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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)