Treatment of chloroquine-resistant malaria with esters of cephalotaxine: homoharringtonine.
The esters of cephalotaxine-harringtonine, homoharringtonine and deoxyharringtonine--have been reported by both Chinese and American oncologists as useful in the treatment of human nonlymphoblastic leukaemias and selected solid tumours of the head and neck. We report our results with homoharringtonine, currently a Phase II clinical trial drug with the National Cancer Institute, in the treatment of malaria. Homoharringtonine, 2.7-3.4 nM, was effective in causing 50% growth inhibition of two strains of chloroquine-resistant Plasmodium falciparum malaria in vitro. In vivo tests in mice infected with P. yoelii showed that this drug was effective in inhibiting parasite growth in this system as well. Histologically, the drug was associated with karyorrhexis. Drug-exposed cells showed decreased levels of putrescine and spermidine and increased spermine levels. Our findings not only demonstrate the potential usefulness of homoharringtonine in the treatment of chloroquine-resistant malaria, but also demonstrate the advantage of applying comparative biochemistry and an understanding of biological mechanisms in a rational approach to the development and treatment of diseases including malaria.
Whaun
J M
JM
Division of Pathology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Brown
N D
ND
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002738:Chloroquine / Q000627:therapeutic use; D004351:Drug Resistance; D006248:Harringtonines / Q000627:therapeutic use*; D000077863:Homoharringtonine; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism; D010967:Plasmodium yoelii; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
D000962:Antimalarials; D006248:Harringtonines; D013096:Spermine; D000077863:Homoharringtonine; D002738:Chloroquine; D013095:Spermidine; D011700:Putrescine