Characterization of alpha-difluoromethylornithine resistant Leishmania donovani and its susceptibility to other inhibitors of the polyamine biosynthetic pathway.

The promastigote form of Leishmania donovani is sensitive to growth inhibition by DL-alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, exhibiting an IC50 of 125 microM. Exposure of a wild type cell population to gradually increasing concentrations of DL-alpha-difluoromethylornithine resulted in the selection of a strain of Leishmania, which was capable of proliferating in 5 mM DFMO with an IC50 value of 10 mM. This resistant strain showed increased ornithine decarboxylase activity and higher levels of putrescine. It was sensitive to growth inhibition by bis (benzyl) analogs of spermine and a potent S-adenosylmethionine decarboxylase inhibitor, CGP 40215A. These results indicate the potential value of other inhibitors of the polyamine biosynthetic pathway as therapeutic agents in conditions where ODC inhibitors are ineffective.