摘    要

胶质瘤是一种颅内最常见,并且其发病率逐年增高的恶性肿瘤。目前，胶质瘤分子生物学研究的新焦点——异柠檬酸脱氢酶基因1(IDH1)突变，作为神经胶质瘤发生、发展的早期行为，频频发生在继发性胶质细胞瘤或低级别胶质细胞瘤中。随着研究的深入，越来越多的证据表明IDH1基因突变与胶质瘤密切相关。IDH1基因突变存在于在40%的胶质瘤中，尤其在继发性胶质母细胞瘤中变异率最高。作为一种代谢的关键酶，IDH1基因突变后可将α-酮戊二酸（α-KG）转变成2-羟基戊二酸（2-HG），2-HG具有促进细胞增殖和促进肿瘤发生的作用。正常情况下，IDH1催化异柠檬酸（ICT）生成还原性辅酶（NADPH）和α-KG。IDH1基因突变后，伴随着IDH1的活性丧失，而且R132H和R132C突变蛋白以NADPH作为辅因子，进一步将α-酮戊二酸（α-KG）还原成D-2-羟基戊二酸（D-2-HG）。高浓度D-2-HG抑制α-KG依赖性双加氧酶，组蛋白脱甲基酶，从而引起广泛的组蛋白高甲基化。鉴于组蛋白赖氨酸甲基化在基因调控以及癌症起始中的关键作用，这些异常的表观遗传改变导致了癌症的起始。目前在不同级别的胶质瘤中，IDH1突变已经成为一个与预后密切相关的独立预测因素。IDH1基因突变分子机制的进一步明确将促进神经胶质瘤的基因靶向治疗的发展。目前，国内外研究机构集中于以此为靶点，合成不同的小分子化合物抑制IDH1基因的突变，如二酰胺化合物和1-羟基吡啶-2-酮化合物，开发新型的抗肿瘤新药。85133

毕业论文关键词：IDH1； 胶质瘤； 突变； 抑制剂

Abstract

Glioma is the commonest intracranial malignant tumor, with its incidence rate increasing every year。 At present, glioma molecular biology research of the new focus-isocitrate dehydrogenase gene 1 (IDH1) mutation, as glioma occurrence, the development of early behavior, frequently occurring in secondary glioblastoma or Low grade glioblastoma。 With the deepening of research, there is growing evidence that IDH1 gene mutations are closely related to gliomas。IDH1 gene mutation is present in 40% of gliomas, especially in secondary glioblastoma。 As a key enzyme for metabolism,IDH1 gene mutation can be α-ketoglutarate (α-KG) into 2-hydroxypentanedioic acid (2-HG),2-HG has to promote cell proliferation and promote tumorigenesis the role。Under normal circumstances,IDH1 catalyzes isocitrate (ICT) to produce reduced coenzyme (NADPH) and alpha-KG。(Α-KG) was further reduced to D-2-hydroxypentanedioic acid (D-(2-hydroxypentanedioic acid) by reducing the activity of IDH1 and R132H and R132C mutein with NADPH as cofactor,2-HG)。High concentrations of D-2-HG inhibit alpha-KG-dependent dioxygenase, histone demethylase, which causes extensive histone hypermethylation。 In view of the critical role of histone lysine methylation in gene regulation and cancer initiation,t hese abnormal epigenetic changes have led to the onset of cancer。 At present, different levels of gliomas, IDH1 mutations have become an independent prognostic factor closely related to prognosis。 The further clarification of the molecular mechanism of IDH1 gene mutation will promote the development of gene targeting therapy for glioma。 At present, domestic and foreign research institutions focus on this as a target, the synthesis of different small molecule compounds inhibit IDH1 gene mutations, such as diamide compounds and 1-hydroxypyridin-2-one compounds, the development of new anti-tumor drugs。来自优W尔Y论W文C网WWw.YoueRw.com 加QQ7520,18766

Keyword: IDH1； Glioma； Mutation； Inhibitors

目    录

1 胶质瘤 5

1。1 胶质瘤的现状 5

1。2 IDH1基因突变与胶质瘤之间的联系研究发现