Induction of apoptosis in multidrug-resistant and radiation-resistant acute myeloid leukemia cells by a recombinant fusion toxin directed against the human granulocyte macrophage colony-stimulating factor receptor.
Multiagent chemotherapy regimens fail to cure more than one-half of the patients with acute myeloid leukemia (AML) because of the emergence of dominant multidrug-resistant subclones of leukemia cells. We have developed a recombinant diphtheria toxin-human granulocyte macrophage colony-stimulating factor chimeric fusion protein (DTctGMCSF) that specifically targets GMCSF receptor-positive AML cells. This novel biotherapeutic agent induced rapid apoptotic cell death of chemotherapy-resistant AML cell lines and primary leukemic cells from treatment-refractory AML patients. Our results suggest that DTctGMCSF may be useful in the treatment of AML patients whose leukemia has recurred and developed resistance to contemporary chemotherapy programs.
Perentesis
J P
JP
Biotherapy Institute, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Waddick
K G
KG
Bendel
A E
AE
Shao
Y
Y
Warman
B E
BE
Chandan-Langlie
M
M
Uckun
F M
FM
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053938:DNA Fragmentation / Q000187:drug effects; D004167:Diphtheria Toxin / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000633:toxicity*; D018922:HL-60 Cells; D006801:Humans; D000922:Immunotoxins / Q000633:toxicity*; D007951:Leukemia, Myeloid; D015470:Leukemia, Myeloid, Acute; D011836:Radiation Tolerance; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000633:toxicity*; D014407:Tumor Cells, Cultured
C114196:DTctGMCSF protein, recombinant; D004167:Diphtheria Toxin; D000922:Immunotoxins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor