Ternary complex formation and reduced folate in surgical specimens of human adenocarcinoma tissues

Abstract

Background and 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 fluoropyrimdines, 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.

Clinical implications of dihydropyrimidine dehydrogenase (DPD) activity in 5-FU-based chemotherapy: mutations in the DPD gene, and DPD inhibitory fluoropyrimidines

“…DPD activity in carcinoma tissue has been demonstrated to be significantly higher than the activity of orotate phosphoribosyltransferase (OPRT), which is considered to be a rate-limiting enzyme in the 5-FU activating pathway. 12 In 5-FU-based chemotherapy, escape from the degradation catalyzed by DPD is important. Furthermore, in mammals, this catabolic pathway is the only route for the synthesis of F--alanine, which is excreted in urine.…”

“…5-FU is glucosylated through three pathways; OPRT (pathway 1), uridine phosphorylase (pathway 2), and thymidine phosphorylase (pathway 3). 12 The cofactors of the reaction catalyzed by these three enzymes are phosphoribosyl pyrophosphate (PRPP), ribose-5Ј-monophosphate (R-5Ј-P), and deoxyribose-5Ј-monophosphate (dR-5Ј-P), respectively (Fig. 2).…”

Tissue Levels of Reduced Folates in Patients with Colorectal Carcinoma After Infusion of Folinic Acid at Various Dose Levels

“…13) and at doses of 45 mg/m 2 given as a single bolus injection (n = 2) or divided in 3 bolus injections (n = 3; ref. 14). Pretreatment with FA resulted in an increase of reduced folate pools in primary CRC by 2-to 8-fold and 0.5-to 5-fold, respectively (13,14).…”

“…14). Pretreatment with FA resulted in an increase of reduced folate pools in primary CRC by 2-to 8-fold and 0.5-to 5-fold, respectively (13,14). However, due to the very limited number of patients, no firm conclusions can be made with respect to the optimal dose of FA to be used in the clinical setting.…”

Challenging Drug Resistance in Cancer Therapy: Review of the First Nordic Conference on Chemoresistance in Cancer Treatment, October 9th and 10th, 1997

“…Furthermore, the concentrations of TS are higher in tumour tissue than in normal liver tissue (92). Decreased levels of reduced folates may contribute to insufficient TS inhibition (93). On the other hand, the addition of high-dose leucovorin, a prodrug of tetrahydrofolates, is associated with increased TS inhibition (94).…”