Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles.
Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles.
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DOI：
10.1038/sj.bjc.6602699
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发表时间：
2005-08-22
影响因子：
8.8
通讯作者：
Isaksson A
中科院分区：
文献类型：
--
作者：
Rickardson L;Fryknäs M;Dhar S;Lövborg H;Gullbo J;Rydåker M;Nygren P;Gustafsson MG;Larsson R;Isaksson A
获得性耐药性是癌症治疗中的主要问题。为了探索涉及化疗敏感性和耐药性的基因，10个人肿瘤细胞系，包括亲本细胞和耐药亚型选择多柔比星，美法仑，替尼泊苷和长春新碱的耐药性，分析7400基因的mRNA表达，使用cDNA微阵列技术。在细胞系上评估了66种抗癌药物的药物活性，并计算了药物活性与基因表达之间的相关性并进行了排序。基于药物-基因相关性的药物的层次聚类产生具有相似作用机制的药物簇。将与药物敏感性和耐药性相关的基因导入PathwayAssist软件中，以鉴定所涉及的推定分子途径。大量的促凋亡和抗凋亡基因，如信号转导和转录激活因子1，丝裂原活化蛋白激酶1和黏着斑激酶被发现与耐药性相关，而与细胞周期控制和增殖相关的基因，如细胞分裂周期25 A和信号转导转录激活因子5A，与一般药物敏感性相关。结果表明，从药物活性和基因表达的耐药为基础的细胞系面板的组合信息可能会提供新的知识，参与抗癌药物耐药性的基因，并成为药物开发的有用工具。
Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug–gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development.
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影响因子：
8.8
作者：
通讯作者：
--
影响因子：
2.9
作者：
Mao, Y;Yu, C;Liu, LF
通讯作者：
Liu, LF
影响因子：
2.6
作者：
Martinez-Lostao, L;Briones, J;Juarez, C
通讯作者：
Juarez, C
影响因子：
3.8
作者：
BOYD, MR;PAULI, KD
通讯作者：
PAULI, KD
影响因子：
6.4
作者：
NYGREN, P;LARSSON, R
通讯作者：
LARSSON, R