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

Wang, W., McLeod, H., Cassidy, J. and Collie-Duguid, E. (2007) Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: thymidylate synthase dependent and independent networks. Cancer Chemotherapy and Pharmacology, 59(6), pp. 839-845. (doi: 10.1007/s00280-006-0384-5)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cassidy, Professor James
• Authors: Wang, W., McLeod, H., Cassidy, J., and Collie-Duguid, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Chemotherapy and Pharmacology
• ISSN: 0344-5704
• ISSN (Online): 1432-0843