Amundson Sally A, Do Khanh T, Vinikoor Lisa C, Lee R Anthony, Koch-Paiz Christine A, Ahn Jaeyong, Reimers Mark, Chen Yidong, Scudiero Dominic A, Weinstein John N, Trent Jeffrey M, Bittner Michael L, Meltzer Paul S, Fornace Albert J
Center for Radiological Research, Columbia University Medical Center, New York, New York 10032, USA.
Cancer Res. 2008 Jan 15;68(2):415-24. doi: 10.1158/0008-5472.CAN-07-2120.
The 60 cell lines of the National Cancer Institute Anticancer Drug Screen (NCI-60) constitute the most extensively characterized in vitro cancer cell model. They have been tested for sensitivity to more than 100,000 potential chemotherapy agents and have been profiled extensively at the DNA, RNA, protein, functional, and pharmacologic levels. We have used the NCI-60 cell lines and three additional lines to develop a database of responses of cancer cells to ionizing radiation. We compared clonogenic survival, apoptosis, and gene expression response by microarray. Although several studies have profiled relative basal gene expression in the NCI-60, this is the first comparison of large-scale gene expression changes in response to genotoxic stress. Twenty-two genes were differentially regulated in cells with low survival after 2-Gy gamma-rays; 14 genes identified lines more sensitive to 8 Gy. Unlike reported basal gene expression patterns, changes in expression in response to radiation showed little tissue-of-origin effect, except for differentiating the lymphoblastoid cell lines from other cell types. Basal expression patterns, however, discriminated well between radiosensitive and more resistant lines, possibly being more informative than radiation response signatures. The most striking patterns in the radiation data were a set of genes up-regulated preferentially in the p53 wild-type lines and a set of cell cycle regulatory genes down-regulated across the entire NCI-60 panel. The response of those genes to gamma-rays seems to be unaffected by the myriad of genetic differences across this diverse cell set; it represents the most penetrant gene expression response to ionizing radiation yet observed.
美国国立癌症研究所抗癌药物筛选项目（NCI - 60）中的60种细胞系构成了特征最为全面的体外癌细胞模型。它们已接受了对超过100000种潜在化疗药物的敏感性测试，并在DNA、RNA、蛋白质、功能和药理学水平上进行了广泛的分析。我们利用NCI - 60细胞系及另外三种细胞系建立了一个癌细胞对电离辐射反应的数据库。我们通过微阵列比较了克隆形成存活率、细胞凋亡及基因表达反应。尽管已有多项研究分析了NCI - 60中相对基础的基因表达情况，但这是首次对基因毒性应激反应中大规模基因表达变化进行的比较。在接受2 Gy γ射线照射后存活率较低的细胞中，有22个基因的表达存在差异调节；14个基因可识别出对8 Gy更敏感的细胞系。与已报道的基础基因表达模式不同，辐射诱导的表达变化除了能区分淋巴母细胞系与其他细胞类型外，几乎没有组织起源效应。然而，基础表达模式在放射敏感和抗性更强的细胞系之间有很好的区分度，可能比辐射反应特征更具信息量。辐射数据中最显著的模式是一组在p53野生型细胞系中优先上调的基因，以及一组在整个NCI - 60细胞系中下调的细胞周期调节基因。这些基因对γ射线的反应似乎不受这个多样细胞群体中众多遗传差异的影响；它代表了迄今为止观察到的对电离辐射最显著的基因表达反应。
