Overview: rational basis for development of fluoropyrimidine/5-formyltetrahydrofolate combination chemotherapy.

Abstract:

:Fluorodeoxyuridylate (FdUMP) and thymidylate synthase (TS) are one of the better understood systems of drug-target interaction in cancer chemotherapy. Isolation and characterization of TS (initially from Lactobacillus casei and later from a variety of other sources), cloning and sequencing of the gene, determination of the 3-D structure of the enzyme by X-ray diffraction, and elucidation of the structure of both the catalytic intermediate and the enzyme-inhibitor complex have revealed critical parameters of the target at the molecular level. Potentiation of FdUMP binding by 5,10-methylenetetrahydrofolate (CH2-FH4), discovered at the enzymatic level, has been exploited to increase the clinical effectiveness of fluoropyrimidines. CH2-FH4 can be generated from folate, 5-methyltetrahydrofolate, or 5-formyltetrahydrofolate (citrovorum factor, CF); the latter is the compound of choice for therapeutic regimens. Transformation of CF to CH2-FH4 can occur via two pathways: (a) CF----5,10-methyltetrahydrofolate----CH2-FH4; or (b) CF----tetrahydrofolate----CH2-FH4. The relative importance of these pathways in various cells is not yet clear. The role of CH2-FH4 in FdUMP toxicity, and its central position in folate coenzyme-dependent C1 metabolism, emphasize the need for development of methods to quantitate intracellular levels of this compound.

journal_name

Adv Exp Med Biol

authors

Huennekens FM,Montejano YD,Vitols KS

doi

10.1007/978-1-4684-5607-3_1

subject

Has Abstract

pub_date

1988-01-01 00:00:00

pages

1-11

eissn

0065-2598

issn

2214-8019

journal_volume

244

pub_type

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