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

• Published in: Cancer chemotherapy and pharmacology 2007-06, Vol.59 (6), p.839-845
• Main Authors: WEIGUANG WANG, MCLEOD, Howard L, CASSIDY, James, COLLIE-DUGUID, Elaina S. R
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Drug Resistance, Neoplasm; Fluorouracil - pharmacology; Humans; Medical sciences; NF-kappa B - metabolism; Pharmacology. Drug treatments; Quinazolines - pharmacology; Thiophenes - pharmacology; Thymidine - pharmacology; Thymidylate Synthase - metabolism; Transfection; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-006-0384-5

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. 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. 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. 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.