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Cancer Chemother Pharmacol. 2007 May;59(6):839-45. Epub 2006 Nov 22.

Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: thymidylate synthase dependent and independent networks.

Author information

1
Research Institute in Healthcare Science, School of Applied Sciences, University of Wolverhampton, Wolverhampton, WV1 1SB, UK. w.wang2@wlv.ac.uk

Abstract

PURPOSE:

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.

CONCLUSION:

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.

PMID:
17119966
DOI:
10.1007/s00280-006-0384-5
[Indexed for MEDLINE]

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