Feasibility of measuring 5-fluorouracil catabolic potential by oral loading.

The efficacy of 5-fluorouracil (5-FU) treatment and the incidence of adverse events differ among patients and depend to some extent on individual variations in drug catabolism. This feasibility study aimed to determine the optimum conditions for a 5-FU oral load test, which would allow the simple evaluation of individual differences in 5-FU catabolism. Patients with colon cancer were given oral 5-FU (200 mg/day) for 3 days (n = 36) or a single 100 mg dose (n = 14). Serum concentrations of uracil, dihydrouracil, 5-FU and 5-fluoro-5,6-dihydrouracil were measured before and after 5-FU administration. The results suggested that a decline in 5-FU metabolism was associated with continuous administration and increasing age. We conclude that a continuous load of 5-FU is necessary in order to predict the efficacy and side-effects of the drug. The 3-day regimen, with its ease of administration, merits further study to assess its possible clinical application.

[Correlation between 5-fluorouracil (5-FU) sensitivity as measured by collagen gel droplet embedded culture drug sensitivity test (CD-DST) and expression of orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) in colorectal cancer].

The levels of OPRT, DPD, and TS were determined in colorectal cancer tissue specimens, and 5-FU sensitivity was measured by CD-DST. The correlation between enzyme activity and 5-FU sensitivity was then studied. Six patients with colorectal carcinoma who had undergone surgical resection in our institution between May and August 2000 were studied. The CD-DST method was used to measure the sensitivity to 5-FU under three sets of conditions: 0.2 microgram/ml x 5 days (A), 1.0 microgram/ml x 1 day (B), and 10.0 micrograms/ml x 3 h (C). The coefficients of correlation of tumor sensitivity to 5-FU and OPRT activity were A: 0.8246, B: 0.7670, and C: 0.7856, and to DPD activity were A: 0.2525, B: 0.3928, and C: 0.4337, while the coefficients of correlation to TS enzyme levels were A: -0.5240, B: -0.4770, and C: -0.6131. These findings demonstrate a high degree of correlation between OPRT activity at the tumor site and tumor sensitivity to 5-FU under a variety of conditions, suggesting that OPRT activity can be a useful indicator in predicting the anti-tumor effectiveness of 5-FU for a specific tumor.

[Expression and pathophysiologic features of orotate phosphoribosyl transferase activity (OPRT) in gastric carcinoma].

Orotate phosphoribosyl transferase (OPRT) is an enzyme that converts the pyrimidine fluoride-class anticancer drug 5-fluorouracil (5-FU) into the active nucleotide form. As such, it can be considered a primary enzyme in the first stage inhibiting DNA and RNA expression. The present study measured OPRT activity both in gastric carcinoma tissue and in surrounding normal tissue, and investigated the correlation between these findings and clinicopathologic characteristics in the patients. The study subjects were 20 patients with gastric carcinoma who were treated by surgical resection in our department. The relationship between OPRT activity in gastric carcinoma and surrounding normal tissue and patient age, sex, tissue type, extent of tumor invasion, extent of metastasis to the lymph nodes, lymphatic invasion and the existence of venous invasion of the gastric wall were investigated. The mean OPRT activity for all patients was 0.039 +/- 0.042 nmol/min/mg-prot in normal tissue and 0.120 +/- 0.099 nmol/min/mg-prot in tumor tissue, and the mean ORPT activity was significantly higher in tumor tissue than in surrounding normal tissue (p < 0.01). The OPRT ratio for tumor tissue/normal tissue (T/N) was significantly decreased as the invasiveness of the tumor increased, and was also significantly lower in patients with lymph node metastasis (p < 0.05) than in patients without lymph node metastasis. A decrease of OPRT activity in tumor tissue is a possible reason for the equivocal results of 5-FU-based chemotherapy in advanced gastric carcinoma.