CHARACTERIZATION OF ALPHA-DIFLUOROMETHYLORNITHINE RESISTANT LEISHMANIA-DONOVANI AND ITS SUSCEPTIBILITY TO OTHER INHIBITORS OF THE POLYAMINEBIOSYNTHETIC-PATHWAY

The promastigote form of Leishmania donovani is sensitive to growth in hibition by DL-alpha-difluoromethylornithine, an irreversible inhibito r of ornithine decarboxylase, exhibiting an IC50 of 125 mu M. Exposure of a wild type cell population to gradually increasing concentrations of DL-alpha-difluoromethylornithine resulted in the selection of a st rain of Leishmania, which was capable of proliferating in 5 mM DFMO wi th an IC50 value of 10 mM. This resistant strain showed increased orni thine decarboxylase activity and higher levels of putrescine. It was s ensitive to growth inhibition by bis (benzyl) analogs of spermine and a potent S-adenosylmethionine decarboxylase inhibitor, CGP 40215A. The se results indicate the potential value of other inhibitors of the pol yamine biosynthetic pathway as therapeutic agents in conditions where ODC inhibitors are ineffective. (C) 1996 The Italian Pharmacological S ociety