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.

PATIENTS AND 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.

CONCLUSION

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.