Systems pharmacology assessment of the 5-fluorouracil pathway. (March 2011)

• Record Type: Journal Article
• Authors: Muhale, Filipe A; Wetmore, Barbara A; Thomas, Russell S; McLeod, Howard L
• Is Part Of: Pharmacogenomics. Volume 12:Number 3(2011)
• Page Start: 341
• Page End: 350
• Publication Date: 2011-03
• Subjects: 5-fluorouracil pathway -- candidate genes prioritization -- colon cancer -- pharmacogenomics -- RNAi; Pharmacogenomics -- Periodicals; 615.1
• DOI: 10.2217/pgs.10.188
• Languages: English
• ISSNs: 1462-2416

Abstract

Aim: To assess the impact of the 5-fluorouracil (5-FU) drug-pathway genes on cytotoxicity, and determine whether loss-of-function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes.Materials & methods: Dose-response experiments were used to quantify the phenotype of sensitivity to 5-FU following the specific knockdown of genes selected from the 5-FU PharmGKB drug pathway in three human colorectal cell lines. Changes in sensitivity were considered significant if the IC50 for shRNA-exposed cells were three standard deviations outside the mean IC50 for control-treated cells.Results: Of the 24 genes analyzed, 13 produced significant changes on the phenotype of sensitivity to 5-FU ( DHFR, DPYS, DTYMK, DUT, FPGS, GGH, NME1, NT5C, RRM1, TYMS, UCK2, UNG and UMPS ).Conclusion: The RNAi screening strategy enabled prioritization of the genes from the 5-FU drug pathway. Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples. Original submitted 28 May 2010; Revision submitted 16 November 2010.