Biological and biochemical properties of new anticancer folate antagonists

Abstract

We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTXinsensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.

Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast

“…Aminopterin inhibits the activity of dihydrofolate reductase (DHFR), an enzyme that is required for purine biosynthesis and for which there is a high demand in rapidly growing cells [28]. Given that these two deletants have reduced growth rates even in the absence of drugs (data not shown), it may be that the consequent reduced demand for DHFR activity makes them less susceptible to the deleterious effects of DHFR inhibitors such as aminopterin.…”

Maternal tea consumption during early pregnancy and the risk of spina bifida

“…The inhibition of DHFR may also lead to decreased intestinal uptake of folate, because DHFR plays a role in intestinal absorption of folate (Alemdaroglu et al, 2007). In addition, catechins are structurally similar to the chemotherapy agents methotrexate and aminopterin, both of which are known folate antagonist and inhibitors of DHFR (Fry and Jackson, 1987;Berman and Werbel, 1991;Longo-Sorbello and Bertino, 2001;Navarro-Perán et al, 2005;Alemdaroglu et al, 2007).…”

Synthesis and anticancer activity evaluation of novel derivatives of 7-amino-4-methylquinolin-2(1H)-one

“…These drugs are most effective in cells with high production of nucleic acids, which are rapidly proliferating (among others tumor cells). The protected hydroxyl groups indicate a structural correlation with trimetrexate, which is a folic acid antagonist (7,8).…”