Effect of a bis(benzyl)polyamine analogue, and DL-α-difluoromethylornithine on parasite suppression and cellular polyamine levels in golden hamster during Leishmania donovani infection

Abstract

We examined the antileishmanial activity of DL-α-difluoromethylornithine (DFMO) and a bis(benzyl)polyamine analogue (MDL 27695; N,N'-bis{3[(phenyl-methyl)amino] propyl} 1,7-diaminoheptane) in L. donovani infected golden hamsters. DFMO, an enzyme activated irreversible inhibitor of ornithine decarboxylase, the rate limiting enzyme in polyamine biosynthesis, has potent antileishmanial activity. When given as a 2% solution in drinking water 2 days after infection and continued for 4 days, it suppressed liver parasites by 90% and spleen parasites by 99%. Liver parasites were suppressed by 50% and spleen parasites by 77% in L. donovani infected hamsters when treated three times per day for 4 days with a total dose of 60 mg kg^-1 body weight of MDL 27695. The polyamine content of the liver and spleen of hamsters was determined after 8 days of L. donovani infection and also after treatment with these drugs. Putrescine and spermidine levels increased significantly in both liver and spleen after Leishmania infection of golden hamsters. Treatment with drugs that inhibit the growth of Leishmania amstigotes in the liver and spleen of golden hamsters also reduced polyamine levels of previously infected golden hamsters. There is a close correlation between the therapeutic activity of the drugs and the polyamine content.