Trypanosoma brucei: lack of cross-resistance to melarsoprol in vitro by cymelarsan-resistant parasites.
We have examined cross-resistance between trypanocidal drugs using a well-characterised drug-sensitive line, 247, and its cymelarsan-resistant derivative, 247melCyR. The cymelarsan-resistant line was cross-resistant to trimelarsen and melarsen oxide, and partially cross-resistant to two diamidines, pentamidine and berenil (diminazene aceturate). It was cross-resistant to lipid-soluble melarsoprol in vivo but to only a trivial degree in two in vitro assays. The potential role of adenosine transport in arsenical-induced killing of parasites was investigated. Adenosine, adenine, and the diamidines, but not inosine, were able to inhibit killing of drug-sensitive STIB 247 trypanosomes by cymelarsan and melarsen oxide in a concentration-dependent manner. These results are consistent with the view that these arsenical compounds enter trypanosomes via an adenosine-specific transporter. Melarsoprol-induced killing of trypanosomes was unaffected, however, by either purine and to only a slight degree by the diamidines. These data suggest that melarsoprol can enter trypanosomes by a route other than through an adenosine transporter and that there may be two mechanisms contributing to arsenical resistance in this drug-resistant line of trypanosomes.
Scott
A G
AG
Division of Infection and Immunity, University of Glasgow, United Kingdom.
Tait
A
A
Turner
C M
CM
D000225:Adenine / Q000494:pharmacology; D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007288:Inosine / Q000494:pharmacology; D008549:Melarsoprol / Q000494:pharmacology*; D051379:Mice; D010419:Pentamidine / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism
D001152:Arsenicals; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; C029341:oxophenylarsine; C044719:melarsen oxide; C015980:melarsonic acid; D007288:Inosine; D010419:Pentamidine; C062789:melaminylthioarsenate; D000225:Adenine; C003915:diminazene aceturate; D000241:Adenosine; D004133:Diminazene; D008549:Melarsoprol