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Cytotoxicity of a recombinant diphtheria toxin-granulocyte colony-stimulating factor fusion protein on human leukemic blast cells.
- Source :
-
Leukemia & lymphoma [Leuk Lymphoma] 1993 Oct; Vol. 11 (3-4), pp. 249-62. - Publication Year :
- 1993
-
Abstract
- Granulocyte colony-stimulating factor (G-CSF) is a potent stimulator of the growth of normal and malignant hematopoietic cells and synergizes with other factors such as interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The action of G-CSF is mediated through a specific membrane receptor, however it is not clear if all of the effects of G-CSF are direct or indirect. As a step towards addressing this problem, a recombinant diphtheria toxin (DT)-related human G-CSF fusion protein has been constructed and purified from E. coli. The 70,000 dalton chimeric protein has immunologic determinants characteristic of both DT and G-CSF. At high concentrations, DAB486-G-CSF is cytotoxic towards G-CSF-dependent OCI/AML1 cells, but not factor independent OCI/AML3 cells; colony formation by G-CSF-responsive leukemic blasts from a patient with acute myeloblastic leukemia (AML) was also inhibited. The G-CSF fusion toxin displayed ADP-ribosyltransferase activity in a cell-free system. Genetic conjugation of G-CSF to an enzymatically inactive DT mutant, CRM197, resulted in a 200-fold reduction in the ability of G-CSF to stimulate normal bone marrow colony formation. These results suggest that fusion of G-CSF to DT sequences interferes with some of the activity but not the specificity of the ligand binding domain of the molecule. Nevertheless, DAB486-G-CSF may be included with the increasing number of other toxin-hormone fusion proteins whose toxicity is directed towards specific receptor-bearing cells, and may represent a novel approach towards the study and treatment of leukemia.
- Subjects :
- ADP Ribose Transferases metabolism
Animals
Base Sequence
CHO Cells
Cell Survival drug effects
Cricetinae
Escherichia coli genetics
Humans
Leukemia, Myeloid, Acute drug therapy
Molecular Sequence Data
Protein Biosynthesis
Recombinant Fusion Proteins biosynthesis
Tumor Cells, Cultured
Diphtheria Toxin pharmacology
Granulocyte Colony-Stimulating Factor pharmacology
Leukemia, Myeloid, Acute pathology
Recombinant Fusion Proteins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1042-8194
- Volume :
- 11
- Issue :
- 3-4
- Database :
- MEDLINE
- Journal :
- Leukemia & lymphoma
- Publication Type :
- Academic Journal
- Accession number :
- 7505148
- Full Text :
- https://doi.org/10.3109/10428199309087002