Effects of 2',3'-dideoxyinosine on Toxoplasma gondii cysts in mice

Abstract

The activity against Toxoplasma gondii of 2',3' dideoxyinosine (ddI), an anti-human immunodeficiency virus drug, was examined in an in vitro and in vivo study. Cell cultures infected with a strain known to cause chronic infections were used to show the dose-dependent effect of this drug compared with spiramycin and sulfadiazine. When a dose of 4 microg/ml was used, no infected THP-1 cells or parasites were found after 60 h of incubation. An electron-microscopic study confirmed that after 12 h at 1 microg/ml, the few parasites observed were severely altered. The treatment of chronically infected mice 3 months postinfection showed that a 30-day treatment with 2 mg of ddI/ml induced a significant reduction in the number of T. gondii cysts in the cerebral tissue. These cysts were not viable, as confirmed by immunofluorescence and reinfection experiments. These experiments suggest a possible role for ddI in the treatment of toxoplasmosis, and this possibility deserves further investigation.

Nucleoside Transport as a Potential Target for Chemotherapy in Malaria

“…(2)), were found to exhibit potent antimalarial activity towards the erythrocytic stage of P. knowlesi, the agent of simian malaria [63]. Moreover, unpublished results from our laboratory suggest that the effect of DDI on Plasmodium is similar to its reported activity against the other apicomplexan protozoans Cryptosporidum parvum and Toxoplasma gondii [64,65].…”

Use of a non-adherent cell culture system for testing the effect of 2′,3′-dideoxyinosine against Cryptosporidium parvum

“…We have successfully developed an in vitro culture model using the non-adherent myelomonocytic human cell line THP-1 which provides an enhanced versatility and allows the determination of the various parasitic stages [3]. We used this system to test 2P,3P-dideoxyinosine (ddI), a purine analog active against HIV and Toxoplasma gondii in vitro and in vivo [4,5]. Paromomycin, an aminoglycoside reported to exert some activity against C. parvum in vitro [6^8], in animal models [9^11] and AIDS patients [12] was used as a positive control.…”

Use of a non-adherent cell culture system for testing the effect of 2′,3′-dideoxyinosine againstCryptosporidium parvum

“…We have recently shown that the purine analog 2′,3′‐dideoxyinosine (ddI) was highly active against T. gondii cultured in THP‐1 cells and suggested the purine salvage pathway of this parasite as a promising chemotherapeutic target [4,5]. As an Apicomplexan, C. parvum possesses some different metabolic pathways [13] and also lacks a de novo purine synthesis, as reported recently [14].…”

“…This molecule is taken up by the monocyte/macrophage populations, especially the resting cells [18,19] where its metabolite ddATP is found, as well as ddI‐derived radioactivity incorporated into the cell DNA and RNA pool [20]. In contrast to T. gondii where low concentrations were rapidly active [4,5], the lower inhibition of C. parvum probably reflects the different metabolic activity of this parasite. Furthermore, ddI must penetrate into the THP‐1 cells where it may be metabolized before entering the parasite, thus reducing its subsequent inhibitory activity.…”