Correlation between clinicopathologic factors and kinetics of metabolic enzymes for 5-fluorouracil given to patients with colon carcinoma by two different dosage regimens.
OBJECTIVE
Using tumor tissue specimens from colon carcinoma patients given 5-fluorouracil (5-FU) by two different administration methods, we investigated the degree of correlation between clinicopathologic factors and the kinetics of metabolic enzymes for 5-FU.


METHODS
Group A patients received 500 mg/day of 5-FU as a rapid infusion over 2 h for 3 days preoperatively, and group B patients received 500 mg/day of 5-FU as a continuous infusion for 3 days preoperatively. The activities of orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), uridine phosphorylase (UP), and dihydropyrimidine dehydrogenase (DPD) were measured by separation on ion-exchange filter paper, by high-performance liquid chromatography (HPLC) with UV detection and by HPLC with radioactive flow monitoring, respectively, and the [(3)H]-5-fluorodeoxyuridine monophosphate binding site in thymidylate synthetase (TS) was determined as an index of the amount of TS using a radiobinding assay. The TS inhibition rate (TSIR) was calculated from the formula: 1-(TS(free)/TS(total))x100. Finally, 5-FU incorporation into RNA (FRNA) was measured by capillary gas chromatography-mass spectrometry.


RESULTS
In group A patients, FRNA showed a positive correlation only with OPRT, and TSIR showed positive correlations with OPRT and TP, but a negative correlation with TS. In group B patients, FRNA showed a negative correlation with DPD, and TSIR showed a negative correlation with TS. No difference in TSIR levels was seen between groups A and B. FRNA was higher in group A than in group B, but the difference was not statistically significant.


CONCLUSIONS
The method of administration may influence 5-FU metabolism in colon carcinoma patients.
Katsumata
Kenji
K
Department of Digestive Tract Surgery, Hachioji Medical Center, Tokyo Medical University, 1163, Tate-machi, Hachioji, Tokyo, 193-0944, Japan. k.katsu@col.ne.jp
Tomioka
Hidenori
H
Sumi
Tetsuo
T
Yamashita
Shinya
S
Takagi
Makoto
M
Kato
Fumiaki
F
Nakamura
Ryuji
R
Koyanagi
Yasuhisa
Y
Aoki
Tatsuya
T
Kato
Kohichiro
K
D000368:Aged; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP); D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism*; D013940:Thymidylate Synthase / Q000378:metabolism*; D014543:Uridine Phosphorylase / Q000378:metabolism*
D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; D005472:Fluorouracil