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Crit Rev Oncol Hematol. 2016 Oct;106:118-31. doi: 10.1016/j.critrevonc.2016.08.001. Epub 2016 Aug 9.

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

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Norris Cancer Center and Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
Per Lindberg Consulting AB, Mellangatan 7, Gothenburg, Sweden.
Merck & Cie, Schaffhausen, Switzerland, a Subsidiary of Merck KGaA, Darmstadt, Germany.
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands, The Netherlands. Electronic address:
Helen F Graham Cancer Center and Research Institute at Christiana Care Health System, Newark, DE, USA.


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.


5-Fluorouracil, [6R]-5,10-methylene-tetrahydrofolate; Folate metabolism; Leucovorin; Mechanism of action

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