Human neurological cancer cells express interleukin-4 (IL-4) receptors which are targets for the toxic effects of IL4-Pseudomonas exotoxin chimeric protein.
Glioblastoma, glioma or neuroblastoma cells were examined for the expression of IL-4 receptors (IL-4R) by flow cytometric analysis and 125I-IL-4 binding. These cancer cell lines expressed IL-4R which were of high affinity (KD = 700 x 10(-12) M) on glioblastoma cells. To investigate the function of these receptors and to target potent cytotoxic antitumor agents to human neurological cancers, we utilized IL4-PE4E, which is composed of IL-4 and mutant Pseudomonas exotoxin (IL4-PE4E). This chimeric molecule was cytotoxic toward human glioblastoma, neuroblastoma and glioma tumor cells in a dose-dependent manner. The cytotoxicity of IL4-PE4E was specific, since it was neutralized by excess IL-4, and by an anti-IL-4 monoclonal antibody in all types of brain tumor tested. IL2-PE4E and IL6-PE4E were not cytotoxic, nor was an IL4-PE4E mutant lacking ADP-ribosylating activity, indicating the IL4-PE4E-mediated cytotoxicity of the brain tumor cells required both IL-4R binding and enzymatic toxin activity. These data indicate that human neurological cancer cells express IL-4R which are targets for the cytotoxic effects of IL4-toxin. In addition, our data also suggest that IL4-PE4E should be studied further as a potential treatment for human neurological cancers.
Puri
R K
RK
Laboratory of Molecular Tumor Biology, Food and Drug Administration, Bethesda, MD 20892.
Leland
P
P
Kreitman
R J
RJ
Pastan
I
I
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism*; D005098:Exotoxins; D005434:Flow Cytometry; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism; D011550:Pseudomonas aeruginosa; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A