[Targeted toxin therapy in the treatment of leukemia].
A chimeric toxin in which the cell surface binding domain of Pseudomonas exotoxin was replaced with mature human granulocyte colony-stimulating factor (G-CSF) was produced in Escherichia coli, partially purified and tested for its biological activity on a G-CSF-dependent murine myeloid leukemia cell line, NFS60. This fusion protein, termed as G-CSF-PE40, can displace [125I] G-CSF binding to its receptor. After 48 hrs incubation in the presence of G-CSF, G-CSF-PE40 inhibited protein synthesis and revealed cytotoxicity in NFS60 cells in a concentration dependent manner. The half maximal dose of G-CSF-PE40 for protein synthesis inhibition (ID50) in NFS60 cells was estimated at around 100pM. Additionally, relatively low concentration of G-CSF-PE40 stimulated DNA synthesis in NFS60 cells after 16 hrs' incubation in the absence of G-CSF, suggesting that G-CSF-PE40 also can transduce a transient mitogenic signal. Thus, G-CSF-PE40 may be useful in the selective elimination of myeloid cells expressing G-CSF receptors, especially in combination with chemotherapeutic agents like cytosine arabinoside.
Tojo
A
A
Department of Hematology and Oncology, University of Tokyo.
Oshima
Y
Y
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000627:therapeutic use*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D004273:DNA, Neoplasm; D005098:Exotoxins; D016179:Granulocyte Colony-Stimulating Factor; D000922:Immunotoxins; D009363:Neoplasm Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A