Different pathways of 5-fluorouracil metabolism after continuous venous or bolus injection in patients with colon carcinoma: possible predictive value of thymidylate synthetase mRNA and ribonucleotide reductase for 5-fluorouracil sensitivity.
BACKGROUND
The mode of action of 5-fluorouracil (5-FU) was evaluated in patients with advanced colon cancer treated preoperatively with 5-FU.


METHODS
After obtaining informed consent, 30 patients were randomized into three groups: untreated controls (n = 16), continuous intravenous infusion of 5-FU for 5 days at a dose of 320 mg/m2 (CIV group, n = 6), or bolus intravenous injection of 5-FU for 5 days at the same dose (bolus group, n = 8). Surgically-resected samples were analyzed by 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to detect sensitivity to 5-FU. Samples were also assayed for thymidylate synthetase (TS) activity, levels of 5-FU RNA (F-RNA), ribonucleotide reductase (RNR) activity, and TS mRNA levels expressed as the ratio of TS mRNA to beta-actin mRNA.


RESULTS
While similar levels of TS inhibition were observed in the civ and bolus groups, F-RNA levels were significantly increased in the bolus group. The TS mRNA ratio was significantly higher in the 5-FU-resistant group than 5-FU-sensitive group. In the control group, the 5-FU-sensitive group showed higher RNR enzymatic activity compared to the 5-FU-resistant group.


CONCLUSIONS
Our results suggested that the method of administration resulted in the induction of different 5-FU metabolic pathways. High TS mRNA and low RNR activity may be concerned with 5-FU-resistance in patients with advanced colon carcinoma.
Kubota
Tetsuro
T
Department of Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo-160, Japan. tkubota@sc.itc.keio.ac.jp
Watanabe
Masahiko
M
Otani
Yoshihide
Y
Kitajima
Masaki
M
Fukushiuma
Masakazu
M
D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D012264:Ribonucleotide Reductases / Q000378:metabolism*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D012264:Ribonucleotide Reductases; D013940:Thymidylate Synthase; C022616:thiazolyl blue; D005472:Fluorouracil