Bracker Tomke Ute, Sommer Anette, Fichtner Iduna, Faus Hortensia, Haendler Bernard, Hess-Stumpp Holger
Global Drug Discovery, Therapeutic Research Group Oncology, Bayer Schering Pharma AG, 13353 Berlin, Germany.
Int J Oncol. 2009 Oct;35(4):909-20. doi: 10.3892/ijo_00000406.
N-(2-aminophenyl)-4-[N-(pyridine-3yl-methoxy-carbonyl) aminomethyl] benzamide (MS-275) is a second generation histone deacetylase (HDAC) inhibitor with significant anti-tumor efficacy currently in clinical development. We investigated the effect of MS-275 treatment on various colon cancer cell lines, as well as on mouse xenograft models derived from human colorectal cancer. MS-275 exerted strong anti-proliferative effects in five cell lines and increased the acetylation of histones 3 and 4. In vivo testing of the compound in eight different models of human colon cancer derived from primary colorectal cancers or from established cell lines revealed that five models were responders, two non-responders and one an anti-responder. Gene expression profiles were determined in order to identify genes and pathways differentially regulated upon MS-275 treatment in responder versus non-responder models. Principle component analysis revealed a correlation of the anti-tumor efficacy with the sub-clustering of the MS-275 treatment groups in 7 out of 8 models. Although the overall gene expression pattern was rather unique for each individual model, 129 genes were significantly up- and 58 genes significantly down-regulated in at least 2 out of 5 responder models in response to MS-275 treatment. We identified potential biomarkers for response to MS-275, such as PRA1, MYADM and PALM2-AKAP2 which were up-regulated in all responder models and down-regulated or unchanged in all non-responder models. Our results provide a starting point for the development of clinically relevant biomarkers for predicting a response to MS-275 and the understanding of the mode of action of this HDAC inhibitor.
N-(2-氨基苯基)-4-[N-(吡啶-3-基甲氧基羰基)氨甲基]苯甲酰胺（MS-275）是一种第二代组蛋白去乙酰化酶（HDAC）抑制剂，具有显著的抗肿瘤疗效，目前正处于临床开发阶段。我们研究了MS-275处理对各种结肠癌细胞系以及源自人类结直肠癌的小鼠异种移植模型的影响。MS-275在五种细胞系中发挥了强大的抗增殖作用，并增加了组蛋白3和4的乙酰化。在源自原发性结直肠癌或已建立细胞系的八种不同人类结肠癌模型中对该化合物进行的体内测试显示，五种模型有反应，两种无反应，一种为抗反应。测定基因表达谱以鉴定在反应者与无反应者模型中经MS-275处理后差异调节的基因和途径。主成分分析显示，在8个模型中的7个中，抗肿瘤疗效与MS-275处理组的亚聚类相关。尽管每个个体模型的总体基因表达模式相当独特，但在5个反应者模型中的至少2个中，有129个基因显著上调，58个基因显著下调，这是对MS-275处理的反应。我们鉴定了对MS-反应的潜在生物标志物，例如PRA1、MYADM和PALM2-AKAP2，它们在所有反应者模型中上调，在所有无反应者模型中下调或不变。我们的结果为开发预测对MS-275反应的临床相关生物标志物以及理解这种HDAC抑制剂的作用模式提供了一个起点。
