CN102608052B - System for diagnosis of leukemia - Google Patents
System for diagnosis of leukemia Download PDFInfo
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- CN102608052B CN102608052B CN201210041131.5A CN201210041131A CN102608052B CN 102608052 B CN102608052 B CN 102608052B CN 201210041131 A CN201210041131 A CN 201210041131A CN 102608052 B CN102608052 B CN 102608052B
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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 for diagnosing leukemic system in particular to one.
Background technology
Leukaemia is the malignant tumour of hemopoietic system, be again " leukemia ", in the incidence of disease of paediatrics malignant tumour, occupy first, its mortality ratio cause children and the malignant tumour of the death of adult below 35 years old 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 6-8 position in various tumor incidences at present.
Leukemic pathogeny is the malfunction due to hematopoietic tissue in the marrow of the variation formation of DNA in cell.Stem cell in marrow can be manufactured red blood cell and 7400/1 cubic millimeter white blood cell of approximately 5,400,000/1 cubic millimeter every day, and leukemia patient excessive production white blood cell and most leucocytes are jejune, for juvenile cell, its survival period is longer than under normal circumstances.Although this quantity of leucocyte is very large, but can not be anti-infective as normal leucocyte.This leukocytic increasing in body, meeting directly affect the function of some vitals, affects the output of normal health haemocyte.Due to tumour cell neoplasm, suppress the generation of red blood cell and blood platelet hemostasis, even do not have enough normal leucocytes anti-infective, be easy to be scratched, hemorrhage, infect.And too much leucocyte also harms other work of marrow, 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, in main calcaneum marrow, the destruction of hematopoiesis function is relevant, as continued fever, infects and does not prolongedly heal, anaemia, petechial hemorrhage etc.; Also have blood cell to wear and ooze the symptom that tissue causes, as enlargement of lymph nodes, ostalgia or arthralgia, gum swelling, hepatosplenomegaly etc.
Leukemic diagnosis is very difficult, generally need to comprehensively judge and could finally make a definite diagnosis in conjunction with clinical manifestation, physical examination and laboratory assay three aspects:.White blood cell count(WBC) can reflect the risk that hemopoietic function of bone marrow is abnormal to a certain extent, but only this inspection can not reach the needs of making a definite diagnosis far away.Typically, make a definite diagnosis leukaemia, it is all necessary that periphery blood examination and bone marrow aspiration sampling detect.
But due to bone marrow aspiration and be difficult for being accepted by ordinary person, therefore clinical means that a kind of leukaemia Risk-warning cannot be provided at present, have also hindered leukemic early detection and interventional therapy simultaneously greatly.In the time that patient perceives, often enter the middle and later periods of leukaemia morbidity.In addition, the small residual of cancer cells in blood is an important indicator of prognosis, for the accurate detection of minimal residual disease, to instructing next step treatment of doctor significant.But the sensitivity that clinical conventional molecular biology for detection (PCR) can reach is at present only for every 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, for centuries, follows its unique physics and chemistry, optical property to be found, and is used as gradually developer, photosensitizer, nonlinear optical material etc.
Summary of the invention
It is a kind of for diagnosing leukemic system that one aspect of the present invention provides, and described system comprises kit, uv-visible absorption spectroscopy instrument and fluorescence spectrophotometer.
According to system of the present invention, wherein said kit comprises reagent I and reagent II, and wherein reagent I is that pH value is 6～8 damping fluid, and reagent II is the compound shown in following formula I
Wherein: R
1for C
1-C
6the phenyl that replaces of alkyl, phenyl, alkyl; R
2, R
3, R
4and R
5independently selected from H or C
1-C
6alkyl, or R
2and R
3together with the carbon atom connecting with them, form the ring structure of 5 yuan to 7 yuan, or R
4and R
5together with the carbon atom connecting with them, form the ring structure of 5 yuan to 7 yuan; R
6and R
7independently selected from C
1-C
6alkyl; Y is 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 recording in 547-551, also can prepare with additive method well known in the art.
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
5independently 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 being connected with them can form saturated rings structure or the unsaturated ring structure of 5 yuan to 7 yuan, and described 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 being connected with them can form saturated rings structure or the unsaturated ring structure of 5 yuan to 7 yuan, and described 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:
The whole blood DNA that extracts experimenter, is dissolved in the whole blood DNA of extraction in reagent I and obtains DNA solution A, and wherein reagent I is as defined above;
By solution A at the temperature of 80 DEG C～95 DEG C, preferably at the temperature of 85 DEG C～95 DEG C, heat 2 to 15 minutes, so that the DNA sex change in solution A, that is, making double-stranded DNA depolymerization is single stranded form, then, make at the temperature of solution A below 20 DEG C, preferably at the temperature below 10 DEG C, more preferably rapid quenching at the temperature of 4 DEG C, and under quenching temperature hold over night, obtain solution B;
The hyperfluorescenceZeng Yongminggaoyingguang intensity of measuring the fluorescence emission peak of solution B within the scope of 570-580nm by fluorescence spectrophotometer, is designated as Fl
m 0;
Appropriate solution B is mixed to prepare solution C with appropriate reagent I and reagent II, and described reagent I and reagent II are as defined above; Wherein the addition of solution B depends on that the solution C that uses uv-visible absorption spectroscopy instrument mensuration is in the absorbance at 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 the concentration of solution C Chinese style I compound, and the compound concentration of solution C Chinese style I is 1uM to 100uM;
Measure respectively the following index of solution C:
The strongest absorbance of the absorption peak within the scope of 550-560nm, is designated as A
m;
The strongest absorbance of the absorption peak within the scope of 515-525nm, is designated as A
d;
The hyperfluorescenceZeng Yongminggaoyingguang intensity of the fluorescence emission peak within the scope of 570-580nm, is designated as Fl
m;
The hyperfluorescenceZeng Yongminggaoyingguang intensity of the fluorescence emission peak within the scope of 605-615nm, is designated as Fl
d;
According to above measurement 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) is less than 5.2, can assert that experimenter suffers from leukaemia.
The method according to this invention, wherein, in the step of preparation solution C, can directly mix to prepare solution C with reagent I box reagent II by solution B; Also can first reagent II be dissolved in reagent I, then the solution obtaining is mixed to prepare solution C with solution B.
Compared with prior art, be provided by the inventionly for the advantage of diagnosing leukemic kit and using method thereof and diagnostic system:
Detected object is experimenter's peripheral blood, does not need to carry out bone marrow aspiration and can obtain diagnostic result accurately, 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 the more than 100 times of traditional single molecule probe;
High specific, directly for the DNA extract in whole blood, the about 85-97% of leukemia diagnosis accuracy rate;
Only need a step dyeing, without washing, simple to operate, detection time is short;
Instrument highly versatile, only needs to use routine clinical detecting instrument (uv-visible absorption spectroscopy instrument or fluorescence spectrophotometer);
Brief description of the drawings
Fig. 1 is the statistical graph of MD (A) index that represents the experimenter who obtains according to one embodiment of the invention;
Fig. 2 is the statistical graph of MD (FI) index that represents the experimenter who obtains according to one embodiment of the invention.
Embodiment
In the mode of specific embodiment, the present invention is described in more detail below with reference to accompanying drawings, but be to be understood that, the present invention can implement in a different manner, it is only in order to make this instructions fully with complete that these embodiment are provided, so that those skilled in the art can implement the present invention, scope of the present invention should not be defined as listed specific embodiment herein.
This tests all blood samples is all by Contract Research Organization (Contract Research Organization, CRO), obtains after signing formal clinical testing contract with hospital.The test of all blood samples is all passed through discussion through Hospital Ethical Committee.
Embodiment 1
Extract 19 health volunteers and 33 leukaemics' whole blood DNA, the PBS damping fluid that is 6.0 with pH respectively by the whole blood DNA of extraction dissolves, and obtains 52 parts of DNA solution A.
Every part of solution A is heated 15 minutes in the water-bath of 80 DEG C, then rapid quenching in the refrigerator of 4 DEG C, and in the refrigerator of 4 DEG C hold over night, obtain 52 parts of solution B.
Measure the hyperfluorescenceZeng Yongminggaoyingguang intensity Fl of every part of solution B fluorescence emission peak within the scope of 570-580nm by fluorescence spectrophotometer
m 0.
Getting appropriate solution B and appropriate pH is 6.0 PBS damping fluid and the compounds that are
preparation solution C, making 52 parts of prepared solution C is 0.1-0.3 in the absorbance at 260nm place, in solution C, the concentration of compound is 1uM.
Then measure respectively the following index of each solution C:
The strongest absorbance of the absorption peak within the scope of 550-560nm, is designated as A
m;
The strongest absorbance of the absorption peak within the scope of 515-525nm, is designated as A
d;
The hyperfluorescenceZeng Yongminggaoyingguang intensity of the fluorescence emission peak within the scope of 570-580nm, is designated as Fl
m;
The hyperfluorescenceZeng Yongminggaoyingguang intensity of the fluorescence emission peak within the scope of 605-615nm, is designated as Fl
d;
According to above measurement result, calculate following index:
MD(A)＝A
M/A
D；
MD(Fl)＝Fl
M/Fl
D；
MD (A) index to 52 parts of solution C by obtaining with upper type is carried out statistical study, and result as shown in Figure 1.MD (FI) index to 52 parts of solution C by obtaining with upper type is carried out respectively statistical study, and result 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, accuracy rate of diagnosis is 87.9%), only 10.5% health volunteer's blood sample MD (A) index is less than 1.4 (, 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, accuracy rate of diagnosis is 97.0%), only % health volunteer's blood sample MD (Fl) index is greater than 5.2 (, false positive rate is 5.3%).Therefore, adopt the diagnostic mode of this fact Example easily normal subjects and leukaemic's blood sample to be made a distinction.
Embodiment 2
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, use the PBS damping fluid that pH is 6.5, at 85 DEG C, heat 8 minutes then rapid quenchings at 10 DEG C, 52 parts of prepared solution C are 0.1-0.3 in the absorbance at 260nm place, and the compound using is
Compound concentration is 10uM
Testing result: adopting the Detection accuracy of MD (A) index is 93.94%, and false positive rate is 10.52%; Adopting the Detection accuracy of MD (Fl) index is 90.91%, and false positive rate is 0%.
Embodiment 3
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, use the PBS damping fluid that pH is 7.0, at 90 DEG C, heat 5 minutes then rapid quenchings at 5 DEG C, 52 parts of prepared solution C are 0.2-0.7 in the absorbance at 260nm place, and the compound that uses is
The concentration of compound is 20uM.
Testing result: adopting the Detection accuracy of MD (A) index is 96.97%, and false positive rate is 5.26%; Adopting the Detection accuracy of MD (Fl) index is 93.94%, and false positive rate is 5.26%.
Embodiment 4
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, the PBS damping fluid that uses pH to be, at 95 DEG C, heat 4 minutes then rapid quenchings at 10 DEG C, 52 parts of prepared solution C are 0.5-0.9 in the absorbance at 260nm place, and the compound that uses is
The concentration of compound is 40uM.
Testing result: adopting the Detection accuracy of MD (A) index is 87.88%, and false positive rate is 15.79%; Adopting the Detection accuracy of MD (Fl) index is 93.94%, and false positive rate is 15.79%.
Embodiment 5
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, the PBS damping fluid that uses pH to be, at 95 DEG C, heat 4 minutes then rapid quenchings at 5 DEG C, 52 parts of prepared solution C are 0.05-0.4 in the absorbance at 260nm place, and the compound that uses is
The concentration of compound is 50uM.
Testing result: adopting the Detection accuracy of MD (A) index is 90.91%, and false positive rate is 10.52%; Adopting the Detection accuracy of MD (Fl) index is 96.97%, and false positive rate is 5.26%.
Embodiment 6
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, the PBS damping fluid that uses pH to be, at 90 DEG C, heat 5 minutes then rapid quenchings at 4 DEG C, 52 parts of prepared solution C are 0.2-0.5 in the absorbance at 260nm place, and the compound that uses is
The concentration of compound is 70uM.
Testing result: adopting the Detection accuracy of MD (A) index is 93.94%, and false positive rate is 5.26%; Adopting the Detection accuracy of MD (Fl) index is 96.97%, and false positive rate is 0%.
Embodiment 7
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, the PBS damping fluid that uses pH to be, at 90 DEG C, heat 5 minutes then rapid quenchings at 4 DEG C, 52 parts of prepared solution C are 0.1-0.3 in the absorbance at 260nm place, and the compound that uses is
The concentration of compound is 100uM.
Testing result: adopting the Detection accuracy of MD (A) index is 90.91%, and false positive rate is 15.79%; Adopting the Detection accuracy of MD (Fl) index is 90.91%, and false positive rate is 10.52%.
Comparative example
Adopt the step identical with embodiment 1 to detect above 52 experimenters' whole blood DNA, difference is, uses compound
obtain solution C, the concentration of this compound in solution C is 50uM.
Testing result: adopting the Detection accuracy of MD (A) index is 60.61%, and false positive rate is 63.16%; Adopting the Detection accuracy of MD (Fl) index is 69.70%, and false positive rate is 36.84%.
As can be seen here, in the time using this compound, health volunteer and leukaemic's blood sample can not be distinguished.
Although described the present invention in detail in the mode of specific embodiment, but be apparent that to those skilled in the art, in the case of not departing from the spirit and scope of the present invention that appended claims limits, can carry out variations and modifications to the present invention, these variations and amendment comprise within the scope of the invention equally.
Claims (8)
1. for diagnose a leukemic system, described system to comprise reagent I and reagent II and uv-visible absorption spectroscopy instrument and fluorescence spectrophotometer by peripheral blood, wherein said reagent I is that pH value is 6～8 damping fluid, and described reagent II is the compound of formula I:
Wherein: R
1for C
1-C
6the phenyl that replaces of alkyl, phenyl, alkyl; R
2and R
3independently selected from H or C
1-C
6alkyl, or R
2and R
3together with the carbon atom connecting with them, form the ring structure of 5 yuan to 7 yuan; R
4and R
5independently selected from H or C
1-C
6alkyl, or R
4and R
5together with the carbon atom connecting with them, form the ring structure of 5 yuan to 7 yuan; R
6and R
7independently selected from C
1-C
6alkyl; Y is halogen; X
1, X
2independently be selected from C, O, S, Se, Te.
2. the system as claimed in claim 1, wherein said damping fluid is the damping fluid that contains monovalent metallic ion.
3. system as claimed in claim 1 or 2, 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 as claimed in 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 as claimed in claim 1, wherein R
2, R
3, R
4and R
5independently 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 as claimed in claim 1, wherein at R
2and R
3the carbon atom being connected with them forms in the situation of ring structure, and described ring structure is saturated rings or unsaturated ring, contains or do not contain N or S atom.
7. the system as claimed in claim 1, wherein at R
4and R
5the carbon atom being connected with them forms in the situation of ring structure, and described ring structure is saturated rings or unsaturated ring, contains or do not contain N or S atom.
8. the system as claimed in 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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| 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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| CN101946171A (en) * | 2007-12-14 | 2011-01-12 | 拜奥蒂乌姆股份有限公司 | Fluorescent compounds |
| WO2011151287A1 (en) * | 2010-05-31 | 2011-12-08 | Ludwig-Maximilians-Universität München | Naphthocyanines for use as contrast agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101587066B (en) * | 2008-05-23 | 2011-03-30 | 中国科学院化学研究所 | Novel use of cyanine dye in detection of G-quadruplex DNA |
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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 |
| WO2011151287A1 (en) * | 2010-05-31 | 2011-12-08 | Ludwig-Maximilians-Universität München | Naphthocyanines for use as contrast agents |
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| Cyanines during the 1990s: A Review;Amaresh Mishra etal;《Chem. Rev》;20000905;第100卷(第6期);第1992页左栏第21行至左栏结尾，右栏第2段1-9行和第3段，以及结构式14、34、154 * |
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