5-Fluorouracil: identification of novel downstream mediators of tumour response.
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.
Boyer
John
J
Department of Oncology, Cancer Research Centre, Queen's University Belfast, Belfast, N. Ireland.
Maxwell
Pamela J
PJ
Longley
Daniel B
DB
Johnston
Patrick G
PG
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
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