Overview: rational basis for development of fluoropyrimidine/5-formyltetrahydrofolate combination chemotherapy.
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.
Huennekens
F M
FM
Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California 92037.
Montejano
Y D
YD
Vitols
K S
KS
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015195:Drug Design; D005472:Fluorouracil / Q000008:administration & dosage; D005575:Formyltetrahydrofolates / Q000008:administration & dosage; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000378:metabolism
D005575:Formyltetrahydrofolates; D011743:Pyrimidines; D013940:Thymidylate Synthase; D005472:Fluorouracil