Parasitol Res (2008) 102:1227–1234 DOI 10.1007/s00436-008-0897-4 ORIGINAL PAPER Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer Eunice Nduati & Abdi Diriye & Sheila Ommeh & Leah Mwai & Steven Kiara & Victor Masseno & Gilbert Kokwaro & Alexis Nzila Received: 6 December 2007 / Accepted: 21 January 2008 / Published online: 9 February 2008 # The Author(s) 2008 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 tetra- hydrofolate (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 This study was supported by Pfizer-Royal Society Award, UK (to AN), the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834, and the European & Developing Countries Clinical Trials Partnership (EDCPT). Electronic supplementary material The online version of this article (doi:10.1007/s00436–008–0897–4) contains supplementary material, which is available to authorized users. E. Nduati : A. Diriye : L. Mwai : S. Kiara : V. Masseno : A. Nzila (*) Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya e-mail: Anzila@kilifi.kemri-wellcome.org S. Ommeh : G. Kokwaro (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 43640, 00100 Nairobi, Kenya A. Nzila Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L53 QA5, UK A. Nzila Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK antifolates methotrexate (MTX), aminopterin, and trime- trexate (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. Abbreviations 5-Me-THF 5-methyl-tetrahydrofolate ATV atovaquone CCG chlorcycloguanil CQ chloroquine CPG chlorproguanil DDS dapsone DHFR dihydrofolate reductase DHPS dihydropteroate synthase DEAQ desethyl-amodiaquine DHA dihydroartemisinin FA folic acid FD folate derivatives FNA folinic acid HLF halofantrine LD-MTX low dose of methotrexate LM lumefantrine QN quinine