Thymidylate synthase expression and activity: relation to S-phase parameters and 5-fluorouracil sensitivity

• Published in: British journal of cancer 1998-07, Vol.78 (1), p.62-68
• Main Authors: Mirjolet, J-F, Barberi-Heyob, M, Merlin, J-L, Marchal, S, Etienne, M-C, Milano, G, Bey, P
• Format: Article
• Language: English
• Subjects: Antimetabolites, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Division - drug effects; Chemotherapy; Dihydrouracil Dehydrogenase (NADP); Drug Resistance; Epidemiology; experimental-therapeutics; Fluorouracil - pharmacology; Gene Expression Regulation, Enzymologic; Humans; Medical sciences; Molecular Medicine; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Oncology; Oxidoreductases - metabolism; Pharmacology. Drug treatments; S Phase - physiology; Thymidylate Synthase - genetics; Thymidylate Synthase - metabolism; Tumor Cells, Cultured - drug effects
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.1998.443

Six human cancer cell lines exhibiting a large range of sensitivity to 5-fluorouracil (5-FU) were evaluated for thymidylate synthase (TS) and p53 gene expression, TS and dihydropyrimidine dehydrogenase (DPD) activity, as well as cell cycle parameters, S-phase fraction (SPF), bromodeoxyuridine labelling index (LI) and S-phase duration (SPD). All these parameters were investigated for 7 days in asynchronously growing cell populations and compared with the cell sensitivity to 5-FU. No significant correlation was found between S-phase parameters and TS gene expression and/or activity. TS activity was higher in proliferating cells; however, it was not significantly higher in rapidly growing cell lines with short SPD. Neither TS gene expression nor activity was found to correlate with 5-FU sensitivity. On the another hand, a statistically significant correlation (P < 0.0001) was observed between LI and SPD and 5-FU sensitivity. The present results suggest that cell cycle parameters such as SPD and/or LI could be better parameters for 5-FU sensitivity prediction than TS gene expression and/or activity. This could be especially informative in cases of concomitant radio-chemotherapy as S-phase parameters are already proposed for hyperfractionated radiotherapy planning.