An EGF-pseudomonas exotoxin A recombinant protein with a deletion in toxin binding domain specifically kills EGF receptor bearing cells |
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Authors: | Lee, Chi-Hon Lee, E-Ching Tsai, Shih-Tzer Kung, Hsing-Jien Liu, Yin-Chang Hwang, Jaulang |
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Affiliation: | 1Institute of Molecular Biology, Academia Sinica Taipei 2Institute of Life Sciences, National Tsing Hua University Hsinchu 3Clinical Research Center, Veterans General Hospital Taipei, Taiwan 4Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University Cleveland, OH, 44106, USA |
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Abstract: | We constructed two chimeric toxins; one composed of epidermalgrowth factor (EGF) and pseudomonas exotoxin A (PE), designatedEGF-PE and the other composed of EGF and PE with a deletionof the Ia domain (cell-binding domain), designated EGF-PE (Ia).Both chimeric toxins reacted with anti-EGF and anti-PE antibodies.The cell-killing experiments showed that EGF-PE, but not EGF-PE(Ia),was cytotoxic to the murine fibroblast cell line NR6, whichcarried the PE receptor, but not the EGF receptor. However,after NR6 was transfected with DNA for the expression of humanEGF receptor, the transfected cell line, designated NRHER5,overexpressed human EGF receptors and became sensitive to EGF-PE(IA).The cytotoxicity of EGF-PE(Ia), but not EGF-PE, to NRHER5 canbe completely blocked by an excess amount of EGF. To completelyreverse the cytotoxicity of EGF-PE on NRHER5, both the EGF receptorpathway and the PE receptor pathway need to be blocked. Theseresults suggest that EGF-PE exhibits both EGF and PE bindingactivities, while EGF-PE(IA) possesses only EGF binding activity.Thus, EGF-PE(Ia) may be a better chimeric toxin than EGF-PEin terms of target specificity to EGF receptor bearing cells.We, therefore, examined the cytotoxicity of EGF-PE(Ia) to varioushuman cancer cell lines. We find that human cancer cells containingmore EGF receptors are more sensitive to EGF-PE(Ia). |
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Keywords: | chimera/ EGF/ pseudomonas exotoxin A |
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