invention relates to a composition for predicting toxicity biomarkers of irinotecan chemotherapy, which comprises the following components in parts by weight: use of glycocholic acid and phenylalanine in the preparation of a composition for predicting toxicity biomarkers of irinotecan chemotherapy.
The invention relates to a composition for predicting toxicity biomarkers of irinotecan chemotherapy, which comprises the following components in parts by weight: application of glycocholic acid, phenylalanine, cholic acid and deoxycholic acid in preparation of markers for predicting irinotecan tardive diarrhea.
Compared with a non-sensitive group with delayed diarrhea, the sensitive group individual is up-regulated in glycocholic acid, cholic acid and deoxycholic acid and down-regulated in phenylalanine before administration.
The present invention relates to a composition for predicting sensitivity to irinotecan chemotherapy toxicity:
glycocholic acid: 2.04 to 2.86;
phenylalanine: 55.23 to 69.07;
cholic acid: 24.44-34.12;
deoxycholic acid: 1.72 to 2.52;
and/or, the unit: either one of μmol and μmol/L.
The invention relates to a non-sensitive composition for predicting the chemotherapeutic toxicity of irinotecan, which comprises the following components in parts by weight:
glycocholic acid: 1.47-2.25;
phenylalanine: 62.66-75.78;
cholic acid: 16.56-22.68;
deoxycholic acid: 1.43 to 2.09; and/or,
And/or, the unit: either one of μmol and μmol/L.
The invention relates to a composition for predicting toxicity biomarkers of irinotecan chemotherapy, which comprises the following components in parts by weight: application of glycocholic acid, phenylalanine, lysine and tryptophan in preparation of markers for predicting bone marrow suppression of irinotecan.
The invention relates to a composition for predicting toxicity biomarkers of irinotecan chemotherapy, which comprises the following components in parts by weight:
detecting serum samples before administration of rats in a sensitive group and a non-sensitive group of irinotecan chemotherapy toxicity;
pre-dose serum samples of mammals from both the irinotecan chemotherapy toxicity-sensitive and non-sensitive groups were tested.
Pre-dose serum samples of subjects in the sensitive and non-sensitive groups of irinotecan chemotherapy toxicity were tested.
Compared with a myelosuppressive non-sensitive group, the sensitive group of individuals is up-regulated in glycocholic acid and down-regulated in phenylalanine, lysine and tryptophan before administration.
The invention relates to a sensitive composition for predicting the chemotherapeutic toxicity of irinotecan, which comprises the following components in parts by weight:
glycocholic acid: 2.04 to 2.86;
phenylalanine: 55.23 to 69.07;
lysine: 264.31-312.01;
tryptophan: 53.76 to 65.62;
and/or, the unit: either one of μmol and μmol/L.
The invention relates to a composition of non-sensitive biomarkers for predicting the toxicity of irinotecan chemotherapy, which comprises the following components in parts by weight:
glycocholic acid: 1.47-2.25;
phenylalanine: 62.66-72.78;
lysine: 303.39-349.95;
tryptophan: 60.43-71.93;
and/or, the unit: either one of μmol and μmol/L.
The technical scheme adopted by the invention is as follows: the method is characterized in that non-targeted metabonomics analysis based on liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry technologies is applied, a multivariate data analysis and processing method is combined, serum metabonomics research of individuals with different irinotecan chemotherapy toxicity is carried out, combination of endogenous small molecular biomarkers capable of predicting irinotecan chemotherapy toxicity in serum is searched, the small molecular biomarkers are accurately quantified by a quantitative method based on liquid chromatography-mass spectrometry, and a Logit equation prediction model is established.
The biomarker determination process for predicting the chemotherapeutic toxicity of irinotecan of the invention is as follows:
materials: methanol, acetonitrile and formic acid (chromatographically pure) were purchased from Merck (Merck) germany; methoxyamine chloride and N-methyl-N- (trimethylsilane) trifluoroacetamide (containing 1% trimethylchlorosilane) were purchased from Sigma-Aldrich, USA;
deionized water was prepared from the Milli-Q ultrapure water system from Millipore, Inc., USA;
standard compounds include: cholic acid, deoxycholic acid, glycocholic acid, phenylalanine, lysine, tryptophan, all available from Sigma-Aldrich, USA;
the internal standard compounds cortisone acetate and fudosteine were purchased from the chinese food & drug testing institute.
Collecting a serum sample: 40 healthy male SD rats (SPF grade, 200 + -10 g, from Shanghai Spirol-Bikay laboratory animals Co., Ltd.) were collected before tail vein injection of irinotecan (60mg/kg, from Jiangsu Henry Co., Ltd.) and blood collection was performed in the morning on an empty stomach.
Preparation and analysis process of non-target metabonomics research samples:
GC/MS
the sample processing method comprises the following steps: precisely sucking 10 mu L of a serum sample, placing the serum sample into a 1.5mL high-speed centrifuge tube, adding internal standard heptadecanoic acid (100 mu L of 10 mu g/mL methanol solution), uniformly mixing the serum sample in a vortex manner for 3min, precisely sucking 80 mu L of supernatant into a brown reaction tube after high-speed centrifugation (16000rpm, 4 ℃, 10min), adding 25 mu L of MOX reagent (10 mg/mL) into the brown reaction tube, oscillating the mixture at 37 ℃ and 1200rpm for reaction for 1.5h, and drying the reacted solution in vacuum at 50 ℃ for 2 h; then, 120. mu.L of MSTFA reagent (MSTFA: ethyl acetate 1: 1) was added to the reaction tube, and after vortex mixing, the reaction was carried out at 37 ℃ and 1200rpm for 2 hours with shaking, and the solution after the reaction was immediately subjected to sample injection analysis.
GC/MS conditions: shimadzu (Shimadzu) GCMS-QP2010 gas chromatograph-mass spectrometer. The chromatographic column is an Rtx-5MS quartz capillary column (30m multiplied by 0.25mm multiplied by 0.25 mu m); gradient heating mode: 0-2min at 70 deg.C, 2-27min at 70-320 deg.C, and 27-29min at 320 deg.C; the carrier gas flow rate was 57cm/s (99.99% helium); the temperature of a sample inlet is 250 ℃; the sample injection amount is 1 mu L (split ratio is 50: 1); ionization energy is 70 eV; the ion source temperature is 200 ℃; the interface temperature is 250 ℃; the solvent delay time is 5 min; the mass scanning range is m/z and 45-600 daltons.
UPLC-IT-TOF/MS
The sample processing method comprises the following steps: precisely sucking 20 mu L of serum, placing the serum into a 1.5mL centrifuge tube, adding 140 mu L of acetonitrile solution (5 mu g/mL) containing internal standard glibenclamide, vortexing for 5min, and transferring supernatant to a sample injection vial for UPLC-IT-TOF/MS analysis after high-speed centrifugation (4 ℃, 16000rpm, 10 min).
UPLC-IT-TOF/MS conditions: shimadzu (Shimadzu) liquid chromatography-mass spectrometer. The chromatographic column is Phenomenex Kinetex C18column (100X 2.1mm, 2.6 μm, Phenomenex, USA); the mobile phase comprises two solvents: a is 0.1% formic acid, B is acetonitrile; the flow rate is 0.4 mL/min; the column temperature was 40 ℃; the injector temperature was 16 ℃; injecting sample with volume of 5 μ L; the chromatographic gradient elution conditions were: 5-95% B in 0-20min, 95-5% B in 20-23min, and 5% B in 23-30 min; an electrospray ion source (ESI) adopts a positive and negative ion mode to simultaneously acquire data, the atomization gas rate is 1.5L/min, the drying gas pressure is 0.1MPa, the detection voltage is 1.70KV, the ion source interface voltage is 4.5kV at the positive electrode, and-3.5 kV at the negative electrode; the mass scan range is m/z: 100-.
Data processing and analysis
And introducing data obtained by GC/MS and UPLC-IT-TOF/MS into SIMCA-p software (version 11.0, Umetrics) for multivariate statistical analysis. Differential metabolites were screened by establishing an OPLS-DA (orthogonal partial least squares-discriminant analysis) model.
The results showed that the chemotherapy toxicity-sensitive group (23, 57.5% of the total) exhibited more severe late diarrhea and myelosuppression after the administration than the non-sensitive group (17, 42.5% of the total). Individuals in the chemotoxic-sensitive and non-sensitive groups were clearly distinguished in the OPLS-DA plots before administration. As shown in figure one.
The structure of the substance was searched by databases such as HMDB (http:// www.hmdb.ca /) and Metline (http:// metlin. script. edu /), the differential metabolites were identified by the precise molecular weights provided in the databases and the MS/MS profiles obtained as described above, and the differential metabolites were confirmed by standard alignment.
To further characterize the two common chemotherapeutic toxicities of irinotecan: biomarkers for delayed diarrhea and myelosuppression were differentiated and we screened biomarkers associated with delayed diarrhea and myelosuppression, respectively, using a Lasso regression analysis ((http:// www.r-project. org).
The results show that glycocholic acid, cholic acid, deoxycholic acid and phenylalanine can be used for predicting late diarrhea, and glycocholic acid, phenylalanine, lysine and tryptophan can be used for predicting bone marrow suppression;
and identifying 6 characterized compounds, namely glycocholic acid, cholic acid, deoxycholic acid, phenylalanine, tryptophan and lysine, wherein the chromatographic retention time of the compounds is consistent with that of the standard, and the multistage mass spectrum fragment information of the compounds is identical with the structural characteristics of the standard.
The accurate quantitative process of the differential metabolite:
bile acid substances:
the sample processing method comprises the following steps: 50 μ L of serum was aspirated precisely, 10 μ L of internal standard (cortisone acetate, 100 μ g/mL) and 200 μ L of methanol were added, vortexed for 5min, and after high speed centrifugation (4 ℃, 14000rpm, 10min), the supernatant was transferred to a sample vial for LC/MS analysis.
LC/MS conditions: saimerfi (Thermo Fisher) U.S. triple quadrupole mass spectrometer (column ZORBAX Eclipse XDB-C18 (2.1X 150mm,3.5 μm, Agilent, USA) with mobile phase containing two solvents: a is 0.1% formic acid, B is acetonitrile; the flow rate is 0.45 mL/min; the column temperature was 45 ℃; the injector temperature was 15 ℃; injecting sample with volume of 5 μ L; the chromatographic gradient elution conditions were: 68-73% A in 0-21min, 73% A in 21-28min, 73-60% A in 28-31min, and 60-68% A in 31-56 min; an electrospray ion source (ESI) adopts an anion mode to collect data, the source spray voltage is 3.8kV, and the temperature of an ion transmission capillary is 360 ℃. The sample spectrum is shown in figure two.
Amino acids:
the sample processing method comprises the following steps: accurately aspirating 40. mu.L of serum, adding 10. mu.L of internal standard (Fudosteine, 80. mu.g/mL) and 350. mu.L of acetonitrile, vortexing for 5min, high speed centrifuging (4 ℃, 14000rpm, 10min), transferring the supernatant to a sample vial for LC/MS analysis.
LC/MS conditions: U.S. Saimerfi (Thermo Fisher) triple quadrupole mass spectrometer with column BEH HILIC (2.1X 100mm,1.7 μm, Ireland Waters) and mobile phase containing two solvents: a is 0.01% formic acid, B is acetonitrile; the flow rate is 0.30 mL/min; the column temperature is 30 ℃; the injector temperature was 15 ℃; injecting sample with volume of 5 μ L; the chromatographic gradient elution conditions were: 5-15% A in 0-3min, 15-60% A in 3-6min, and 15% A in 6-10 min; an electrospray ion source (ESI) adopts a positive ion mode to collect data, the source spray voltage is 4.5kV, and the temperature of an ion transmission capillary is 270 ℃. The sample spectrum is shown in figure two.
And establishing a Logit equation for predicting the toxicity of chemotherapy based on the accurate quantitative result of the marker compound and the delayed diarrhea and myelosuppression difference shown by the individual after administration.
The results show that the method has the advantages of high yield,
the prediction equation for late-onset diarrhea is logit (p) 26.190+1.403CA +3.652DCA +5.717GCA-1.196 Phe;
the predictive equation for bone marrow suppression is logit (p) 26.381-0.205Phe-0.056Lys-0.059Trp +4.002 GCA;
when the value of the prediction equation Logit is more than 0, the individual is toxic sensitive, and when the value of the prediction equation Logit is less than 0, the individual is non-sensitive.
The invention relates to a composition for predicting toxicity biomarkers of irinotecan chemotherapy, which comprises the following components in parts by weight: application of glycocholic acid and phenylalanine in preparing a composition for predicting toxicity biomarkers of irinotecan chemotherapy.
The invention relates to the use of cholic acid, deoxycholic acid, glycocholic acid and phenylalanine for the preparation of a composition for predicting irinotecan tardive diarrhea biomarkers; the invention relates to a composition for preparing a bone marrow suppression biomarker for predicting irinotecan by using lysine, tryptophan, phenylalanine and glycocholic acid. The results are shown in Table 1.
TABLE 1 biomarker summary for prediction of irinotecan late diarrhea and myelosuppression
And (3) verification: and further adopting a Receiver Operating Curve (ROC) method to test the prediction accuracy of the logic equation fitted by the four biomarkers glycocholic acid, phenylalanine, cholic acid and deoxycholic acid on irinotecan tardive diarrhea.
The results show that in the training set, the area under the curve is 0.987, and the equation prediction accuracy is 95%. A new batch of animal model (25) serum samples are selected for verification, and the result shows that after the serum samples are grouped by using a prediction equation, individuals in a sensitive group (15 individuals accounting for 60 percent of the total number) and individuals in a non-sensitive group (10 individuals accounting for 40 percent of the total number) show obvious difference in the degree of delayed diarrhea, and the sensitive group develops more severe delayed diarrhea, and the result is shown in figure 3.
And further adopting a Receiver Operating Curve (ROC) method to test the prediction accuracy of the logic equation fitted by the four biomarkers of phenylalanine, lysine and tryptophan on the bone marrow inhibition of the irinotecan.
The results show that in the training set, the area under the curve is 0.967, and the equation prediction accuracy is 87.5%. A new batch of animal model (25) serum samples are selected for verification, and the result shows that after the animal model is divided into groups by using a prediction equation, the sensitive group (14, accounting for 56 percent of the total number) and the non-sensitive group (11, accounting for 44 percent of the total number) show obvious difference in bone marrow suppression degree, and the sensitive group generates more serious bone marrow suppression, and the result is shown in figure 3.
In conclusion, the invention provides a new biomarker group for clinically predicting irinotecan tardive diarrhea and bone marrow suppression through serum metabonomics and accurate quantification of endogenous micromolecular substances, and the method has the advantages of rapidness, simplicity, convenience, economy and no wound.
The method has important significance for predicting the chemotherapy toxicity of irinotecan and provides important basis for clinical medication, dose adjustment and individualized treatment of irinotecan.
Drawings
FIG. 1: in the examples, individual difference maps of a chemotherapy toxicity sensitive group vs chemotherapy toxicity non-sensitive group are shown.
FIG. 2: in the examples, the chromatogram for measuring the content of glycocholic acid, cholic acid, deoxycholic acid, phenylalanine, lysine and tryptophan is shown.
FIG. 3: in the examples, predictive biomarker panels are shown in the validation set of predictive accuracy of the training set versus toxicity of irinotecan chemotherapy.
Detailed explanation of FIGS. 1 to 3
A in FIG. 1 is: a curve chart of diarrhea score of chemotherapy toxicity sensitive group and non-sensitive group;
b in FIG. 1 is: a cytometric map of chemotherapy toxicity sensitive group and non-sensitive group;
c of fig. 1 is: OPLS-DA pattern under GC/MS before administration of chemotherapy toxicity sensitive group and non-sensitive group;
d in fig. 1 is: OPLD-DA pattern in UPLC-IT-TOF/MS positive ion mode before administration for chemotherapy toxicity sensitive group and non-sensitive group;
e of fig. 1 is: OPLD-DA pattern of chemotherapy toxicity-sensitive and non-sensitive groups in UPLC-IT-TOF/MS anion mode before administration;
a in FIG. 2 is: chromatogram for measuring contents of glycocholic acid, cholic acid and deoxycholic acid;
b in FIG. 2 is: a chromatogram for measuring the contents of phenylalanine, lysine and tryptophan;
a in FIG. 3 is: training a working curve of a sensitive group subject and a non-sensitive group subject suffering from delayed diarrhea in a set;
b in FIG. 3 is: verifying a diarrhea score curve graph of a sensitive group and a non-sensitive group of the centralized delayed diarrhea;
c of fig. 3 is: training a working curve of a centralized bone marrow suppression sensitive group subject and a non-sensitive group subject;
d in fig. 3 is: and (5) verifying the cytometric map of the centralized myelosuppression sensitive group and the non-sensitive group.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Biomarker combinations for predicting irinotecan tardive diarrhea, the composition and exact content of which are shown in table 2:
TABLE 2 differential metabolites predicting the sensitivity to late-onset diarrhea versus non-sensitivity to vs
Example 2
Biomarker combinations for predicting irinotecan myelosuppression, with compositions and exact amounts shown in table 3: TABLE 3 prediction of myelosuppression-sensitive vs non-sensitive differential metabolites
Example 3:
a composition for predicting sensitivity to irinotecan chemotherapeutic toxicity, the ratio of components being:
glycocholic acid: 2.04 to 2.86;
phenylalanine: 55.23 to 69.07;
cholic acid: 24.44-34.12;
deoxycholic acid: 1.72 to 2.52;
and/or, the unit: either one of μmol and μmol/L.
The application of the composition is as follows: taking the composition as a reference substance, and detecting the contents of the above four substances in a sample, thereby predicting the sensitivity of organisms to the toxicity of irinotecan chemotherapy.
Example 4:
a non-sensitive composition for predicting the chemotherapeutic toxicity of irinotecan, comprising the following components in parts by weight:
glycocholic acid: 1.47-2.25;
phenylalanine: 62.66-75.78;
cholic acid: 16.56-22.68;
deoxycholic acid: 1.43 to 2.09;
and/or, the unit: either one of μmol and μmol/L.
The application of the composition is as follows: taking the composition as a reference substance, and detecting the contents of the above four substances in a sample, thereby predicting that an organism is not sensitive to the toxicity of irinotecan chemotherapy.
Example 5:
a sensitive composition for predicting the chemotherapeutic toxicity of irinotecan, comprising the following components in parts by weight:
glycocholic acid: 2.04 to 2.86;
phenylalanine: 55.23 to 69.07;
lysine: 264.31-312.01;
tryptophan: 53.76 to 65.62;
and/or, the unit: either one of μmol and μmol/L.
The application of the composition is as follows: taking the composition as a reference substance, and detecting the contents of the above four substances in a sample, thereby predicting the sensitivity of organisms to the toxicity of irinotecan chemotherapy.
Example 6:
a non-sensitive composition for predicting the chemotherapeutic toxicity of irinotecan, comprising the following components in parts by weight:
glycocholic acid: 1.47-2.25;
phenylalanine: 62.66-72.78;
lysine: 303.39-349.95;
tryptophan: 60.43-71.93;
and/or, the unit: either one of μmol and μmol/L.
The application of the composition is as follows: taking the composition as a reference substance, and detecting the contents of the above four substances in a sample, thereby predicting that an organism is not sensitive to the toxicity of irinotecan chemotherapy.
Claims (7)
1. A composition for predicting sensitivity to irinotecan chemotherapeutic toxicity, comprising: the proportion of each component is
Glycocholic acid: 2.04 to 2.86;
phenylalanine: 55.23 to 69.07;
cholic acid: 24.44-34.12;
deoxycholic acid: 1.72 to 2.52;
unit: either one of μmol and μmol/L.
2. A composition for predicting non-susceptibility to chemotherapeutic toxicity to irinotecan, comprising: the proportion of each component is
Glycocholic acid: 1.47-2.25;
phenylalanine: 62.66-75.78;
cholic acid: 16.56-22.68;
deoxycholic acid: a non-sensitive group is 1.43-2.09;
unit: either one of μmol and μmol/L.
3. A composition for predicting sensitivity to irinotecan chemotherapeutic toxicity, comprising: the proportion of each component is
Glycocholic acid: 2.04 to 2.86;
phenylalanine: 55.23 to 69.07;
lysine: 264.31-312.01;
tryptophan: 53.76 to 65.62 of a sensitive group;
unit: either one of μmol and μmol/L.
4. A composition for predicting sensitivity to irinotecan chemotherapeutic toxicity, comprising: the proportion of each component is
Glycocholic acid: 1.47-2.25;
phenylalanine: 62.66-72.78;
lysine: 303.39-349.95;
tryptophan: 60.43-71.93;
unit: either one of μmol and μmol/L.
5. Use of a composition according to claims 1-4 for the preparation of a medicament, characterized in that: use in the preparation of a biomarker for predicting the degree of delayed diarrhea and myelosuppressive sensitivity following irinotecan administration.
6. Use of a composition according to claims 1-4 for the preparation of a medicament, characterized in that: use in the preparation of a biomarker for predicting tardive diarrhea following irinotecan administration.
7. Use of a composition according to claims 1-4 for the preparation of a medicament, characterized in that: use in the preparation of a biomarker for predicting myelosuppression following irinotecan administration.
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