Appel J R, Johnson J, Narayanan V L, Houghten R A
Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Mol Divers. 1998;4(2):91-102. doi: 10.1023/a:1026441400053.
A new strategy is presented here which integrates combinatorial library technology with the antitumor in vitro screening system at the National Cancer Institute in the search for novel antitumor agents. Mixture-based synthetic combinatorial libraries (SCLs) representing hundreds of thousands to millions of individual compounds were screened against the cell-based assay, which evaluates compounds for their ability to inhibit the growth of 60 different human tumor cell lines. Five different SCLs, composed of peptides, peptidomimetics, polyamines or small molecules were first tested against three cell lines to identify the most active SCLs. Two SCLs, namely the N-perbenzylated pentamine and the N-acylated permethylated triamine, were deconvoluted to yield individual compounds having significant activities against the 60 tumor cell lines. Active compounds were tested in mice to determine the maximum tolerated dose, followed by in vivo testing in a hollow fiber assay. Using this strategy, three different compounds identified directly from SCLs are currently being evaluated in human tumor xenografts. This study demonstrates for the first time the use of in vitro cell-based assays to identify antitumor lead compounds from mixture-based combinatorial libraries.
本文提出了一种新策略，该策略将组合文库技术与美国国立癌症研究所的体外抗肿瘤筛选系统相结合，以寻找新型抗肿瘤药物。针对基于细胞的检测方法，对代表数十万至数百万种单个化合物的基于混合物的合成组合文库（SCL）进行了筛选，该检测方法评估化合物抑制60种不同人类肿瘤细胞系生长的能力。首先针对三种细胞系测试了由肽、拟肽、多胺或小分子组成的五种不同SCL，以鉴定活性最高的SCL。对两种SCL，即N-全苄基化五胺和N-酰化全甲基化三胺进行解卷积，以产生对60种肿瘤细胞系具有显著活性的单个化合物。在小鼠中测试活性化合物以确定最大耐受剂量，随后在中空纤维试验中进行体内测试。使用该策略，目前正在对直接从SCL中鉴定出的三种不同化合物进行人肿瘤异种移植体内评估。这项研究首次证明了使用基于细胞的体外检测方法从基于混合物的组合文库中鉴定抗肿瘤先导化合物。
