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

doi:10.1007/s00436-008-0897-4

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

49 Scopus citations

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 IC ₅₀<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.

Original language	English
Pages (from-to)	1227-1234
Number of pages	8
Journal	Parasitology Research
Volume	102
Issue number	6
DOIs	https://doi.org/10.1007/s00436-008-0897-4
State	Published - May 2008
Externally published	Yes

Bibliographical note

Funding Information:
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).

Funding Information:
Acknowledgments We thank the director of the Kenya Medical Research Institute for permission to publish these data. Part of this work was supported by Pfizer-Royal Society Award, UK (to AN) and the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834. AN is a European & Developing Countries Clinical Trials Partnership (EDCPT) senior fellow and LM is an EDCPT Ph.D.-funded student. The experiments comply with the current laws of Kenya.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Parasitology
General Veterinary
Insect Science
Infectious Diseases

Access to Document

10.1007/s00436-008-0897-4

Cite this

@article{3b697cf2fc1d49cab95543f6fa46202b,

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 IC 50<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.",

author = "Eunice Nduati and Abdi Diriye and Sheila Ommeh and Leah Mwai and Steven Kiara and Victor Masseno and Gilbert Kokwaro and Alexis Nzila",

note = "Funding Information: 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). Funding Information: Acknowledgments We thank the director of the Kenya Medical Research Institute for permission to publish these data. Part of this work was supported by Pfizer-Royal Society Award, UK (to AN) and the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834. AN is a European \& Developing Countries Clinical Trials Partnership (EDCPT) senior fellow and LM is an EDCPT Ph.D.-funded student. The experiments comply with the current laws of Kenya.",

year = "2008",

month = may,

doi = "10.1007/s00436-008-0897-4",

language = "English",

volume = "102",

pages = "1227--1234",

number = "6",

}

TY - JOUR

T1 - Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

AU - Nduati, Eunice

AU - Diriye, Abdi

AU - Ommeh, Sheila

AU - Mwai, Leah

AU - Kiara, Steven

AU - Masseno, Victor

AU - Kokwaro, Gilbert

AU - Nzila, Alexis

N1 - Funding Information: 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). Funding Information: Acknowledgments We thank the director of the Kenya Medical Research Institute for permission to publish these data. Part of this work was supported by Pfizer-Royal Society Award, UK (to AN) and the EU Commission under Framework 6 as part of the AntiMal Integrated Project 018834. AN is a European & Developing Countries Clinical Trials Partnership (EDCPT) senior fellow and LM is an EDCPT Ph.D.-funded student. The experiments comply with the current laws of Kenya.

PY - 2008/5

Y1 - 2008/5

N2 - 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 IC 50<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.

AB - 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 IC 50<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.

UR - https://www.scopus.com/pages/publications/42049115684

U2 - 10.1007/s00436-008-0897-4

DO - 10.1007/s00436-008-0897-4

M3 - Article

C2 - 18259776

AN - SCOPUS:42049115684

SN - 0932-0113

VL - 102

SP - 1227

EP - 1234

JO - Parasitology Research

JF - Parasitology Research

IS - 6

ER -

Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer

Abstract

Bibliographical note

UN SDGs

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this