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Medicine for treating or preventing drug-resistant relapse of acute lymphoblastic leukemia and its application

A technology for acute lymphocytes and leukemia, which is applied in the field of drugs for the treatment or prevention of drug-resistant relapse of acute leukemia, and can solve the problems of lack of detection and treatment methods

Active Publication Date: 2019-12-06
SHANGHAI CHILDRENS MEDICAL CENT AFFILIATED TO SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention: In view of the lack of detection and treatment methods for drug-resistant relapse in children with ALL, the present invention provides a drug target for preventing or treating drug-resistant relapse of acute lymphoblastic leukemia, and a drug-resistant drug for treating acute lymphoblastic leukemia. Application of relapsed RNA drug and inhibitor of one or more enzymes in all enzymes in purine de novo synthesis pathway in the preparation of drugs for preventing or treating drug-resistant relapse of acute lymphoblastic leukemia

Method used

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  • Medicine for treating or preventing drug-resistant relapse of acute lymphoblastic leukemia and its application
  • Medicine for treating or preventing drug-resistant relapse of acute lymphoblastic leukemia and its application
  • Medicine for treating or preventing drug-resistant relapse of acute lymphoblastic leukemia and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Detection of PRPS1 gene mutations in samples:

[0071] Using whole-exome sequencing technology, PRPS1 was sequenced on the first-onset, remission and relapse samples of 16 groups of children with ALL and 144 relapse samples.

[0072] Quality control of samples: The quality of samples is directly related to the reliability of sequencing results. The following three methods are used to ensure the quality of samples used for deep sequencing and subsequent verification: ① Leukemic cells in the bone marrow can account for all of the leukemia cells at the onset and recurrence of leukemia. For more than 90% of nucleated cells, the remaining normal granulocytes and nucleated red blood cells can be removed by Ficoll density gradient centrifugation, so that high-purity leukemia cells can be obtained for subsequent DNA extraction and sequencing; ②The combination of multicolor fluorescent antibodies can Distinguish between leukemia cells and normal bone marrow hematopoietic cells. Fo...

Embodiment 2

[0105] Detection of mutations in genes related to purine metabolism pathway in samples

[0106] Purine metabolism-related enzymes HGPRT, IMPDH, NT5C2, PRPS2, ATIC, ADSL, GART, and PFAS were sequenced in 160 children with relapsed ALL samples by conventional next-generation sequencing technology.

[0107] Sample quality control, preparation, amplification of gene exons are the same as in Example 1

[0108] Sequencing analysis: After the PCR is successful, the target band is sequenced, and the target sequence is compared with the corresponding gene sequence in NCBI to analyze the gene mutation. If a genetic mutation is found in a relapse sample, test a primary sample from the same patient to determine if it is a relapse-specific mutation. The experimental results are shown in Table 4.

[0109] Through sequencing and sequence comparison, it was found that the purine metabolism-related enzymes PRPS2, ATIC, ADSL, GART, and PFAS all had recurrence-specific mutations.

[0110] Tab...

Embodiment 3

[0114] Construction of PRPS1 prokaryotic expression vector

[0115] 1. Acquisition of the target gene fragment: According to the PRPS1 (gene ID: 5631, NM 002764) sequence provided by NCBI, design the PCR primer sequence of wild-type PRPS1, forward primer: 5'cgcggcagccatATGCCGAATATCAAAATCTTCAG3', reverse primer: 5'gtggtggtgctcgagTTATAAAGGGACATGGCTGAATAGGTA3' (Primer Description: Contains exchange paired bases, restriction sites, and contains the 5' end partial sequence of the target gene for PCR to capture the target gene). Using the extracted cDNA of Reh cells as a template, PRPS1 was captured by PCR, and the size of the PCR product was 957bp, and the product sequence was shown in the sequence table SEQ ID No.1.

[0116] 2. Linearization of the prokaryotic expression vector: treat the pET28a vector with restriction endonuclease NdeI / XhoI, the pET28a vector map is as follows image 3 shown.

[0117] 3. Recombinant plasmid construction: through In-Fusion of clontech company T...

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Abstract

The invention provides a medicine for treating or preventing drug-resistant relapse of acute lymphoblastic leukemia (ALL) and application thereof. The drug acts on enzymes in the purine synthesis pathway, and reduces the drug-resistant relapse of ALL by reducing the concentration of hypoxanthine. The invention also provides the application of the compound lometrexol and related targeting GART and ATIC preparations in the preparation of drugs for preventing or treating drug-resistant relapse of ALL. The present invention also provides a kit for assessing the risk of drug-resistant relapse in ALL and a method of use thereof, which includes reagents for lysing sample cells and instructions for use. The usage method includes: (1) collecting and lysing sample cells; (2) detecting the contents of hypoxanthine, IMP, AICAR and inosine; (3) judging the risk of drug-resistant relapse of acute lymphoblastic leukemia in samples. The invention provides powerful technical means and support for the prevention and treatment of drug-resistant relapse of ALL.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a drug for treating or preventing drug-resistant relapse of acute leukemia and its application. Background technique [0002] Acute Lymphoblastic Leukemia (ALL) is a common malignant hematological neoplasm in childhood and one of the important causes of death in children in my country. Although the treatment and prognosis of children with ALL have been significantly improved after many efforts in the past few decades, 15% to 20% of children will relapse, and once they relapse, the cure rate is less than 40%. Leading cause of treatment failure and death in ALL. Relapse has increasingly become a hot spot and focus of research on children's ALL at home and abroad. [0003] During the treatment of children with ALL, chemotherapy is one of the main means of inducing remission and post-remission treatment. Chemotherapeutic drugs commonly used in clinical practice usually use nucleotide an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/113C12N15/11C12N15/867C12N15/55A61K48/00A61K31/713A61K31/7088A61P35/02G01N27/62
Inventor 李慧李本尚周斌兵
Owner SHANGHAI CHILDRENS MEDICAL CENT AFFILIATED TO SHANGHAI JIAOTONG UNIV SCHOOL OF MEDICINE
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