来自北卡罗来纳大学教堂山分校(UNC)医学院的科学家发现了一种化合物可以加以修改从而用于治疗最致命的癌症中的一种,还发现了一个特殊的基因突变如何对肿瘤的生长有贡献。
这些发现以及可能的治疗适用于一种称为继发性多形性胶质母细胞瘤(GBM)的脑瘤。GBM是更大的一类脑瘤的一部分,被称为恶性脑胶质瘤,这是爱德华·肯尼迪参议员所患的癌症。
该研究的报告将发表在2009年4月10日出版的《科学》杂志上。在对肿瘤细胞进行的实验中,这组科学家通过补充一种称为α-酮戊二酸(α-KG) 的化合物从而逆转了异柠檬酸脱氢酶-1基因(IDH1)的一个突变造成的效应。
“当IDH1基因突变后,α-KG的浓度减少,而这又会通过帮助增加向肿瘤细胞供应营养和氧从而对肿瘤生长有贡献。当我们向肿瘤细胞加入α-KG后,由IDH1突变造成的效应被逆转了,” William R. Kenan Jr.教席生物化学和生物物理学卓越教授、UNC的Lineberger综合癌症中心的成员熊月博士说。
“如果科学家可以把α-KG开发成临床药物,它可能有潜力用于治疗具有这种特定基因突变的脑瘤患者。α-KG化合物已经存在了;唯一需要的是把它改为可以临床使用,因此这可能节省很多时间,”Xiong说。
熊月是该研究的通讯作者之一,另一位通讯作者是加州大学圣地亚哥分校的药理学教授管坤良博士。这些发现和可能的治疗适用于大多数继发性GBM,而不是一种称为原发性GBM的不同类型的肿瘤。熊月说,大约75%的继发性GBMs的IDH1基因有突变,但是只有5%的原发性GBMs有这种突变。即便这两种类型的GBM有类似的最终结果,这些类型的肿瘤以不同的方式发展,而医生将需要非常不同的疗法去抑制它们。这篇《科学》杂志论文的第一作者是中国上海复旦大学的赵世民博士。(生物谷Bioon.com)
生物谷推荐原始出处:
Science 10 April 2009:DOI: 10.1126/science.1170944
Glioma-Derived Mutations in IDH1 Dominantly Inhibit IDH1 Catalytic Activity and Induce HIF-1α
Shimin Zhao,1,2 Yan Lin,1* Wei Xu,1,2* Wenqing Jiang,1,2* Zhengyu Zha,1 Pu Wang,1,2 Wei Yu,1,2 Zhiqiang Li,4 Lingling Gong,5 Yingjie Peng,6 Jianping Ding,6 Qunying Lei,1,3 Kun-Liang Guan,1,3,7Yue Xiong1,2,8
Heterozygous mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) occur in certain human brain tumors, but their mechanistic role in tumor development is unknown. We have shown that tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. Forced expression of mutant IDH1 in cultured cells reduces formation of the enzyme product, α-ketoglutarate (α-KG), and increases the levels of hypoxia-inducible factor subunit HIF-1, a transcription factor that facilitates tumor growth when oxygen is low and whose stability is regulated by α-KG. The rise in HIF-1 levels was reversible by an α-KG derivative. HIF-1 levels were higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Thus, IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway.
1 Molecular and Cell Biology Laboratory, Institute of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
2 School of Life Sciences, Fudan University, 220 Han-Dan Road, Shanghai 200433, China.
3 Department of Biological Chemistry, School of Medicine, Fudan University, 130 Dong-An Road, Shanghai 200032, China.
4 Department of Neurosurgery, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
5 Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China.
6 State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
7 Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
8 Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA.