In vivo targeting of leukemic cells using diphtheria toxin fused to murine GM-CSF.
We have previously demonstrated that diphtheria toxin (DT) fused to human GM-CSF effectively eliminates human long-term leukemia initiating cells in SCID mice. However, because huGM-CSF does not react with the murine GM-CSF receptor possible side-effects to nonleukemic tissues could not be analyzed in the AML/SCID model. To overcome this problem, we used murine GM-CSF fused to DT and studied the therapeutic index in the rat leukemia model BNML/LT12. In DT-mGM-CSF dose escalation experiments, severe dose-dependent toxicity to organs such as liver, kidney and lung was observed. Therefore, the antileukemic effects were evaluated with the lower doses. Daily intraperitoneal bolus injections of 75 microg/kg/day for 7 days induced a 3 log leukemic cell kill. The dose of 75 microg/kg/day had no effect on the hemopoietic progenitor cell subsets. These in vivo studies show that the DT-GM-CSF fusion protein can be used for specifically targeting leukemic cells and thus has potential as a therapeutic agent in the treatment of AML.
Rozemuller
H
H
Institute of Hematology, Erasmus University, Rotterdam, The Netherlands.
Rombouts
E J
EJ
Touw
I P
IP
FitzGerald
D J
DJ
Kreitman
R J
RJ
Hagenbeek
A
A
Martens
A C
AC
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced; D004167:Diphtheria Toxin / Q000494:pharmacology* / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology* / Q000633:toxicity; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D051381:Rats; D011914:Rats, Inbred BN; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004167:Diphtheria Toxin; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor