title: A recombinant GM-CSF-PE40 ligand toxin is functionally active but not cytotoxic to cells.
abstract: A granulocyte/macrophage colony-stimulating factor (GM-CSF)-Pseudomonas exotoxin (PE) 40 fusion protein was constructed for potential use in the treatment of myeloid leukaemias, as a conditioning agent prior to allogeneic bone marrow transplantation or for ex vivo purging of malignant cells prior to autologous bone marrow transplantation. The GM-CSF-PE40 fusion protein successfully binds to the GM-CSF receptor and is capable of initiating a mitogenic signal similar to native GM-CSF in the GM-CSF-dependent TF1 cell line. The toxin component also appears to be fully functional as determined by an in vitro adenosine diphosphate-ribosylation assay. The GM-CSF-PE40 fusion protein, however, was not cytotoxic to a number of myeloid leukaemia cell lines. It is suggested that the mechanism of internalization of the GM-CSF receptor is not appropriate for the translocation of PE to the cytosol where it can fulfil its cytotoxic potential.
authors.affiliation: Department of Haematology, St Vincents Hospital, New South Wales, Australia.
authors.forename: P
authors.initials: P
authors.lastname: O'Brien
authors.forename: A
authors.initials: A
authors.lastname: Smythe
authors.forename: J C
authors.initials: JC
authors.lastname: Biggs
authors.forename: G M
authors.initials: GM
authors.lastname: Smith
mesh_terms: D036002:ADP Ribose Transferases; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001693:Biological Transport, Active; D016465:Bone Marrow Purging; D016026:Bone Marrow Transplantation; D016923:Cell Death / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007951:Leukemia, Myeloid / Q000628:therapy; D016133:Polymerase Chain Reaction; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D019172:Transplantation Conditioning; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000246:Adenosine Diphosphate Ribose; D001427:Bacterial Toxins; D017931:DNA Primers; D005098:Exotoxins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000922:Immunotoxins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A