title: 5-Fluorouracil: identification of novel downstream mediators of tumour response.
abstract: BACKGROUND
  5-Fluorouracil (5-FU) is routinely used in the treatment of gastrointestinal, breast and head and neck cancers. A major limitation to the use of this drug is acquired or inherent resistance.
  
  
  METHODS
  To examine the downstream molecular signals activated in response to 5-FU, we used DNA microarray technology to examine global transcriptional changes in 5-FU-treated MCF-7 breast cancer cells.
  
  
  RESULTS
  We identified several novel 5-FU-inducible target genes that have not previously been linked to 5-FU response, including spermine/spermidine acetyl transferase (SSAT) and annexin II. Treatment of MCF-7 cells with the antifolate tomudex (TDX) and the DNA damaging agent oxaliplatin also caused up-regulation of each target gene. Inactivation of wild-type p53 abrogated the 5-FU-mediated induction of SSAT and annexin II. Inducible expression of thymidylate synthase completely abrogated TDX-, but not 5-FU-mediated induction of each gene. Furthermore, basal expression of SSAT and annexin II was elevated in cells resistant to 5-FU.
  
  
  CONCLUSIONS
  These data demonstrate the potential of microarray analysis to identify novel genes associated with response or resistance to chemotherapeutic agents.
authors.affiliation: Department of Oncology, Cancer Research Centre, Queen's University Belfast, Belfast, N. Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Boyer
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Maxwell
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Longley
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
mesh_terms: D000123:Acetyltransferases / Q000096:biosynthesis / Q000235:genetics; D017306:Annexin A2 / Q000096:biosynthesis / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077146:Irinotecan; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D011799:Quinazolines / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D017306:Annexin A2; D000964:Antimetabolites, Antineoplastic; D002166:Camptothecin; D005472:Fluorouracil; D005493:Folic Acid Antagonists; D000077146:Irinotecan; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011799:Quinazolines; D013876:Thiophenes; D013940:Thymidylate Synthase; D000099228:Diamine N-Acetyltransferase; C068874:raltitrexed