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- Title
Use of isogenic human cancer cells for high-throughput screening and drug discovery.
- Authors
Torrance, C J; Agrawal, V; Vogelstein, B; Kinzler, K W
- Abstract
Cell-based screening for novel tumor-specific drugs has been compromised by the lack of appropriate control cells. We describe a strategy for drug screening based on isogenic human cancer cell lines in which key tumorigenic genes have been deleted by targeted homologous recombination. As a test case, a yellow fluorescent protein (YFP) expression vector was introduced into the colon cancer cell line DLD-1, and a blue fluorescent protein (BFP) expression vector was introduced into an isogenic derivative in which the mutant K-Ras allele had been deleted. Co-culture of both cell lines allowed facile screening for compounds with selective toxicity toward the mutant Ras genotype. Among 30,000 compounds screened, a novel cytidine nucleoside analog was identified that displayed selective activity in vitro and inhibited tumor xenografts containing mutant Ras. The present data demonstrate a broadly applicable approach for mining therapeutic agents targeted to the specific genetic alterations responsible for cancer development.
- Publication
Nature biotechnology, 2001, Vol 19, Issue 10, p940
- ISSN
1087-0156
- Publication type
Journal Article
- DOI
10.1038/nbt1001-940