DIFFERENTIAL CYTOTOXICITY OF IRON CHELATORS ON MALARIA-INFECTED CELLSVERSUS MAMMALIAN-CELLS

Iron chelators of the hydroxamate class arrest in vitro proliferation of malaria parasites and of mammalian cells. The factors determining t he biological activity of the chelators have classically been attribut ed to the chelators' capacity for binding iron and to their ability to traverse membranes as free chelators and as chelator-iron complexes. We show in this work that the nature of the chelatable pool of cell ir on also contributes to the susceptibility of cells to iron chelators. A class of N-terminal (N-t) derivatives of desferrioxamine (DFO), (N-t -DFO), is shown here to differentially affect growth and replication o f intraerythrocytic parasites (Plasmodium falciparum). Methyl-anthrani lic DFO (MADFO), the relatively less hydrophilic member of the N-t-DFO s series, reduced parasite proliferation (48 hour test) with an IC50 o f 4 +/- 1 mu mol/L and mammalian cell (K562 and HepG2) proliferation w ith an IC50 > 100 mu mol/L. On the other hand, the more hydrophilic N- t-free DFO, displayed IC50 values of 21 +/- 5 mu mol/L for parasites a nd 7 +/- 1 mu mol/L for mammalian cells. The selective antiparasitic a ctivity of MA-DFO, as reflected in the speed of action and IC50 values on cell proliferation, is attributed primarily to membrane permeation and iron(III) binding properties of the drug. In contrast, the relati vely low antiproliferative activity of the more permeant MA-DFO on mam malian cells, resulted from MA-DFO's reduced capacity for scavenging i ntracellular iron. This is apparent from MA-DFO reduced effects on: (1 ) the chelatable iron(II) pool that is associated with the cell cytoso l; (2) the cell chelator-extractable iron, and (3) cell ferritin level s. The potent antimalarial efficacy and biological selectivity of MA-D FO relative to the parent DFO, is of importance for improved design of chemotherapeutic agents. (C) 1996 by The American Society of Hematolo gy.