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Wolverhampton Intellectual Repository and E-Theses > Research Institutes > Research Institute in Healthcare Science > Cancer Research Group > Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells.

Please use this identifier to cite or link to this item: http://hdl.handle.net/2436/29505
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Title: Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells.
Authors: Wang, Weiguang
Cassidy, James
O'Brien, Vincent
Ryan, Kevin
Collie-Duguid, Elaina
Citation: Cancer Research, 64 (22): 8167-76
Publisher: American Association for Cancer Research
Journal: Cancer Research
Issue Date: 2004
URI: http://hdl.handle.net/2436/29505
DOI: 10.1158/0008-5472.CAN-04-0970
PubMed ID: 15548681
Additional Links: http://cancerres.aacrjournals.org/cgi/content/full/64/22/8167
Abstract: Gene expression was analyzed in five pairs of 5-fluorouracil (5-FU) resistant and parental cancer cell lines on DNA microarrays. In unsupervised analysis, a prediction rule was built from the expression profiles of 29 genes, and 5-FU sensitivity class was predicted with 100% accuracy and high predictive strength. In supervised analysis of key 5-FU pathways, expression of 91 genes was associated with 5-FU sensitivity phenotype and segregated samples accordingly in hierarchical analysis. Key genes involved in 5-FU activation were significantly down-regulated (thymidine kinase, 2.9-fold; orotate phosphoribosyltransferase, 2.3-fold; uridine monophosphate kinase, 3.2-fold; pyrimidine nucleoside phosphorylase 3.6-fold) in resistant cells. Overexpression of thymidylate synthase and its adjacent gene, c-Yes, was detected in the resistant cell lines. The mRNA and protein overexpression of nuclear factor kappaB (NFkappaB) p65 and related antiapoptotic c-Flip gene was detected in resistant cells. The 5-FU-resistant cell lines also showed high NFkappaB DNA-binding activity. Cotransfection of NFkappaB p50 and p65 cDNA induced 5-FU resistance in MCF-7 cells. Both NFkappaB- and 5-FU-induced resistant cell lines manifested reduced expression of genes governing G(1)-S and S-phase transition. Expression of genes involved in DNA replication was also down-regulated in resistant cell lines. These findings were highly consistent with the slower growth rate, higher proportion of G(1), and lower proportion of S-phase cells in the resistant cell lines. This phenotype may protect resistant cells from cell death induced by incorporation of 5-FU into DNA chains, by allowing time to repair 5-FU-induced damage. Our findings may provide novel targets for tackling 5-FU resistance.
Type: Article
Language: en
MeSH: Base Sequence
Cell Line, Tumor
DNA Primers
Down-Regulation
Drug Resistance, Neoplasm
Flow Cytometry
Fluorouracil
G1 Phase
Gene Expression Profiling
Humans
Oligonucleotide Array Sequence Analysis
Phenotype
ISSN: 0008-5472
Appears in Collections: Cancer Research Group

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