本文選題：急性髓系白血病(AML) + ATR　； 參考：《吉林大學(xué)》2017年碩士論文

【摘要】：急性髓系白血病(acute myeloid leukemia,AML)是最為常見的急性白血病,兒童患者的生存率為65%左右,而成人患者的生存率則僅為25%左右。阿糖胞苷在過去40年里一直是治療AML最有效的臨床一線藥物之一。盡管對多數(shù)病人來說傳統(tǒng)化療能使病情達到完全緩解,但是這些病人的大多數(shù)會復(fù)發(fā)。AML細胞對阿糖胞苷的耐藥是應(yīng)用阿糖胞苷治療AML失敗的主要原因。因此急需一種新的、更加有效的治療方案來對抗這種惡性疾病。導(dǎo)致阿糖胞苷產(chǎn)生耐藥的一個主要機制就是化療導(dǎo)致的DNA損傷激活了細胞DNA損傷應(yīng)答(the DNA damage response,DDR)信號網(wǎng)絡(luò)。ATR(ataxia telangiectasia and Rad3 relate)和ATM(ataxia telangiectasia mutated)是DDR信號網(wǎng)絡(luò)中兩個重要的組成蛋白。當(dāng)細胞發(fā)生DNA雙鏈斷裂或者復(fù)制叉停滯時,細胞會對其進行修復(fù)并產(chǎn)生單鏈DNA,此時ATR就會被激活以應(yīng)對單鏈DNA的產(chǎn)生。ATR能夠調(diào)節(jié)多種重要的生物學(xué)功能,如調(diào)節(jié)DNA損傷修復(fù)、緩解DNA復(fù)制壓力和激活細胞周期檢驗點等。ATR是促進DNA受損傷細胞存活的重要調(diào)節(jié)因子;此外大多數(shù)的癌細胞因G1細胞周期檢驗點缺失而更加依賴ATR調(diào)節(jié)的S和G2/M細胞周期檢驗點。因此抑制ATR能夠增強DNA損傷類藥物對AML細胞的殺傷活性。ATR抑制劑與吉西他濱、順鉑以及PARP(poly(ADP-ribose)polymerase)抑制劑等DNA損傷類藥物聯(lián)合使用在實體瘤的臨床前模型中有著良好的抗腫瘤效果,預(yù)示著其良好的臨床應(yīng)用前景。ATR在多種重要的細胞活動中扮演重要的角色,探尋ATR抑制劑在聯(lián)合用藥中的具體作用機制有助于提升人們對此類藥物的認識,并為合理設(shè)計用于治療AML的藥物聯(lián)合方案提供重要的理論依據(jù)。在本研究中,我們用AML細胞株和AML患者臨床樣本細胞探究了ATR抑制劑AZ20單獨或與阿糖胞苷聯(lián)合使用抗AML的效果。結(jié)果表明,AZ20能夠誘導(dǎo)細胞凋亡,部分解除G2/M細胞周期阻滯,引起DNA復(fù)制壓力和DNA損傷,并導(dǎo)致非CDK1依賴的核苷酸還原酶(Ribonucleotide reductase,RR)M1亞基(RRM1)與M2亞基(RRM2)蛋白表達水平的下調(diào)。同時,AZ20能夠協(xié)同增強阿糖胞苷誘導(dǎo)的AML細胞凋亡,解除阿糖胞苷誘導(dǎo)的S與G2/M細胞周期阻滯,增強阿糖胞苷誘導(dǎo)的DNA復(fù)制壓力與DNA損傷。同時我們用另一種ATR的選擇性抑制劑AZD6738驗證了以上發(fā)現(xiàn)。因此,抑制ATR協(xié)同增強阿糖胞苷殺傷AML細胞活性的機制主要有兩個:一是抑制ATR能夠增強阿糖胞苷引起的DNA復(fù)制壓力和DNA損傷;二是抑制ATR能夠解除阿糖胞苷誘導(dǎo)的S和G2/M細胞周期阻滯。我們的研究闡明了ATR抑制劑AZ20和AZD6738與阿糖胞苷協(xié)同抗AML的分子機制,為ATR抑制劑與阿糖胞苷在AML治療中的聯(lián)合應(yīng)用提供了重要的理論依據(jù)與實驗基礎(chǔ)。
[Abstract]:Acute myeloid leukemia (acute myeloid leukemiaAML) is the most common acute leukemia. The survival rate of children is about 65%, and that of adult patients is only 25%. Cytarabine has been one of the most effective first-line drugs in the treatment of AML for the past 40 years. Although traditional chemotherapy can lead to complete remission in most patients, the resistance of most AML cells to cytarabine is the main reason for the failure of cytosine arabinoside therapy. Therefore, a new and more effective treatment is urgently needed to combat this malignant disease. One of the main mechanisms leading to cytarabine resistance is that chemotherapy-induced DNA damage activates the damage response relate signaling network. ATR (ataxia telangiectasia and Rad3 relate and ATM (ataxia telangiectasia mutated) are two important proteins in the DDR signaling network. When a cell has a DNA double strand break or a replication fork stops, the cell will repair it and produce a single strand DNA, and ATR will be activated to respond to the production of single strand DNA. ATR can regulate several important biological functions, such as regulating DNA damage repair. ATR is an important regulatory factor to promote the survival of DNA damaged cells. In addition, most cancer cells are more dependent on ATR regulated S and G 2 / M cell cycle test points due to the absence of G1 cell cycle detection points. Therefore, inhibiting ATR can enhance the cytotoxicity of DNA-damaging drugs to AML cells. ATR inhibitors combined with gemcitabine, cisplatin and PARP (poly (ADP-ribose) polymerase) inhibitors have a good anti-tumor effect in the preclinical model of solid tumor. ATR plays an important role in many important cellular activities. Exploring the specific mechanism of ATR inhibitors in combination drugs will help to promote the understanding of such drugs. It also provides an important theoretical basis for the rational design of drug combination regimen for AML. In this study, we used AML cell lines and AML patient clinical sample cells to investigate the effects of ATR inhibitor AZ20 alone or in combination with cytarabine. The results showed that AZ20 could induce apoptosis, partially relieve G _ 2 / M cell cycle arrest, induce DNA replication pressure and DNA damage, and down-regulate the expression of non-CDK1-dependent nucleotide reductase-RR M1 subunit (RRM1) and M2 subunit (RRM2). AZ20 could enhance apoptosis of AML cells induced by cytarabine, relieve cycle arrest of S and G _ 2 / M cells induced by cytosine arabinoside, and enhance DNA replication pressure and DNA damage induced by cytosine arabinoside. At the same time, we verify the above findings with AZD 6738, another selective inhibitor of ATR. Therefore, inhibition of ATR synergistically enhances the cytotoxicity of cytarabine to AML cells through two mechanisms: first, inhibiting ATR can enhance the DNA replication pressure and DNA damage induced by cytarabine; Second, inhibition of ATR can relieve cytarabine induced cell cycle arrest in S and G 2 / M cells. The molecular mechanism of ATR inhibitor AZ20 and AZD6738 combined with cytarabine against AML has been elucidated, which provides an important theoretical and experimental basis for the combined application of ATR inhibitor and cytarabine in the treatment of AML.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R733.71

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