ive Metabol ism in In fec ted and Un

Leishmaniasis is initiated when sandflies inject the extracellular promastigote form of the parasite into the skin. Promastigotes are rapidly phagocytized, after which they transform into the intracellular amastigote form. The multiplication of the latter within macrophages leads to clinical disease. Treatment of leishmaniasis is primarily with pentavalent antimonials, parenteral and potentially toxic drugs with a 10-25% failure rate. The inosine analogue formycin B (FOB) inhibits multiplication of promastigotes (1-3) and is leishmanicidal to both antimony-sensitive and antimony-resistant amastigotes within human macrophages in vitro (4). FoB is also leishmanicidal to Leishmania donovani amastigotes in infected hamsters after either intraperitoneal (1) or oral administration (J. D. Berman et al., Exp. Parasitol. In press). Biochemical studies of the metabolism of FoB in promastigotes revealed that this compound is initially converted to its 5'nucleotide, formycin B 5'-monophosphate (FoB-MP), which is subsequently metabolized to adenosine nucleotide analogues of formycin A (FoA) that become incorporated into RNA (2, 3). The FoA nucleotides or FoA incorporation into RNA are believed to be responsible for the cytotoxic effects of FoB towards promastigotes. The present study was undertaken to determine the metabolism and mechanism of action of FoB in amastigotes within cultured human macrophages, a model that is comparable to the clinical situation. In addition, the metabolism of FoB in uninfected human macrophages and in free amastigotes was investigated.