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.