Potent receptor-mediated cytotoxicity of granulocyte colony-stimulating factor-Pseudomonas exotoxin, a fusion protein against myeloid leukemia cells.
A chimeric toxin in which the cell-surface binding domain of Pseudomonas exotoxin A was replaced with mature human granulocyte colony-stimulating factor (G-CSF) was produced in Escherichia coli, purified and tested for its biological activity on the human G-CSF-responsive myeloid leukemia cell line, UT7/GR. This fusion protein, termed G-CSF-PE40, showed potent cytotoxicity in the cell line in a dose-dependent manner. G-CSF-PE40 displaced binding of biotinylated G-CSF to its receptor, and the cytotoxicity of G-CSF-PE40 was neutralized by an excess of wild-type G-CSF, indicating the receptor-mediated effects of this chimeric toxin. When G-CSF-PE40 was injected into normal mice, they showed transient neutropenia but no significant changes in the numbers of red blood cells or platelets. Furthermore, G-CSF-PE40 prolonged the survival of mice transplanted with syngeneic myeloid leukemia cells. These observations suggest that G-CSF-PE40 may be useful in targeted therapy of myeloid leukemia cells expressing G-CSF receptors.
Oshima
Yasuo
Y
Department of Hematology/Oncology, The Institutes of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Tojo
Arinobu
A
Fujimura
Akio
A
Niho
Yoshiyuki
Y
Asano
Shigetaka
S
D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism
D001427:Bacterial Toxins; D016188:Receptors, Granulocyte Colony-Stimulating Factor