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Folates as adjuvants to anticancer agents: Chemical rationale and mechanism of action

Artikel i vetenskaplig tidskrift
Författare P. V. Danenberg
Bengt Gustavsson
P. Johnston
P. Lindberg
R. Moser
Elisabeth Odin
G. J. Peters
N. Petrelli
Publicerad i Critical Reviews in Oncology Hematology
Volym 106
Sidor 118-131
ISSN 1040-8428
Publiceringsår 2016
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för kirurgi
Sidor 118-131
Språk en
Länkar dx.doi.org/10.1016/j.critrevonc.201...
Ämnesord Folate metabolism, Leucovorin, Mechanism of action, 5-Fluorouracil, [6R]-5,10-methylene-tetrahydrofolate, gamma-glutamate synthetase, one-carbon metabolism, ternary, complex-formation, thymidylate synthase, folic-acid, colorectal-cancer, folylpolyglutamate synthetase, intracellular metabolism, substrate-analogs, mammalian-cells, Oncology, Hematology
Ämneskategorier Cancer och onkologi

Sammanfattning

Folates have been used with cytotoxic agents for decades and today they are used in hundreds of thousands of patients annually. Folate metabolism is complex. In the treatment of cancer with 5-fluorouracil, the administration of folates mechanistically leads to the formation of [6R]-5,10-methylene-tetrahydrofolate, and the increased concentration of this molecule leads to stabilization of the ternary complex comprising thymidylate synthase, 2'-deoxy-uridine-5'-monophosphate, and [6R]-5,10-methylene-tetrahydrofolate.The latter is the only natural folate that can bind directly in the ternary complex, with other folates requiring metabolic activation. Modulation of thymidylate synthase activity became central in the study of folate/cytotoxic combinations and, despite wide use, research into the folate component was neglected, leaving important questions unanswered. This article revisits the mechanisms of action of folates and evaluates commercially available folate derivatives in the light of current research. Better genomic insight and availability of new analytical techniques and stable folate compounds may open new avenues of research and therapy, ultimately bringing increased clinical benefit to patients. (C) 2016 The Authors. Published by Elsevier Ireland Ltd.

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