Sausville E A, Johnson J I
Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 6130 Executive Blvd. Suite 8000, Rockville, MD 20852, USA.
Br J Cancer. 2000 Dec;83(11):1401-4. doi: 10.1054/bjoc.2000.1473.
A new approach to cancer drug discovery targets molecules important in cancer pathogenesis. This approach is thought to be of greater promise than the antiproliferative screens which discovered cytotoxic agents and dominated cancer drug discovery for 60 years. However, one cannot lose sight of the fact that these targets exist in the cellular environment consisting of many additional influences on target function, and that effective drug treatment will take into account drug uptake, metabolism and elimination at the level of the cell as well as the organism. A key goal is to define for the new millennium a path to cancer drug discovery and development which accounts for the cancer cell phenotype in its totality rather than as arising solely from single molecular targets. The US National Cancer Institute maintains a cell-based drug discovery screen which can define a context for drug action in the milieu of more than 300 molecular targets and thousands of gene expression patterns which have been measured in the 60 human tumour cell lines which comprise the screening panel. The challenge of the millennium will be addressed by molecules active against defined targets but with selectivity of action occurring in the milieu of deregulated cancer cell biology in all its aspects.
一种癌症药物研发的新方法靶向在癌症发病机制中起重要作用的分子。这种方法被认为比发现细胞毒性药物并主导癌症药物研发60年的抗增殖筛选更具前景。然而，不能忽视这样一个事实，即这些靶点存在于由许多对靶点功能有额外影响的因素组成的细胞环境中，而且有效的药物治疗将在细胞以及生物体水平上考虑药物的摄取、代谢和消除。一个关键目标是为新千年定义一条癌症药物研发和开发的路径，该路径要全面考虑癌细胞表型，而不是仅源于单个分子靶点。美国国立癌症研究所维持着一个基于细胞的药物研发筛选体系，该体系能够在由构成筛选小组的60种人类肿瘤细胞系中测量的300多个分子靶点和数千种基因表达模式的环境中确定药物作用的背景。针对在癌细胞生物学全面失调的环境中具有活性且作用具有选择性的分子，将应对千年挑战。
