Iron chelators as therapeutic agents against Pneumocystis carinii.
Iron plays a critical role in host-parasite interactions, and iron chelators have been demonstrated to serve as effective adjunct therapeutic agents against malaria. The effects of the parenteral iron chelator deferoxamine (DFO) on the growth of rat-derived Pneumocystis carinii were studied in a human fibroblast cell culture model and in two in vivo models of experimental infection. In addition, the effects of the investigational oral iron chelator CP20 and its 3-hydroxypyridin-4-one analogs CP51, CP94, and CP96 on the growth of P. carinii in vitro were assessed. DFO suppressed the growth of P. carinii in vitro in a dose-dependent manner, and daily injections of DFO markedly reduced the intensity of P. carinii infection in both mice and rats. Cell cultures treated with iron chelators that are administered orally to humans also showed substantial P. carinii growth inhibition. Reduction of P. carinii numbers after iron chelator therapy correlated with alterations in P. carinii morphology, as viewed by transmission electron microscopy. Since the use of current anti-P. carinii drugs is limited by toxicity or incomplete efficacy, or both, the role of iron chelation as adjunctive anti-P. carinii chemotherapy merits additional investigation.
Weinberg
G A
GA
Department of Pediatrics, James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis 46202-5225.
D000818:Animals; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology / Q000627:therapeutic use; D005347:Fibroblasts / Q000382:microbiology; D006801:Humans; D007165:Immunosuppression Therapy; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D011010:Pneumocystis / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D016720:Pneumocystis Infections / Q000188:drug therapy* / Q000382:microbiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D007502:Iron Chelating Agents; D003676:Deferoxamine