Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations
Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations
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DOI：
10.1002/ijc.21570
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发表时间：
2006-04-01
影响因子：
6.4
通讯作者：
Lage, H
中科院分区：
文献类型：
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作者：
Györffy, B;Surowiak, P;Lage, H
具有相似分级、分期和组织发生的肿瘤的癌症患者对不同化疗剂的治疗反应可以显著不同。到目前为止，单个标记物未能正确预测抗癌药物的耐药性。我们测试了30种癌细胞系对5-氟尿嘧啶、顺铂、环磷酰胺、多柔比星、依托泊苷、甲氨蝶呤、丝裂霉素C、米托蒽醌、紫杉醇、拓扑替康和长春碱的敏感性，这些药物的浓度可以在患者中全身达到。测定耐药指数以将细胞系指定为敏感或耐药，然后比较每种药物的耐药细胞系与敏感细胞系的子集。所有细胞系的基因表达特征通过询问Affytron U133 A阵列获得。应用微阵列预测分析进行特征选择。构建了一个包含42297个基因的对每种化疗药物耐药的个体预测谱。留一法交叉验证中预测的总体准确度为86%。确定了与对至少4种抗癌药物的耐药性相关的前67个多药耐药候选基因的列表。此外，还使用TaqMan微流控卡系统通过定量RT-PCR测量了46个选择的基因的差异表达。由于单个基因可与对几种药剂的抗性相关，因此分别检测到76个基因和抗性表型与抗性的关联。这项研究的重点是在体内浓度下的耐药性，使未来的临床癌症反应预测可行。TaqMan验证的基因表达模式为多药耐药提供了新的候选基因。本文的补充材料可以在国际癌症杂志网站http://www.interscience.wiley.com/jpages/0020-7136/suppmat上找到。(c)2005 Wiley-Liss，Inc.
Cancer patients with tumors of similar grading, staging and histogenesis can have markedly different treatment responses to different chemotherapy agents. So far, individual markers have failed to correctly predict resistance against anticancer agents. We tested 30 cancer cell lines for sensitivity to 5-fluorouracil, cisplatin, cyclophosphamide, doxorubicin, etoposide, methotrexate, mitomycin C, mitoxantrone, paclitaxel, topotecan and vinblastine at drug concentrations that can be systemically achieved in patients. The resistance index was determined to designate the cell lines as sensitive or resistant, and then, the subset of resistant vs. sensitive cell lines for each drug was compared. Gene expression signatures for all cell lines were obtained by interrogating Affymetrix U133A arrays. Prediction Analysis of Microarrays was applied for feature selection. An individual prediction profile for the resistance against each chemotherapy agent was constructed, containing 42297 genes. The overall accuracy of the predictions in a leave-one-out cross validation was 86%. A list of the top 67 multidrug resistance candidate genes that were associated with the resistance against at least 4 anticancer agents was identified. Moreover, the differential expressions of 46 selected genes were also measured by quantitative RT-PCR using a TaqMan micro fluidic card system. As a single gene can be correlated with resistance against several agents, associations with resistance were detected all together for 76 genes and resistance phenotypes, respectively. This studs focuses on the resistance at the in vivo concentrations, making future clinical cancer response prediction feasible. The TaqManvalidated gene expression patterns provide new gene candidates for multidrug resistance. Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat. (c) 2005 Wiley-Liss, Inc.