TRYPANOSOMA-BRUCEI - LACK OF CROSS-RESISTANCE TO MELARSOPROL IN-VITROBY CYMELARSAN-RESISTANT PARASITES

We have examined cross-resistance between trypanocidal drugs using a w ell-characterised drug-sensitive Line, 247, and its cymelarsan-resista nt derivative, 247melCy(R). The cymelarsan-resistant line was cross-re sistant to trimelarsen and melarsen oxide, and partially cross-resista nt to two diamidines, pentamidine and berenil (diminazene aceturate). It was cross-resistant to lipid-soluble melarsoprol in vivo but to onl y a trivial degree in two in vitro assays. The potential role of adeno sine transport in arsenical-induced killing of parasites was investiga ted. Adenosine, adenine, and the diamidines, but not inosine, were abl e to inhibit killing of drug-sensitive STIB 247 trypanosomes by cymela rsan and melarsen oxide in a concentration-dependent manner. These res ults are consistent with the view that these arsenical compounds enter trypanosomes via an adenosine-specific transporter. Melarsoprol-induc ed killing of trypanosomes was unaffected, however, by either purine a nd to only a slight degree by the diamidines. These data suggest that melarsoprol can enter trypanosomes by a route other than through an ad enosine transporter and that there may be two mechanisms contributing to arsenical resistance in this drug-resistant line of trypanosomes. ( C) 1997 Academic Press.