Thymidylate synthase expression and activity: relation to S-phase parameters and 5-fluorouracil sensitivity.
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.
Mirjolet
J F
JF
Centre Alexis Vautrin, Laboratoire de Recherche en Oncologie, Vandoeuvre-les-Nancy, France.
Barberi-Heyob
M
M
Merlin
J L
JL
Marchal
S
S
Etienne
M C
MC
Milano
G
G
Bey
P
P
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D016196:S Phase / Q000502:physiology*; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil