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

Weiguang Wang, Howard L. McLeod, James Cassidy, Elaina S. R. Collie-Duguid

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29 Citations (Scopus)

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-kappa B 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 mu M) 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-kappa B 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-kappa B 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-kappa B over-expression may be involved in TS-independent 5-FU chemoresistance in some cancer cell lines.

Original languageEnglish
Pages (from-to)839-845
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume59
Issue number6
Early online date22 Nov 2006
DOIs
Publication statusPublished - Jun 2007

Keywords

  • 5-fluorouracil
  • tomudex
  • thymidylate synthase
  • cross-resistance
  • NF-kappaB
  • cancer cell-lines
  • colorectal-cancer
  • dihydropyrimidine dehydrogenase
  • protein expression
  • inhibitors
  • resistant
  • cytotoxicity
  • fluorouracil
  • sensitivity
  • thymidine

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