title: Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer.
abstract: The folate derivatives folic acid (FA) and folinic acid (FNA) decrease the in vivo and in vitro activities of antifolate drugs in Plasmodium falciparum. However, the effects of 5-methyl-tetrahydrofolate (5-Me-THF) and tetrahydrofolate (THF), the two dominant circulating folate forms in humans, have not been explored yet. We have investigated the effects of FA, FNA, 5-Me-THF, and THF on the in vitro activity of the antimalarial antifolates pyrimethamine and chlorcycloguanil and the anticancer antifolates methotrexate (MTX), aminopterin, and trimetrexate (TMX), against P. falciparum. The results indicate that these anticancers are potent against P. falciparum, with IC50 < 50 nM. 5-Me-THF does not significantly decrease the activity of all tested drugs, and none of the tested folate derivatives significantly decrease the activity of these anticancers. Thus, malaria folate metabolism has features different from those in human, and the exploitation of this difference could lead to the discovery of new drugs to treat malaria. For instance, the combination of 5-Me-THF with a low dose of TMX could be used to treat malaria. In addition, the safety of a low dose of MTX in the treatment of arthritis indicates that this drug could be used alone to treat malaria.
authors.affiliation: Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, PO Box 230, 80108 Kilifi, Kenya.
authors.forename: Eunice
authors.initials: E
authors.lastname: Nduati
authors.forename: Abdi
authors.initials: A
authors.lastname: Diriye
authors.forename: Sheila
authors.initials: S
authors.lastname: Ommeh
authors.forename: Leah
authors.initials: L
authors.lastname: Mwai
authors.forename: Steven
authors.initials: S
authors.lastname: Kiara
authors.forename: Victor
authors.initials: V
authors.lastname: Masseno
authors.forename: Gilbert
authors.initials: G
authors.lastname: Kokwaro
authors.forename: Alexis
authors.initials: A
authors.lastname: Nzila
mesh_terms: D000630:Aminopterin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D005492:Folic Acid / Q000378:metabolism*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D002955:Leucovorin / Q000378:metabolism; D008727:Methotrexate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D002727:Proguanil / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011739:Pyrimethamine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013763:Tetrahydrofolates / Q000378:metabolism; D014227:Triazines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016597:Trimetrexate / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013763:Tetrahydrofolates; D014227:Triazines; C026009:cycloguanil; C030371:5,6,7,8-tetrahydrofolic acid; D005492:Folic Acid; D000630:Aminopterin; D002955:Leucovorin; D002727:Proguanil; C005984:5-methyltetrahydrofolate; D016597:Trimetrexate; D008727:Methotrexate; D011739:Pyrimethamine