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5-Fluorouracil: identification of novel downstream mediators of tumour response
John Boyer1, Pamela J Maxwell, Daniel B Longley
1Department of Oncology, Cancer Research Centre, Queen's University Belfast, Belfast, N. Ireland.
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.
Materials And 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.
Conclusion:
These data demonstrate the potential of microarray analysis to identify novel genes associated with response or resistance to chemotherapeutic agents.
Insights
Researchers identified novel genes, including SSAT and annexin II, involved in 5-Fluorouracil (5-FU) chemotherapy response and resistance in breast cancer cells using DNA microarrays.
Area of Science:
- Molecular biology
- Genomics
- Cancer research
Background:
- 5-Fluorouracil (5-FU) is a cornerstone chemotherapy for various cancers.
- Acquired or inherent resistance limits 5-FU efficacy.
- Understanding resistance mechanisms is crucial for improving cancer treatment.
Purpose of the Study:
- To identify novel molecular signals and genes involved in the cellular response to 5-FU.
- To investigate the transcriptional changes induced by 5-FU in breast cancer cells.
Main Methods:
- Utilized DNA microarray technology to analyze global transcriptional changes.
- Examined gene expression in MCF-7 breast cancer cells treated with 5-FU.
- Investigated the role of p53 and thymidylate synthase in 5-FU response.
Main Results:
- Identified spermine/spermidine acetyl transferase (SSAT) and annexin II as novel 5-FU-inducible genes.
- Observed similar gene induction with antifolate tomudex (TDX) and oxaliplatin.
- Found that p53 inactivation abrogated 5-FU induction of SSAT and annexin II.
- Noted elevated basal SSAT and annexin II expression in 5-FU-resistant cells.
Conclusions:
- Microarray analysis is a powerful tool for discovering genes linked to chemotherapy response.
- SSAT and annexin II are potential biomarkers for 5-FU sensitivity or resistance.
- These findings contribute to understanding mechanisms of chemotherapy resistance.
