目的：药物表达谱是发现药物新用途的重要模式，本项目探讨药物表达谱模式在结肠癌候选药物筛选中的应用价值。方法：首先，从PubMed的GEO数据库中获取结肠癌表达谱数据集（No.GSE41258），从美国Memorial Sloan-Kettering癌症中心筛选出53对配对的结肠癌与癌旁正常组织样本数据，采用RMAexpress 软件进行质量分析;然后，采用Dchip软件建立结肠癌特征性表达谱；最后通过Connectivity Map(CMAP)进行结肠癌候选化合物的筛选和实验验证。结果：经芯片质量分析，选择36对配对样本进行后续分析；构建了一个由371个基因组成的结肠癌特征性表达谱，其中上调基因94个，下调基因277个；通过CMAP分析，筛选到vorinostat、tanespimycin（17-AAG）等10种候选药物,选择其中一种富集分数较高的药物17-AAG进行验证；后续实验证实17-AAG可有效抑制结肠癌SW480和HT29株细胞的增殖，其作用24和48 h时，SW480细胞的IC50分别为0.73和0.41 μmol/L；而HT29细胞的IC50分别为0.72和0.50 μmol/L。流式术分析显示，17-AAG可使结肠癌细胞阻滞于G1期。结论：本项目基于药物表达谱模式筛选到多种结肠癌候选药物，揭示药物表达谱模式在药物发现中具有重要意义。

Objective:Gene expression profile is an important pattern to discover new uses of the existing drugs. Application value of the gene expression profile in screening of candidate drugs for colon cancer was discussed. Methods: First of all, data set of gene expression profile for colon cancer (No. GSE41258) was obtained from GEO data bank of PubMed. Fifty-three paired data of colon cancer and colonic mucosal tissues were selected from Memorial Sloan-Kettering Cancer Center of the United States, and their qualities analyzed with RMA express software. Then a gene expression profile for characteristics of colon cancer was established with Dchip software. Finally candidate compounds for therapy of colon cancer were screened by Connectivity Map (CMAP) and confirmed by experiments. Results: Thirty-six paired samples were selected through analysis of microarray chips for further research. A gene expression profile for characteristics of colon cancer was composed of 371 genes which include 94 up-regulation genes and 277 down-regulation genes. With analysis of CMAP, 10 candidate compounds, including vorinostat, tanespimycin (17-AAG) etc, were screened out, in which 17-AAG with high enrichment scores was selected for the validation. By the following experiments, it was confirmed that 17-AAG can effectively inhibit proliferation of colon cancer SW480 and HT29 cell lines. After treatment of 17-AAG for 24 and 48h, the IC50 values of SW480 cell line were 0.73 μmol/L and 0.41 μmol/L respectively, while the IC50 values of HT29 cell line was 0.72 μmol/L and 0.5 μmol/L respectively. Analysis of flow cytometry assay showed that 17-AAG could block cell cycle of the colon cancer cells at G1 phase. Conclusion: Multiple candidate therapeutic compounds for colon cancer were identified based on a pattern of gene expression profiles. A pattern of gene expression profiles might be of an important significance in screening of candidate drugs.

广东省中医药局建设中医药强省项目（No. 20121001）