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Aspects of one-carbon folate cycling related to fluoropyrimidine and antifolate therapy

1995; Springer Science+Business Media; Linguagem: Inglês

10.1007/978-1-4615-2007-8_6

2509-8497

Colin Paul Spears, Göran Carlsson, Franco M. Muggia, George Jaresko, Bengt Gustavsson,

Folate and B Vitamins Research

Leucovorin (LV) addition to 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine (FUdR) therapy of neoplasms was developed on the rationale that 5-fluorodeoxyuridylate (FdUMP) inhibition of thymidylate synthase (TS) occurs by the ordered, sequential binding of TS, FdUMP, and then 5-10-methylenetetrahydrofolate (CH2FH4) [1–8]. In cell-free kinetic systems, CH2FH4 must be in excess for maximal TS-FdUMP-CH2FH4 ternary complex formation and complete inhibition of TS activity [9–20]. This is called the covalent ternary complex, because of the presence of the methylene bridge between the N5 pteridine and C5 of the 5-FU ring, although the first, but weak, covalent bond exists between the TS active site cysteinyl SH and carbon 6 of 5-FU. Abrogation of TS activity associated with consequent decreases in total TS (ternary complex-bound enzyme plus free enzyme) may be therapeutic goals in colon carcinoma in vivo [21]. This hypothesis was examined in post-5-FU-treated surgical samples of epithelial tumors and normal liver, with suggestive data that high dUMP is associated with poor efficiency of TS inhibition, presumably because of low intratumoral CH2FH4 [22,23].