Trypanosoma brucei: lack of cross-resistance to melarsoprol in vitro by cymelarsan-resistant parasites

Exp Parasitol. 1997 Jul;86(3):181-90. doi: 10.1006/expr.1997.4167.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / pharmacology
  • Adenosine / metabolism
  • Adenosine / pharmacology
  • Animals
  • Arsenicals / pharmacology*
  • Diminazene / analogs & derivatives
  • Diminazene / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Enzyme Inhibitors / pharmacology
  • Female
  • Inosine / pharmacology
  • Melarsoprol / pharmacology*
  • Mice
  • Pentamidine / pharmacology
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma brucei brucei / drug effects*
  • Trypanosoma brucei brucei / metabolism

Substances

  • Arsenicals
  • Enzyme Inhibitors
  • Trypanocidal Agents
  • oxophenylarsine
  • melarsen oxide
  • melarsonic acid
  • Inosine
  • Pentamidine
  • melaminylthioarsenate
  • Adenine
  • diminazene aceturate
  • Adenosine
  • Diminazene
  • Melarsoprol