Plasmodium falciparumandPlasmodium yoelii:Effect of the Iron Chelation Prodrug Dexrazoxane onin VitroCultures

Abstract

Loyevsky, M., Sacci, J. B., Jr., Boehme, P., Weglicki, W., John, C., and Gordeuk, V. R. 1999.Plasmodium falciparumandPlasmodium yoelii: Effect of the iron chelation prodrug dexrazoxane onin vitrocultures.Experimental Parasitology91, 105–114. To determine if an iron-chelating prodrug that must undergo intracellular hydrolysis to bind iron has antimalarial activity, we examined the action of dexrazoxane onPlasmodium falciparumcultured in human erythrocytes andP. yoeliicultured in mouse hepatocytes. Dexrazoxane was recently approved to protect humans from doxorubucin-induced cardiotoxicity. Using the fluorescent marker calcein, we confirmed that the iron-chelating properties of dexrazoxane are directly related to its ability to undergo hydrolysis. As a single agent, dexrazoxane inhibited synchronized cultures ofP. falciparumin human erythrocytes only at suprapharmacologic concentrations (>200 μM). In combination with desferrioxamine B, dexrazoxane in pharmacologic concentrations (100–200 μM) moderately potentiated inhibition by approximately 20%. In contrast, pharmacologic concentrations of dexrazoxane (50–200 μM) as a single agent inhibited the progression ofP. yoeliifrom sporozoites to schizonts in cultured mouse hepatocytes by 45 to 69% (P< 0.001). These results are consistent with the presence of a dexrazoxane-hydrolyzing enzyme in hepatocytes but not in erythrocytes or malaria parasites. Furthermore, these findings suggest that dexrazoxane must be hydrolyzed to an iron-chelating intermediate before it can inhibit the malaria parasite, and they raise the possibility that the iron chelator prodrug concept might be exploited to synthesize new antimalarial agents.