Yokoi Akira, Kuromitsu Junro, Kawai Takatoshi, Nagasu Takeshi, Sugi Naoko Hata, Yoshimatsu Kentaro, Yoshino Hiroshi, Owa Takashi
Laboratory of Seeds Finding Technology, Eisai Co. Ltd., Ibaraki 300-2635, Japan.
Mol Cancer Ther. 2002 Feb;1(4):275-86.
A series of small molecules from sulfonamide-focused libraries have been evaluated in these laboratories to discover novel antitumor agents. Cell-based screens using flow cytometric analysis revealed the presence of two distinct classes of cell cycle inhibitors in this series; one (including E7010 and ER-67865) arrested mitosis by preventing tubulin polymerization; and the other (including E7070 and ER-68487) caused a decrease in the S-phase fraction along with cell cycle perturbation in G1 and/or G2 via an unknown mechanism(s). To further characterize both classes of antitumor sulfonamides with respect to their effects on gene expression, we used oligonucleotide microarray analysis for representative compounds. Consistent with the phenotypic observations, essentially the same transcription profiles were found between E7010 and ER-67865 and also between E7070 and ER-68487. However, there was very little overlap between genes affected by E7010 and E7070. As a characteristic expression change for microtubule-depolymerizing agents, the down-regulation of alpha-tubulin transcripts was evident in both E7010- and ER-67865-treated cells. On the other hand, E7070 and ER-68487 repressed significantly the expression of a variety of genes involved in metabolic processes, cell cycle progression, immune response, and signal transduction. Of the compounds examined, E7010 and E7070 have progressed to clinical trials, demonstrating some objective responses in the Phase I setting. Described herein is profiling of novel anticancer drug candidates from the sulfonamide class based on phenotypic screens and gene expression analysis. This includes a translational research that may suggest potentially useful markers for pharmacodynamic drug assessment in clinic.
在这些实验室中，对一系列来自以磺胺类为重点的文库的小分子进行了评估，以发现新型抗肿瘤药物。使用流式细胞术分析的基于细胞的筛选揭示了该系列中存在两种不同类型的细胞周期抑制剂；一种（包括E7010和ER-67865）通过阻止微管蛋白聚合来阻止有丝分裂；另一种（包括E7070和ER-68487）通过未知机制导致S期比例降低以及G1和/或G2期的细胞周期紊乱。为了进一步表征这两类抗肿瘤磺胺类药物对基因表达的影响，我们对代表性化合物进行了寡核苷酸微阵列分析。与表型观察结果一致，在E7010和ER-67865之间以及E7070和ER-68487之间发现了基本相同的转录谱。然而，受E7010和E7070影响的基因之间几乎没有重叠。作为微管解聚剂的特征性表达变化，α-微管蛋白转录本的下调在E7010和ER-67865处理的细胞中均很明显。另一方面，E7070和ER-68487显著抑制了多种参与代谢过程、细胞周期进程、免疫反应和信号转导的基因的表达。在所检测的化合物中，E7010和E7070已进入临床试验阶段，在I期试验中显示出一些客观反应。本文描述了基于表型筛选和基因表达分析对磺胺类新型抗癌候选药物进行的分析。这包括一项转化研究，该研究可能为临床药效学药物评估提供潜在有用的标志物。
