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

Abstract

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-FU-induced leukoencephalopathy with reversible lesion of splenium of corpus callosum in a patient with colorectal cancer

“…Leucovorin, a compound similar to folinic acid, has almost no side effects of its own. Concomitant use of leucovorin with 5-FU is essential because leucovorin increases the intracellular concentration of 5-FU in the tumour, and hence enhance the antineoplastic activities 4. Irinotecan binds reversibly to topoisomerase I-DNA complex, leading to termination of cellular replication.…”

Cancer drug resistance: a new perspective

“…When a drug, in this case FdUMP, the active metabolite of 5FU, hits its target TS, the cell can respond by modifying the target, e.g., by increasing the gene expression or the (1) at oral administration gut uptake can be poor; (2) i.v. administration can be associated with extensive renal clearance or liver metabolic clearance by phase I and II enzymes; (3) from the tumor blood capillaries the drug can be taken up by either diffusion (single arrow), facilitated transport (tube) or active transport (cross); (4) in the cell the drug can be activated or inactivated; (5) these metabolites can be effluxed; (6) the drug can be sequestered (e.g., in the lysosome, where it can be protonated); (7) the drug can hit a protein kinase; (8) or DNA; (9) or other targets. The cell can respond to changes in any of these processes (either increase or decrease), activate alternative signaling pathways, modify the target, or repair the damage activity of the target, modify the drug binding or enabling the cell to increase the concentration of its target [8] , making it less sensitive.…”

Relationship between folate concentration and expression of folate-associated genes in tissue and plasma after intraoperative administration of leucovorin in patients with colorectal cancer

“…Although the Nordic FLV is a well-established regimen, the evidence for a beneficial effect of the LV dosage and administration used is rather limited. Different regimens used in clinical practice worldwide apply LV concentrations that range from 20 to 500 mg/m 2 and are often empirically evolved [14]. …”