CN102608052A - System for diagnosis of leukemia - Google Patents
System for diagnosis of leukemia Download PDFInfo
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- CN102608052A CN102608052A CN2012100411315A CN201210041131A CN102608052A CN 102608052 A CN102608052 A CN 102608052A CN 2012100411315 A CN2012100411315 A CN 2012100411315A CN 201210041131 A CN201210041131 A CN 201210041131A CN 102608052 A CN102608052 A CN 102608052A
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Abstract
The invention provides a system and a method for diagnosis of leukemia. Peripheral blood of a subject is taken as a testing object, bone marrow puncture is not needed to be performed, but accurate diagnostic results can be obtained. The trauma to a patient is small, the sensitivity is high, the specificity is high, the method only requires staining without washing, the operation is simple, the testing time is short, and the reagent kit and the method facilitate large-scale screening and follow-up treatment.
Description
Technical field
The invention belongs to field of medicaments, be used to diagnose leukemic system in particular to a kind of.
Background technology
Leukaemia is a malignant tumor of hematopoiesis system; Be " leukemia " again; In the incidence of disease of paediatrics malignant tumour, occupy first, its mortality ratio cause children and malignant tumour that adult below 35 years old is dead in row the first, be to threaten children and the modal malignant tumour of between twenty and fifty life and health.The leukemic incidence of disease of China occupies the 6-8 position in various tumor incidences at present.
Leukemic pathogeny is because the malfunction of hematopoietic tissue in the marrow that the variation of DNA forms in the cell.Stem cell in the marrow can be made about 5,400,000/1 cubic millimeter red blood cell and 7400/1 cubic millimeter white blood cell every day; And leukemia patient excessive production white blood cell and most leucocytes are jejune; Be juvenile cell, its survival period is than long under the normal condition.Although this quantity of leucocyte is very big, however can not be anti-infective as normal leucocyte.This leukocytic increasing in the body, meeting directly influence the function of some vitals, influences the output of normal health haemocyte.Because the tumour cell neoplasm suppresses the generation of red blood cell and blood platelet hemostasis, even do not have enough normal leucocytes anti-infective, be easy to receive scratch, hemorrhage, infection.And too much leucocyte also harms other work of marrow, and this function that makes marrow produce other haemocyte reduces.
Leukaemia can be spread to lymph node, spleen, liver, central nervous system other organ of unifying, and produces different symptoms.These symptoms, the destruction of hematopoiesis function is relevant in the main calcaneum marrow, as continuing fever, infects and does not prolongedly heal anaemia, petechial hemorrhage etc.; Also have blood cell to wear and ooze the symptom that tissue causes, like enlargement of lymph nodes, ostalgia or arthralgia, gum swelling, hepatosplenomegaly etc.
Leukemic diagnosis is difficulty very, generally needs to combine clinical manifestation, physical examination and laboratory assay three aspects comprehensively to judge and could finally make a definite diagnosis.White blood cell count(WBC) can reflect the risk that hemopoietic function of bone marrow is unusual to a certain extent, but only this inspection can not reach the needs of making a definite diagnosis far away.Usually, make a definite diagnosis leukaemia, it all is necessary that periphery blood examination and bone marrow aspiration sampling detect.
But because bone marrow aspiration also is difficult for being accepted by ordinary person, the therefore present clinical means that a kind of leukaemia Risk-warning can't be provided have also hindered leukemic early detection and PCI simultaneously greatly.When patient perceives, often got into the middle and later periods of leukaemia morbidity.In addition, the small residual of cancer cell is an important indicator of prognosis in the blood, and be for the accurate detection of minimal residual disease, significant to next step treatment of instructing the doctor.Yet the sensitivity that present clinical molecular Biological Detection method (PCR) commonly used can reach is merely per 10
4Individual haemocyte contains a cancer cell, has limited the detection level to minimal residual disease.
Cyanine dyes is a kind of common dyes, has unique photaesthesia character, since the several centuries, has followed its unique physics and chemistry, optical property to come to light, and is used as developer gradually, photosensitizer, nonlinear optical material etc.
Summary of the invention
One aspect of the present invention provides a kind of leukemic system that is used to diagnose, and said system comprises kit, uv-visible absorption spectroscopy appearance and XRF.
According to system of the present invention, wherein said kit comprises reagent I and reagent II, and wherein reagent I is that the pH value is 6～8 damping fluid, and reagent II is the compound shown in the following formula I
Wherein: R
1Be C
1-C
6The substituted phenyl of alkyl, phenyl, alkyl; R
2, R
3, R
4And R
5Be independently selected from H or C
1-C
6Alkyl, perhaps R
2And R
3Form 5 yuan to 7 yuan ring structure with the carbon atom that they connected, perhaps R
4And R
5Form 5 yuan to 7 yuan ring structure with the carbon atom that they connected; R
6And R
7Be independently selected from C
1-C
6Alkyl; Y is a halogen; X
1, X
2Independently be selected from C, O, S, Se, Te.
According to system of the present invention, wherein for the compound of formula I, its preparation method can be with reference to Leslie G.S.; Brooker and Frank L.W., JACS, 1935; The synthetic route of putting down in writing among the 547-551 also can use additive method well known in the art to prepare.
According to system of the present invention; Wherein reagent I is preferably the damping fluid that contains monovalent metallic ion of pH6～8, includes but not limited to sodium phosphate-dibastic sodium phosphate damping fluid, potassium phosphate-potassium hydrogen phosphate damping fluid, barbital sodium-hydrochloride buffer or citric acid-sodium citrate damping fluid.
According to system of the present invention, wherein C
1-C
6Alkyl be that carbon number is the alkyl of 1 to 6 straight or branched, include but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl, the tert-butyl group, amyl group, isopentyl, n-hexyl or isohesyl etc.
According to system of the present invention, wherein R
1Be selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl, the tert-butyl group, amyl group, isopentyl, n-hexyl, isohesyl, phenyl, aminomethyl phenyl or 3,5-dimethylphenyl.
According to system of the present invention, wherein R
2, R
3, R
4And R
5Be independently selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl, the tert-butyl group, amyl group, isopentyl, n-hexyl or isohesyl.
According to system of the present invention, wherein R
2And R
3The carbon atom that is connected with them can form 5 yuan to 7 yuan saturated rings structure or unsaturated ring structure, and said ring structure can contain or not contain N or S atom.
According to system of the present invention, wherein R
4And R
5The carbon atom that is connected with them can form 5 yuan to 7 yuan saturated rings structure or unsaturated ring structure, and said ring structure can contain or not contain N or S atom.
According to system of the present invention, wherein Y is preferably fluorine, chlorine, bromine or iodine.
The leukemic method of a kind of diagnosis of another aspect of the present invention said method comprising the steps of:
Extract experimenter's whole blood DNA, the whole blood DNA that extracts be dissolved in obtain dna solution A among the reagent I, wherein reagent I such as preamble definition;
Solution A under 80 ℃～95 ℃ temperature, was preferably heated 2 to 15 minutes under 85 ℃～95 ℃ temperature, so that the DNA sex change in the solution A; That is, making the double-stranded DNA depolymerization is single stranded form, then; Make solution A under the temperature below 20 ℃, preferably under the temperature below 10 ℃, more preferably rapid quenching under 4 ℃ temperature; And under quenching temperature hold over night, obtain solution B;
Measure the hyperfluorescence intensity of the fluorescence emission peak of solution B in the 570-580nm scope with XRF, be designated as Fl
M 0
An amount of solution B is mixed with an amount of reagent I and reagent II with the preparation solution C, said reagent I and reagent II such as preamble definition; Wherein the addition of solution B depends on the absorbance of the solution C of use uv-visible absorption spectroscopy appearance mensuration at the 260nm place; Solution C in the absorbance at 260nm place preferably in 0.01 to 1 scope; More preferably in the scope of 0.1-0.3; The addition of reagent I and reagent II depends on solution C Chinese style I compound concentrations, and the compound concentration of solution C Chinese style I is 1uM to 100uM;
Measure the following index of solution C respectively:
The strongest absorbance of the absorption peak in the 550-560nm scope is designated as A
M
The strongest absorbance of the absorption peak in the 515-525nm scope is designated as A
D
The hyperfluorescence intensity of the fluorescence emission peak in the 570-580nm scope is designated as Fl
M
The hyperfluorescence intensity of the fluorescence emission peak in the 605-615nm scope is designated as Fl
D
According to above mensuration result, calculate following index:
MD(A)＝A
M/A
D；
MD(Fl)＝Fl
M/Fl
D；
If MD (A) is less than 1.4, or MD (Fl) can assert then that less than 5.2 the experimenter suffers from leukaemia.
According to the method for the invention, wherein in the step of preparation solution C, can solution B directly be mixed with reagent I box reagent II and prepare solution C; Also can earlier reagent II be dissolved among the reagent I, the solution that obtains be mixed with solution B prepare solution C again.
Compared with prior art, provided by the inventionly be used to diagnose the advantage of leukemic kit and method of application and diagnostic system to be:
Detected object is experimenter's a peripheral blood, need not carry out bone marrow aspiration and can obtain diagnostic result accurately, and is not only little to patient's wound, be more convenient for extensive examination and tracking treatment;
High sensitivity, the employing supermolecule fluorescence probe of novelty, sensitivity is more than 100 times of traditional unimolecule probe;
High specific is directly to the DNA extraction thing in the whole blood, the about 85-97% of leukemia diagnosis accuracy rate;
Only need step dyeing, do not have washing, simple to operate, detection time is short;
The instrument highly versatile only need use routine clinical detecting instrument (uv-visible absorption spectroscopy appearance or XRF);
Description of drawings
Fig. 1 is the statistical graph of the experimenter's that obtains according to one embodiment of the invention of expression MD (A) index;
Fig. 2 is the statistical graph of the experimenter's that obtains according to one embodiment of the invention of expression MD (FI) index.
Embodiment
Come to describe in more detail the present invention with the mode of specific embodiment below with reference to accompanying drawings; But be to be understood that; The present invention can implement in a different manner; It only is in order to make this instructions fully with complete that these embodiment are provided, so that those skilled in the art can embodiment of the present invention, scope of the present invention should not be defined as the listed specific embodiment of this paper.
All blood samples of this experiment all are that (Contract Research Organization CRO), obtains after signing formal clinical testing contract with hospital through the Research on Contract tissue.The test of all blood samples is all passed through discussion through Ethics Committee of hospital.
Extract 19 health volunteers and 33 leukaemics' whole blood DNA, it is 6.0 PBS damping fluid dissolving that the whole blood DNA that extracts is used pH respectively, obtains 52 parts of dna solution A.
Every part of solution A was heated 15 minutes in 80 ℃ water-bath, rapid quenching in 4 ℃ refrigerator then, and in 4 ℃ refrigerator hold over night, obtain 52 parts of solution B.
Measure the hyperfluorescence intensity Fl of the fluorescence emission peak of every part of solution B in the 570-580nm scope with XRF
M 0
Get an amount of solution B and an amount of pH and be 6.0 be PBS damping fluid and compound
preparation solution C; Making the prepared absorbance of 52 parts of solution C at the 260nm place is 0.1-0.3, and compound concentrations is 1uM in the solution C.
Measure the following index of each solution C then respectively:
The strongest absorbance of the absorption peak in the 550-560nm scope is designated as A
M
The strongest absorbance of the absorption peak in the 515-525nm scope is designated as A
D
The hyperfluorescence intensity of the fluorescence emission peak in the 570-580nm scope is designated as Fl
M
The hyperfluorescence intensity of the fluorescence emission peak in the 605-615nm scope is designated as Fl
D
According to above mensuration result, calculate following index:
MD(A)＝A
M/A
D；
MD(Fl)＝Fl
M/Fl
D；
MD (A) index to through 52 parts of solution C obtaining with upper type is carried out statistical study, and the result is as shown in Figure 1.MD (FI) index to through 52 parts of solution C obtaining with upper type is carried out statistical study respectively, and the result is as shown in Figure 2.
With reference to Fig. 1, blood sample MD (A) index that can clearly be seen that 87.9% leukaemic is less than 1.4 (that is, accuracy rate of diagnosis is 87.9%), and only 10.5% health volunteer's blood sample MD (A) index is less than 1.4 (that is, false positive rate is 10.5%); With reference to Fig. 2, blood sample MD (Fl) index that can clearly be seen that 97.0% leukaemic is less than 5.2 (that is, accuracy rate of diagnosis is 97.0%), and only % health volunteer's blood sample MD (Fl) index is greater than 5.2 (that is, false positive rate is 5.3%).Therefore, adopt the diagnostic mode of ability instance can be easily normal subjects and leukaemic's blood sample to be made a distinction.
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; Use pH is 6.5 PBS damping fluid; Heat 8 minutes down then at 10 ℃ of following rapid quenchings at 85 ℃, the prepared absorbance of 52 parts of solution C at the 260nm place is 0.1-0.3, and employed compound does
Compound concentration is 10uM
Testing result: adopting the detection accuracy rate of MD (A) index is 93.94%, and false positive rate is 10.52%; Adopting the detection accuracy rate of MD (Fl) index is 90.91%, and false positive rate is 0%.
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; Use pH is 7.0 PBS damping fluid; Heat 5 minutes down then at 5 ℃ of following rapid quenchings at 90 ℃, the prepared absorbance of 52 parts of solution C at the 260nm place is 0.2-0.7, and the compound that uses does
Compound concentrations is 20uM.
Testing result: adopting the detection accuracy rate of MD (A) index is 96.97%, and false positive rate is 5.26%; Adopting the detection accuracy rate of MD (Fl) index is 93.94%, and false positive rate is 5.26%.
Embodiment 4
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; The PBS damping fluid that uses pH to be; Heat 4 minutes down then at 10 ℃ of following rapid quenchings at 95 ℃, the prepared absorbance of 52 parts of solution C at the 260nm place is 0.5-0.9, and the compound that uses does
Compound concentrations is 40uM.
Testing result: adopting the detection accuracy rate of MD (A) index is 87.88%, and false positive rate is 15.79%; Adopting the detection accuracy rate of MD (Fl) index is 93.94%, and false positive rate is 15.79%.
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; The PBS damping fluid that uses pH to be; Heat 4 minutes down then at 5 ℃ of following rapid quenchings at 95 ℃, the prepared absorbance of 52 parts of solution C at the 260nm place is 0.05-0.4, and the compound that uses does
Compound concentrations is 50uM.
Testing result: adopting the detection accuracy rate of MD (A) index is 90.91%, and false positive rate is 10.52%; Adopting the detection accuracy rate of MD (Fl) index is 96.97%, and false positive rate is 5.26%.
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; The PBS damping fluid that uses pH to be; Heat 5 minutes down then at 4 ℃ of following rapid quenchings at 90 ℃, the prepared absorbance of 52 parts of solution C at the 260nm place is 0.2-0.5, and the compound that uses does
Compound concentrations is 70uM.
Testing result: adopting the detection accuracy rate of MD (A) index is 93.94%, and false positive rate is 5.26%; Adopting the detection accuracy rate of MD (Fl) index is 96.97%, and false positive rate is 0%.
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; The PBS damping fluid that uses pH to be; Heat 5 minutes down then at 4 ℃ of following rapid quenchings at 90 ℃, the prepared absorbance of 52 parts of solution C at the 260nm place is 0.1-0.3, and the compound that uses does
Compound concentrations is 100uM.
Testing result: adopting the detection accuracy rate of MD (A) index is 90.91%, and false positive rate is 15.79%; Adopting the detection accuracy rate of MD (Fl) index is 90.91%, and false positive rate is 10.52%.
Comparative Examples
Adopt the step identical that above 52 experimenters' whole blood DNA is detected with embodiment 1; Difference is; Use compound
obtain solution C, the concentration of this compound in solution C is 50uM.
Testing result: adopting the detection accuracy rate of MD (A) index is 60.61%, and false positive rate is 63.16%; Adopting the detection accuracy rate of MD (Fl) index is 69.70%, and false positive rate is 36.84%.
This shows, when using this compound, can not health volunteer and leukaemic's blood sample be distinguished.
Though the mode with specific embodiment has described the present invention in detail; But be apparent that to those skilled in the art; Under the situation of the spirit and scope of the present invention that do not break away from appended claims and limited; Can carry out variations and modifications to the present invention, these variations and modification comprise within the scope of the invention equally.
Claims (8)
1. one kind is used to diagnose leukemic system, and said system comprises reagent I and reagent II and uv-visible absorption spectroscopy appearance and XRF, and wherein said reagent I is that the pH value is 6～8 damping fluid, and said reagent II is the compound of formula I:
Wherein: R
1Be C
1-C
6The substituted phenyl of alkyl, phenyl, alkyl; R
2, R
3, R
4And R
5Be independently selected from H or C
1-C
6Alkyl, perhaps R
2And R
3Form 5 yuan to 7 yuan ring structure with the carbon atom that they connected, perhaps R
4And R
5Form 5 yuan to 7 yuan ring structure with the carbon atom that they connected; R
6And R
7Be independently selected from C
1-C
6Alkyl; Y is a halogen; X
1, X
2Independently be selected from C, O, S, Se, Te.
2. the system of claim 1, wherein said damping fluid is the damping fluid that contains monovalent metallic ion.
3. according to claim 1 or claim 2 system, wherein said damping fluid is selected from sodium phosphate-dibastic sodium phosphate damping fluid, potassium phosphate-potassium hydrogen phosphate damping fluid, barbital sodium-hydrochloride buffer or citric acid-sodium citrate damping fluid.
4. the system of claim 1, wherein R
1Be selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl, the tert-butyl group, amyl group, isopentyl, n-hexyl, isohesyl, phenyl, aminomethyl phenyl or 3,5-dimethylphenyl.
5. the system of claim 1, wherein R
2, R
3, R
4And R
5Be independently selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl, the tert-butyl group, amyl group, isopentyl, n-hexyl or isohesyl.
6. the system of claim 1 is wherein at R
2And R
3The carbon atom that is connected with them forms under the situation of ring structure, and said ring structure is saturated rings or unsaturated ring, contains or do not contain N or S atom.
7. the system of claim 1 is wherein at R
4And R
5The carbon atom that is connected with them forms under the situation of ring structure, and said ring structure is saturated rings or unsaturated ring, contains or do not contain N or S atom.
8. the system of claim 1, wherein Y is fluorine, chlorine, bromine or iodine.
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|---|---|---|---|
| CN201210041131.5A CN102608052B (en) | 2012-02-21 | 2012-02-21 | System for diagnosis of leukemia |
| PCT/CN2013/071728 WO2013123882A1 (en) | 2012-02-21 | 2013-02-21 | Method, kit and system for diagnosis of leukemia |
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|---|---|---|---|
| CN201210041131.5A CN102608052B (en) | 2012-02-21 | 2012-02-21 | System for diagnosis of leukemia |
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| CN102608052B CN102608052B (en) | 2014-11-05 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013123882A1 (en) * | 2012-02-21 | 2013-08-29 | 中国科学院化学研究所 | Method, kit and system for diagnosis of leukemia |
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2012
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| US5268486A (en) * | 1986-04-18 | 1993-12-07 | Carnegie-Mellon Unversity | Method for labeling and detecting materials employing arylsulfonate cyanine dyes |
| CN101024730A (en) * | 2006-02-23 | 2007-08-29 | 中国科学院化学研究所 | Method for conducting chiral induction to non-chiral cyanine dye aggregate using human serum protein |
| CN101946171A (en) * | 2007-12-14 | 2011-01-12 | 拜奥蒂乌姆股份有限公司 | Fluorescent compounds |
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| WO2013123882A1 (en) * | 2012-02-21 | 2013-08-29 | 中国科学院化学研究所 | Method, kit and system for diagnosis of leukemia |
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