Ternary complex formation and reduced folate in surgical specimens of human adenocarcinoma tissues.
METHODS
Various factors, including thymidylate synthase, thymidine kinase, 5-fluorouracil phosphorylation and degradation pathways, folate concentrations, and the stability of ternary complex, which influence thymidylate synthase inhibition rate of fluoropyrimidines, were studied in 87 human adenocarcinoma tissues.


RESULTS
The activity of the 5-fluorouracil degradation pathway was not significantly lower than the activity of the 5-fluorouracil phosphorylation pathway. The activity of the catabolism pathway of 5-fluorouracil should be considered in human adenocarcinoma tissue during chemotherapy. On the other hand, the means plus or minus standard deviations (means +/- SD) of the concentration of 5,10-methylenetetrahydrofolate and tetrahydrofolate were 0.69 +/- 0.54 and 1.25 +/- 0.69 nM, respectively, for the adenocarcinoma tissues without previous chemotherapy.


CONCLUSIONS
Because the half-life of tritium-labeled ternary complex and folate concentration in cytosol were correlated well, the differences in folate concentration among tumors must influence the dynamic equilibrium of ternary complex formation. Moreover, these results show that the ratio of 5,10-methylenetetrahydrofolate concentration to thymidylate synthase concentration influences the thymidylate synthase inhibition rate in tumor, and that the new synthesis of 5,10-methylenetetrahydrofolate and tetrahydrofolate from other endogenous reduced folates is also important in tumors with high thymidylate synthase concentrations.
Dohden
K
K
Department of Surgery, Faculty of Medicine, Kanazawa University, Japan.
Ohmura
K
K
Watanabe
Y
Y
D000230:Adenocarcinoma / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism; D046508:Culture Techniques; D005472:Fluorouracil / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D002955:Leucovorin / Q000494:pharmacology; D008198:Lymph Nodes / Q000378:metabolism; D010766:Phosphorylation; D013274:Stomach Neoplasms / Q000378:metabolism; D013763:Tetrahydrofolates / Q000032:analysis; D013937:Thymidine Kinase / Q000032:analysis; D013940:Thymidylate Synthase / Q000032:analysis
D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; C030371:5,6,7,8-tetrahydrofolic acid; D005492:Folic Acid; D013940:Thymidylate Synthase; D013937:Thymidine Kinase; D002955:Leucovorin; D005472:Fluorouracil