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Abstract
Resistance to melarsoprol and pentamidine was induced in bloodstream-form Trypanosoma
brucei rhodesiense STIB 900 in vitro, and drug sensitivity was determined for melarsoprol,
pentamidine and furamidine. The resistant populations were also inoculated into immunosuppressed
mice to verify infectivity and to monitor whether rodent passage selects for clones
with altered drug sensitivity. After proliferation in the mouse, trypanosomes were
isolated and their IC(50) values to the three drugs were determined. To assess the
stability of drug-induced resistance, drug pressure was ceased for 2 months and the
drug sensitivity was determined again. Resistance was stable, with a few exceptions
that are discussed. Drug IC(50)s indicated cross-resistance among all drugs, but to
varying extents: resistance of the melarsoprol-selected and pentamidine-selected trypanosomes
to pentamidine was the same, but the pentamidine-selected trypanosome population showed
lower resistance to melarsoprol than the melarsoprol-selected trypanosomes. Interestingly,
both resistant populations revealed the same intermediate cross-resistance to furamidine.
Resistant trypanosome populations were characterised by molecular means, referring
to the status of the TbAT1 gene. The melarsoprol-selected population apparently had
lost TbAT1, whereas in the pentamidine-selected trypanosome population it was still
present.