來自北卡羅來納大學教堂山分校（UNC）醫(yī)學院的科學家發(fā)現(xiàn)了一種化合物可以加以修改從而用于治療最致命的癌癥中的一種,，還發(fā)現(xiàn)了一個特殊的基因突變?nèi)绾螌δ[瘤的生長有貢獻,。
這些發(fā)現(xiàn)以及可能的治療適用于一種稱為繼發(fā)性多形性膠質(zhì)母細胞瘤（GBM）的腦瘤。GBM是更大的一類腦瘤的一部分,，被稱為惡性腦膠質(zhì)瘤,，這是愛德華·肯尼迪參議員所患的癌癥。
該研究的報告將發(fā)表在2009年4月10日出版的《科學》雜志上,。在對腫瘤細胞進行的實驗中,，這組科學家通過補充一種稱為α-酮戊二酸(α-KG) 的化合物從而逆轉(zhuǎn)了異檸檬酸脫氫酶-1基因（IDH1）的一個突變造成的效應。
“當IDH1基因突變后,，α-KG的濃度減少,，而這又會通過幫助增加向腫瘤細胞供應營養(yǎng)和氧從而對腫瘤生長有貢獻。當我們向腫瘤細胞加入α-KG后,，由IDH1突變造成的效應被逆轉(zhuǎn)了，” William R. Kenan Jr.教席生物化學和生物物理學卓越教授,、UNC的Lineberger綜合癌癥中心的成員熊月博士說,。
“如果科學家可以把α-KG開發(fā)成臨床藥物，它可能有潛力用于治療具有這種特定基因突變的腦瘤患者,。α-KG化合物已經(jīng)存在了,；唯一需要的是把它改為可以臨床使用，因此這可能節(jié)省很多時間,，”Xiong說,。
熊月是該研究的通訊作者之一，另一位通訊作者是加州大學圣地亞哥分校的藥理學教授管坤良博士,。這些發(fā)現(xiàn)和可能的治療適用于大多數(shù)繼發(fā)性GBM,，而不是一種稱為原發(fā)性GBM的不同類型的腫瘤,。熊月說，大約75%的繼發(fā)性GBMs的IDH1基因有突變,，但是只有5%的原發(fā)性GBMs有這種突變,。即便這兩種類型的GBM有類似的最終結果，這些類型的腫瘤以不同的方式發(fā)展,，而醫(yī)生將需要非常不同的療法去抑制它們,。這篇《科學》雜志論文的第一作者是中國上海復旦大學的趙世民博士。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
