title: Systems pharmacology assessment of the 5-fluorouracil pathway.
abstract: OBJECTIVE
  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.
  
  
  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 IC(50) for shRNA-exposed cells were three standard deviations outside the mean IC(50) 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).
  
  
  CONCLUSIONS
  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.
authors: UNC Institute for Pharmacogenomics & Individualized Therapy, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7361, USA.
authors: Filipe A
authors: FA
authors: Muhale
authors: Barbara A
authors: BA
authors: Wetmore
authors: Russell S
authors: RS
authors: Thomas
authors: Howard L
authors: HL
authors: McLeod
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005472:Fluorouracil / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; D013940:Thymidylate Synthase; D005472:Fluorouracil