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    Home > Active Ingredient News > Antitumor Therapy > Small: CXCR4 antagonistic polypeptide nanoglue to the treatment of refractive acute myeloid leukemia.

    Small: CXCR4 antagonistic polypeptide nanoglue to the treatment of refractive acute myeloid leukemia.

    • Last Update: 2020-07-18
    • Source: Internet
    • Author: User
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    Acute myeloid leukemia (AML) is a heterogeneous disease of bone marrow, accounting for about 80% of adult acute leukemia.the combination chemotherapy of multiple drugs will not only bring serious side effects, but also face the problems of easy recurrence and drug resistance.although some patients can get complete remission after the first treatment, the recurrence rate is as high as 50-70% within three years, and after recurrence, they are resistant to the original drugs, so they have to increase the dosage and replace the more toxic chemotherapy drugs.at the same time, due to the fact that AML involves thousands of cytogenetic abnormalities and gene mutations, the research and development of targeted drugs for gene mutation is full of challenges, so far, the number of AML patients entering clinical practice is extremely limited.at present, the overall five-year survival rate of AML patients in the world is only about 25%, which is the highest mortality disease in leukemia.clinical evidence shows that some common drug resistance related proteins are overexpressed on the surface of different types of AML cells, and their expression levels are closely related to the poor prognosis of AML patients.chemokine receptor CXCR4 is one of them. CXCR4 is highly expressed in many types of AML cells, while stromal cells in bone marrow and spleen secrete its ligand CXCL12.the CXCR4 on the surface of AML cells interacts with its ligand CXCL12, homing to bone marrow, obtaining proliferation and drug resistance signals, and infiltrating into extramedullary organs.the team of Xu Haiyan, Institute of basic medicine, Chinese Academy of Medical Sciences, cooperated with Wang Chen team of national nano center and Wang Jianxiang team of Hematology Hospital of China Medical University, combined the chemosynthetic CXCR4 antagonistic peptide (E5) with domestic cultured phosphatidylethanolamine (DSPE) to prepare E5 loaded nano micelles (m-e5), which not only improved the physical environment of E5 The results showed that the dissolution stability and half-life of the peptide in rats were more than 14 hours, which was better than that of the same target antagonistic peptide in clinical trials.the research team applied m-e5 to AE & amp; c-kitd816v leukemia mouse model with AML1-ETO fusion gene and c-kit d816 mutation gene; the model has the characteristics of rapid development of disease course, relapse and refractory, and different from xenotransplantation model, it can more truly simulate the bone marrow microenvironment needed for the occurrence and development of leukemia.the results showed that m-e5 could bind to the N-terminal of CXCR4 extracellular domain and prevent the effect of CXCL12.when CXCR4 is highly expressed in bone marrow cells of AML mice, m-e5, as a single drug, can significantly affect its downstream signals by antagonizing CXCR4, effectively inhibit the colonization of AML cells in spleen and bone marrow, and mobilize AML cells into peripheral blood circulation, making it difficult to homing and update, thus promoting apoptosis or differentiation, and increasing the ratio of AML cells in spleen, bone marrow and peripheral blood The survival time of mice was significantly prolonged.on the other hand, when the level of CXCR4 in bone marrow cells of AML mice is in the low level, m-e5 can also be combined with clinical first-line chemotherapy drugs to significantly improve the chemotherapy effect.this study shows that m-e5 is expected to become a safe and effective CXCR4 targeted drug, and has clinical transformation prospects and application value in the treatment of AML.the relevant results were published in small (DOI: 10.1002 / small. 202001890). Associate Professor Meng Jie, Ph.D. students Ge Yangyang and Xing Haiyan were the co first authors of the article, and Professor Xu Haiyan, Professor Wang Chen and Professor Wang Jianxiang were the co corresponding authors.this study was supported by the national key R & D Program (2017yfa020504), the medical and health science and technology innovation project of Chinese Academy of Medical Sciences (2016-i2m-3-004), and the National Natural Science Foundation (NSFC) (81870133, 31771005 and 21721002).original link:
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