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

Research output: Contribution to journalArticle

28 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

Cite this

Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex : thymidylate synthase dependent and independent networks. / Wang, Weiguang; McLeod, Howard L.; Cassidy, James; Collie-Duguid, Elaina S. R.

In: Cancer Chemotherapy and Pharmacology, Vol. 59, No. 6, 06.2007, p. 839-845.

Research output: Contribution to journalArticle

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title = "Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: thymidylate synthase dependent and independent networks",
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.",
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",
author = "Weiguang Wang and McLeod, {Howard L.} and James Cassidy and Collie-Duguid, {Elaina S. R.}",
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TY - JOUR

T1 - Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex

T2 - thymidylate synthase dependent and independent networks

AU - Wang, Weiguang

AU - McLeod, Howard L.

AU - Cassidy, James

AU - Collie-Duguid, Elaina S. R.

PY - 2007/6

Y1 - 2007/6

N2 - 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.

AB - 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.

KW - 5-fluorouracil

KW - tomudex

KW - thymidylate synthase

KW - cross-resistance

KW - NF-kappaB

KW - cancer cell-lines

KW - colorectal-cancer

KW - dihydropyrimidine dehydrogenase

KW - protein expression

KW - inhibitors

KW - resistant

KW - cytotoxicity

KW - fluorouracil

KW - sensitivity

KW - thymidine

U2 - 10.1007/s00280-006-0384-5

DO - 10.1007/s00280-006-0384-5

M3 - Article

VL - 59

SP - 839

EP - 845

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 6

ER -