Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: thymidylate synthase dependent and independent networks.
OBJECTIVE
Thymidylate synthase (TS) over-expression is widely accepted as a major molecular mechanism responsible for 5-fluorouracil (5-FU) and tomudex (TDX) resistance. In this study, the importance of TS in 5-FU and TDX resistance was evaluated.


METHODS
The sensitivity of TS-over-expressing 5-FU (3) and TDX (3) resistant cell lines to 5-FU and TDX was analysed. The cross-resistance between 5-FU and TDX resistant cell lines was determined. The relationship between p53 and NF-kappaB status and the sensitivity to 5-FU and TDX was evaluated.


RESULTS
Compared to relevant parental sensitive cell lines, the 5-FU resistant cell lines were highly cross-resistant to TDX (over 20,000-fold). In contrast, over-expression of TS did not significantly confer 5-FU resistance on the TDX resistant cell lines (0.8- to 1.3-fold). Thymidine (20 microM) rescue induced TDX resistance in TDX sensitive cell lines (over 10,000-fold) but only moderately influenced 5-FU sensitivity in 5-FU sensitive cell lines (1.1- to 2.4-fold). Uridine moderately protected one cancer cell line (RKO) from 5-FU-induced, but not TDX-induced, cytotoxicity. NF-kappaB transfected MCF-7 and p53 knockout HCT116 cells were resistant to 5-FU (4.4- and 2.4-fold, respectively) but not to TDX. TS protein expression in NF-kappaB transfected and p53 knockout cell lines was comparable to the relevant parental cell lines.


CONCLUSIONS
In some cancer cell lines, TS-independent molecular events may play a key role in 5-FU resistance. Loss of p53 function and NF-kappaB over-expression may be involved in TS-independent 5-FU chemoresistance in some cancer cell lines.
Wang
Weiguang
W
Research Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton, Wolverhampton, WV1 1SB, UK. w.wang2@wlv.ac.uk
McLeod
Howard L
HL
Cassidy
James
J
Collie-Duguid
Elaina S R
ES
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D013936:Thymidine / Q000494:pharmacology; D013940:Thymidylate Synthase / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D016328:NF-kappa B; D011799:Quinazolines; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D013940:Thymidylate Synthase; C068874:raltitrexed; D005472:Fluorouracil; D013936:Thymidine