Vekris Antoine, Meynard Delphine, Haaz Marie-Christine, Bayssas Martine, Bonnet Jacques, Robert Jacques
DiGEM S. A., Bordeaux, France.
Cancer Res. 2004 Jan 1;64(1):356-62. doi: 10.1158/0008-5472.can-03-2258.
Gene expression profiling of tumors allows the establishment of relationships between gene expression profiles and sensitivity to anticancer drugs. In an attempt to study the molecular determinants of the activity of platinum compounds, we explored the publicly available databases of the National Cancer Institute (NCI; http://dtp.nci.nih.gov), which allow access to the gene expression profiles of the 60 cell lines for which drug cytotoxicity patterns already existed. Using this database, we have conducted an in silico research to identify the genes the expression of which was positively or negatively correlated to the sensitivity to four platinum compounds (cisplatin, carboplatin, oxaliplatin and tetraplatin). Important similarities were noticed between cisplatin and carboplatin on one hand, and tetraplatin and oxaliplatin on the other hand. In the restricted panel of 1416 genes and molecular markers, we identified 204 markers, among which 120 corresponded to identified genes, that significantly correlated (P < 0.001) with the cytotoxicity of at least one platinum compound. For example, the functionality of the p53-activated pathway appeared positively correlated with the cytotoxicity of all platinum compounds. More specific are the positive correlations between RAS gene mutations and MYC expression and the cellular sensitivity to oxaliplatin. Among the parameters already known as related to the sensitivity to platinum compounds, we identified, in the complete set of 9400 genes, numerous significant relationships, such as the negative correlations between ERB-B2 and BCL-X(L) expressions and the cytotoxicity of the platinum compounds. Public databases mining, therefore, appears to be a valuable tool for the identification of determinants of anticancer drug activity in tumors.
肿瘤的基因表达谱分析有助于建立基因表达谱与抗癌药物敏感性之间的关系。为了研究铂类化合物活性的分子决定因素，我们探索了美国国立癌症研究所（NCI；http://dtp.nci.nih.gov）的公开数据库，该数据库可获取60种细胞系的基因表达谱，这些细胞系已有药物细胞毒性模式。利用该数据库，我们进行了一项计算机模拟研究，以确定那些基因的表达与四种铂类化合物（顺铂、卡铂、奥沙利铂和四铂）的敏感性呈正相关或负相关。一方面，顺铂和卡铂之间，另一方面，四铂和奥沙利铂之间，发现了重要的相似性。在1416个基因和分子标记的受限面板中，我们鉴定出204个标记，其中120个对应于已鉴定的基因，它们与至少一种铂类化合物的细胞毒性显著相关（P < 0.001）。例如，p53激活途径的功能似乎与所有铂类化合物的细胞毒性呈正相关。RAS基因突变和MYC表达与细胞对奥沙利铂的敏感性之间的正相关更为特异。在已知与铂类化合物敏感性相关的参数中，我们在9400个基因的完整集合中鉴定出许多显著关系，例如ERB - B2和BCL - X(L)表达与铂类化合物细胞毒性之间的负相关。因此，挖掘公共数据库似乎是识别肿瘤中抗癌药物活性决定因素的一个有价值的工具。
