CN103627809A - Medication selection and curative effect detection reagent kit of glivec assistance treatment of gastrointestinal stromal tumor - Google Patents
Medication selection and curative effect detection reagent kit of glivec assistance treatment of gastrointestinal stromal tumor Download PDFInfo
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- CN103627809A CN103627809A CN201310673737.5A CN201310673737A CN103627809A CN 103627809 A CN103627809 A CN 103627809A CN 201310673737 A CN201310673737 A CN 201310673737A CN 103627809 A CN103627809 A CN 103627809A
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Abstract
The invention discloses a medication selection and curative effect detection reagent kit of glivec assistance treatment of a gastrointestinal stromal tumor, and relates to a detection reagent kit for molecular biology and medicine. The kit comprises BCR-ABL (Abelson proto-oncogene-breakpoint cluster region) gene PCR (polymerase chain reaction) liquid, Taq (thermus aquaticus) enzyme, a control, a matched multiplex PCR amplification procedure and a wrappage. The kit helps to select appropriate drugs for the gastrointestinal stromal tumor and evaluates a curative effect of the individual glivec assistance treatment of the gastrointestinal stromal tumor by detecting whether a glivec drug target site BCR-ALB fusion gene exists, and is applicable to multiple fields of selection of clinical assistance medication, prognosis judgment and the like of the gastrointestinal stromal tumor.
Description
Technical field
The present invention relates to the detection kit for molecular biology and medical science, especially relate to a kind of medication selection and examination of curative effect test kit of imatinib mesylate assisting therapy gastrointestinal stromal tumor.
Background technology
(the English full name of gastrointestinal stromal tumor is gastrointestinal stromal tumors to gastrointestinal stromal tumor, english abbreviation is GIST) originate from the tumour of gi tract mesenchymal tissue, be a kind of gastral Rare Neoplasms that betides, in nineteen eighty-three, propose first.（Mazur?MT,Clark?HB.Gastric?stromal?tumors.Reappraisal?of?histogenesis[J].Am?J?Surg?Pathol1983;7:507-519）。GIST accounts for 1%～3% of gastrointestinal cancer, estimates that annual morbidity is about (10～20)/1,000,000, and 20%～30%, pernicious.But along with molecular biological, develop rapidly, the diagnosis of GIST and treatment have also obtained huge progress.Especially at present treat the targeted drug of tumour, for specificity target spot, treat, thereby avoid Normocellular injury, obtain the treatment pattern of efficient low side effect, on market, occupied important share.
Targeted drug imatinib, commodity are called imatinib mesylate, and its activeconstituents is first listing of developing of imatinib mesylate ，Shi You Novartis Co.,Ltd for clinical tyrosine kinase inhibitor.It is used for the treatment of chronic myelocytic leukemia and gastrointestinal stromal tumor by FDA approval, its Main Function is to be optionally incorporated into some relevant tyrosine kinase receptor, stop the transfer of phosphate group from Triphosaden to protein substrate, make it phosphorylation that can not catalytic substrate tyrosine residues and activate the signal transduction of downstream effect molecule, thereby suppress cell proliferation and cell death inducing (JABBOUR E, CORTES J E, GHANEM H, et al.Targeted therapy in chronic myeloid leukemia[J] .Expert review of anticancer therapy, 2008, 8 (1): 99-110.).These Tyrosylprotein kinases comprise BCR-ABL, TEL-ABL, ETV6-ABL, C-KIT etc., their extracellular regions are ligand binding domains, part is solubility or membrane-bound polypeptide or protein hormone, comprise Regular Insulin and multiple somatomedin, born of the same parents' inner segment is the catalytic site of tyrosine protein kinase, and has autophosphorylation site.The tyrosine position of phosphorylation becomes the binding site of signal protein in cell immediately, in different cells, after signal protein and the combination of acceptor afterbody phosphorylation position, is activated.Signaling complex passes through several different signal transduction pathways, expansion information, a series of biochemical reaction in activating cells; Or different informixs is got up to cause that the comprehensive of cell reply, as cell proliferation etc.
Imatinib is to suppress BCR-ABL Tyrosylprotein kinase function the earliest, in order to treat the patients with chronic myelocytic leukemia of different stadium, with chronic phase curative effect best, the curative effect of acceleration period and acute transformation phase is obviously poor compared with chronic phase.Clinical data demonstrates good result for the treatment of, there is hematologic response rate completely, about 95%～98%, cytogenetics remission rate completely, when chronic phase, reach 80%～90%, only have 10% chronic phase case can reach molecular level and alleviate (DEININGER M, BUCHDUNGER E, DRUKER B J.The development of imatinib as a therapeutic agent for chronic myeloid leukemia[J] .Blood, 2005,105 (7): 2640-2653.).And in 2000, studies have reported that the unresectable GIST sufferer of the 1st routine imatinib mesylate application for the treatment of, no matter show, be clinically or in histology, have obvious curative effect.Separately there is research application imatinib mesylate to treat the GIST patient in 147 routine progress stages, think that imatinib mesylate is effective and safe, wherein 54% conditions of patients is eased, and 28% conditions of patients is stable, follows up a case by regular visits to and within 9 months, does not find the toxic side effect that is difficult to treatment and controls.Due to the remarkable effect of imatinib mesylate at treatment GIST, the advanced GIST patient that some cannot excise, in application, it carries out after new adjuvant chemotherapy, make excision become possible (DEMETRI G D, von MEHREN M, BLANKE C D, et al.Efficacy and safety of imatinib mesylate in advanced gastrointestinal stronmal tumors[J] .N Engl J Med, 2002,347 (7): 472-480.).There is investigator can not excise to 126 examples the GIST patient that the c-KIT of (comprising the reason of technology and the reason of systemic situation) is positive and study, wherein 16 routine patients complete tumorectomy of row after the treatment of application imatinib mesylate.The GIST case of another 1 example application imatinib mesylate adjuvant chemotherapy has also obtained success, this case is one huge (35cm) abdomen tumour, with shifting with mesentery in liver, because excising, apply imatinib mesylate treatment, 12 weeks rear tumours of medication are contracted to 18cm from 35cm, Intrahepatic metastasis kitchen range transfers cystic disease kitchen range to, the multiple metastasis of primary tumo(u)r and mesentery is excised (SCAIFE C L subsequently completely, HUNT K K, PATEL S R, et al.Is there a role for surgery in patients with imatinib mesylate[J] .AmJ Sury, 2003, 186 (6): 665-669.).
The fusion rotein of being encoded out by BCR-ABL has a continuous activity Tyrosylprotein kinase as a kind of, participate in the adjusting of many A signal pathways, for example disturb mitogen protein kinase path and raise cell proliferation, disturb phosphoinositide 3-kinase/protein kinase B path to cause apoptosis to reduce, final normal operation (the MELO J V that affects cell, DEININGER M W.Biology of chronic myelogenous leukemia--signaling pathways of initiation and transformation[J] .Hematology/oncology clinics of North America, 2004, 18 (3): 545-568.).Visible it in the developing of GIST and chronic myelocytic leukemia, playing the part of key player, and the specificity target spot as targeted drug imatinib mesylate, its existence is selected for the treatment of GIST and is used the therapeutic evaluation after imatinib mesylate treatment all significant, in view of the clinical value in the diagnosis for disease, prognosis, therapeutic evaluation etc., the exploitation of fusion gene detection technique has to have very large marketable value and clinical meaning.
Summary of the invention
The object of the present invention is to provide a kind of medication selection and examination of curative effect test kit of imatinib mesylate assisting therapy gastrointestinal stromal tumor.
Two of object of the present invention is to provide a kind of supporting pcr amplification program.
The medication selection of described imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit, comprise BCR-ABL gene PCR reaction solution, Taq enzyme, reference substance, supporting multiplex PCR amplification program and packing material;
Described BCR-ABL gene PCR reaction solution is comprised of PCR reaction buffer, 2 BCR-ABL gene specific upstream primers, 1 BCR-ABL gene specific downstream primer; BCR upstream region of gene primers F 1 sequence is: 5 '-
tTTGAGGATTGCGGAGGC-3 ', F2 sequence is 5 '-
gGAGCAGCAGAAGAAGTGTT-3 ', abl gene downstream primer R sequence is: 5 '-
gGTCCAGCGAGAAGGTTT-3 ';
Described PCR reaction buffer is by Tris-HCl10mM, KCl50mM, MgCl
20.2mM and dNTPs0.2mM form, and the pH of described Tris-HCl is 8.3; Or PCR reaction buffer is by 100mM Tris-HCl, 500mM KCl, 25mM MgCl
2, 25mM dNTPs forms, and the pH of described Tris-HCl is 8.8.
The primer concentration can be 10 μ M, and every secondary response consumption of described Taq enzyme is 1U.
The amplification program of described PCR is: the first stage: 95 ℃ 1min1 circulation; Subordinate phase: 95 ℃ of 30s, 66～61 ℃ of each circulations of 30s(reduce by 1 ℃), 72 ℃ of 20s, 5 circulations; Phase III 95 ℃ of 30s, 61 ℃ of 30s, 72 ℃ of 20s, 25 circulations; Wherein subordinate phase is for the special product of enrichment, and the phase III is for amplification.
Whether the present invention is existed and is helped gastrointestinal stromal tumor selection suitable drug and assess individual effect of Glivec-assisted treatment on gastrointestinal stromal tumors by detection imatinib mesylate drug targeting site BCR-ABL fusion gene, can be applicable to a plurality of fields such as the selection of clinical adjuvant drug of gastrointestinal stromal tumor and prognosis judgement, contribute to select imatinib mesylate assisting therapy gastrointestinal stromal tumor and evaluate its curative effect, both fast, accurately, economical, inexpensive again.
Accompanying drawing explanation
The BCR-ABL reference substance providing in the medication selection that Fig. 1 is imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit, without the color atlas of template reference substance.In figure, numeral 1 represents BCR-ABL reference substance result, and 2 indicate without template reference substance result.
Embodiment
The present invention is further illustrated in connection with accompanying drawing for following examples.
The medication selection of embodiment imatinib mesylate assisting therapy gastrointestinal stromal tumor and the use of examination of curative effect test kit
1 preparation comprises the test kit of following moiety: BCR-ABL gene PCR reaction solution (1200 μ L) 1 pipe, Taq enzyme system (30 μ L) 1 pipe, reference substance (300 μ L) 1 pipe.
The collection of 2 samples, storage and transport:
2.1 use sample type: fresh blood.
2.2 sample collections, storage and transport: after collecting fresh blood with anticoagulant tube, carry out immediately RNA extracting, or extract white corpuscle and put into liquid nitrogen freezing and be stored in-80 ℃.The long-distance employing dry ice that transports of sample.
3, nucleic acid extracting:
Suggestion utilizes MagCore Compact nucleic acid extraction device, and the specification sheets operation according to its supporting whole blood RNA extraction agent box (MRN-01), can obtain the RNA sample that elution volume is 200 μ L in final every 400 μ L blood samples, carries out immediately afterwards reverse transcription.
4, reverse transcription:
QIAGEN is used in suggestion
reverse Transcription test kit.Operate to specifications.
5, multiple RT-PCR detects:
5.1 reagent are prepared: draw in proportion BCR-ABL gene PCR reaction solution, the Taq enzyme system (BCR-ABL gene PCR reaction solution 19.8 μ L/ person-portion+Taq enzyme 0.2 μ L/ person-portions) of respective amount, after fully mixing, by 20 μ L/ person-portions, are distributed into PCR reaction tubes, and standby.
5.2 application of samples: add the cDNA sample after 5 μ L reverse transcriptions to BCR-ABL gene PCR reaction tubes respectively, to BCR-ABL gene PCR reaction tubes, add 5 μ L reference substance samples product in contrast, to BCR-ABL gene PCR reaction tubes, add 5 μ L distilled waters as NTC simultaneously.
5.3 editors: at Thermal Profile Setup window editor response procedures: the first stage: 95 ℃ 1min1 circulation; Subordinate phase: 95 ℃ of 30s, 66～61 ℃ of each circulations of 30s(reduce by 1 ℃), 72 ℃ of 20s, 5 circulations; Phase III 95 ℃ of 30s, 61 ℃ of 30s, 72 ℃ of 20s, 25 circulations; Wherein subordinate phase is for the special product of enrichment, and the phase III is for amplification.Preservation file after all settings complete, operation.
5.4 results detect: after reaction finishes, PCR product (more than loading volume 0.5 μ L) is put in capillary electrophoresis apparatus, automatically carries out electrophoresis result detection.After detection finishes, open analysis window, select sample aperture, automatic analysis result.The reference substance color atlas (see figure 1) that result and test kit working instructions are provided contrasts, if there is peak value 413bp, 215bp, the 290bp corresponding with BCR-ABL reference substance color atlas in sample color atlas, imatinib mesylate pharmacological agent gastrointestinal stromal tumor is selected in suggestion.
Claims (6)
1. the medication selection of imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit, is characterized in that comprising BCR-ABL gene PCR reaction solution, Taq enzyme, reference substance, supporting multiplex PCR amplification program and packing material;
Described BCR-ABL gene PCR reaction solution is comprised of PCR reaction buffer, 2 BCR-ABL gene specific upstream primers, 1 BCR-ABL gene specific downstream primer; BCR upstream region of gene primers F 1 sequence is: 5 '-
tTTGAGGATTGCGGAGGC-3 ', F2 sequence is 5 '-
gGAGCAGCAGAAGAAGTGTT-3 ', abl gene downstream primer R sequence is: 5 '-
gGTCCAGCGAGAAGGTTT-3 '.
2. the medication selection of imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit as claimed in claim 1, is characterized in that described PCR reaction buffer is by Tris-HCl10mM, KCl50mM, MgCl
20.2mM and dNTPs0.2mM form, and the pH of described Tris-HCl is 8.3.
3. the medication selection of imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit as claimed in claim 1, is characterized in that described PCR reaction buffer is by 100mM Tris-HCl, 500mM KCl, 25mM MgCl
2, 25mM dNTPs forms, and the pH of described Tris-HCl is 8.8.
4. the medication selection of imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit as claimed in claim 1, is characterized in that the primer concentration is 10 μ M.
5. the medication selection of imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit as claimed in claim 1, is characterized in that every secondary response consumption of described Taq enzyme is 1U.
6. the medication selection of imatinib mesylate assisting therapy gastrointestinal stromal tumor and examination of curative effect test kit as claimed in claim 1, is characterized in that the amplification program of described PCR is: the first stage: 95 ℃ 1min1 circulation; Subordinate phase: 95 ℃ of 30s, 66～61 ℃ of 30s, each circulation reduces by 1 ℃, 72 ℃ of 20s, 5 circulations; Phase III 95 ℃ of 30s, 61 ℃ of 30s, 72 ℃ of 20s, 25 circulations; Wherein subordinate phase is for the special product of enrichment, and the phase III is for amplification.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103627810A (en) * | 2013-12-11 | 2014-03-12 | 厦门大学 | Multiplex RT-PCR (reverse transcription-polymerase chain reaction) reagent kit for detecting leukemia BCR-ABL (Abelson proto-oncogene-breakpoint cluster region) |
| CN106987599A (en) * | 2017-03-28 | 2017-07-28 | 重庆医科大学 | Use Zinc finger nuclease technology to destroy people's bcr abl fusions to suppress CML cells propagation and promote its apoptosis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102251031A (en) * | 2011-06-30 | 2011-11-23 | 北京思尔成生物技术有限公司 | TaqMan MGB probe real-time fluorescence PCR detection method for leukemia fusion genes, and special primers, probes and kit used by same |
| CN103627810A (en) * | 2013-12-11 | 2014-03-12 | 厦门大学 | Multiplex RT-PCR (reverse transcription-polymerase chain reaction) reagent kit for detecting leukemia BCR-ABL (Abelson proto-oncogene-breakpoint cluster region) |
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2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102251031A (en) * | 2011-06-30 | 2011-11-23 | 北京思尔成生物技术有限公司 | TaqMan MGB probe real-time fluorescence PCR detection method for leukemia fusion genes, and special primers, probes and kit used by same |
| CN103627810A (en) * | 2013-12-11 | 2014-03-12 | 厦门大学 | Multiplex RT-PCR (reverse transcription-polymerase chain reaction) reagent kit for detecting leukemia BCR-ABL (Abelson proto-oncogene-breakpoint cluster region) |
Non-Patent Citations (2)
| Title |
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| 王春霞: "《BCR-ABL融合基因检测方法的进展》", 《医学综述》, vol. 19, no. 1, 31 January 2013 (2013-01-31), pages 137 - 141 * |
| 黄士波: "《胃肠道间质瘤的诊治进展》", 《中华临床医师杂志（电子版）》, vol. 7, no. 18, 30 September 2013 (2013-09-30), pages 8428 - 8430 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103627810A (en) * | 2013-12-11 | 2014-03-12 | 厦门大学 | Multiplex RT-PCR (reverse transcription-polymerase chain reaction) reagent kit for detecting leukemia BCR-ABL (Abelson proto-oncogene-breakpoint cluster region) |
| CN106987599A (en) * | 2017-03-28 | 2017-07-28 | 重庆医科大学 | Use Zinc finger nuclease technology to destroy people's bcr abl fusions to suppress CML cells propagation and promote its apoptosis |
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Application publication date: 20140312 |