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Systems pharmacology assessment of the 5-fluorouracil pathway.

ABSTRACT: 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.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 IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) for control-treated cells.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).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.

SUBMITTER: Muhale FA

PROVIDER: S-EPMC3124653 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Systems pharmacology assessment of the 5-fluorouracil pathway.

Muhale Filipe A FA Wetmore Barbara A BA Thomas Russell S RS McLeod Howard L HL

Pharmacogenomics 20110301 3

<h4>Aim</h4>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.<h4>Materials & methods</h4>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 consi ...[more]

PMID: 21449674

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