Antimalarial action of nitrobenzylthioinosine in combination with purine nucleoside antimetabolites.
The infection of human erythrocytes by two strains of the human malarial parasite, Plasmodium falciparum (FCQ-27 or the multi-drug-resistant strain K-1), markedly changed the transport characteristics of the nucleosides, adenosine and tubercidin, compared to uninfected erythrocytes. A component of the transport of these nucleosides was insensitive to the classical mammalian nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR). In vitro studies with tubercidin demonstrated ID50 values of 0.43 and 0.51 microM for FCQ-27 and K-1, respectively. In addition, the nucleoside transport inhibitors NBMPR, nitrobenzylthioguanosine (NBTGR), dilazep and dipyridamole also independently exhibited antimalarial activity in vitro. The combination of tubercidin and NBMPR or NBTGR in vitro demonstrated synergistic activity, whilst tubercidin together with dilazep or dipyridamole showed subadditive activity. Analysis by HPLC indicated that NBMPR could permeate the infected cell membrane and provided evidence for the catabolism of NBMPR in vitro, with subsequent alteration of the purine pool in the infected erythrocyte. These observations further indicated the possibility of the utilization of cytotoxic nucleosides against P. falciparum infection in conjunction with a nucleoside transport inhibitor to protect the host tissue.
Gero
A M
AM
School of Biochemistry, University of New South Wales, Kensington, Australia.
Scott
H V
HV
O'Sullivan
W J
WJ
Christopherson
R I
RI
D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004109:Dilazep / Q000494:pharmacology; D004176:Dipyridamole / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007288:Inosine / Q000031:analogs & derivatives*; D015394:Molecular Structure; D009705:Nucleosides / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013872:Thionucleosides / Q000494:pharmacology; D014372:Tubercidin / Q000494:pharmacology*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D009705:Nucleosides; D013872:Thionucleosides; D006151:Guanosine; C002121:6-(4-nitrobenzylthio)guanosine; D013868:Thioinosine; D007288:Inosine; D004176:Dipyridamole; D004109:Dilazep; C001789:4-nitrobenzylthioinosine; D014372:Tubercidin