Cell-specific toxicity of a chimeric protein composed of interleukin-6 and Pseudomonas exotoxin (IL6-PE40) on tumor cells.
IL6-PE40 is a chimeric toxin composed of human interleukin-6 (IL6) linked by a peptide bond to PE40, a form of Pseudomonas exotoxin (PE) devoid of its cell recognition domain. To identify cancer cell lines with high numbers of IL6 receptors and to assess the usefulness of IL6-PE40 as a possible anticancer agent, we evaluated the toxicity of IL6-PE40 on a variety of tumor cell lines and demonstrated that certain human myeloma and hepatoma cell lines were particularly sensitive. IL6 binding to selected hepatoma and myeloma cell lines were determined by using [125I]IL6. IL6 receptor mRNA levels were measured by polymerase chain reactions. When comparisons were made among different hepatoma cell lines, the sensitivity to IL6-PE40 correlated with the number of IL6 receptors. However, the hepatoma line PLC/PRF/5, which contains 2,300 IL6 receptors, was more sensitive to IL6-PE40 (amount of protein required to inhibit protein synthesis by 50% was 5 ng/ml) than both the myeloma cell lines U266 and H929 (for both cell lines, the 50% inhibitory dose was 8 ng/ml), which contain 15,500 and 16,500 IL6 receptors, respectively. RNA analysis confirmed that the sensitivity of these cells to IL6-PE40 and the amount of IL6 receptor RNA detected did not correlate. These data suggest that factors in addition to the number of IL6-binding sites contribute to the sensitivity of cells to IL6-PE40.
Siegall
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CB
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Nordan
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RP
FitzGerald
D J
DJ
Pastan
I
I
D036002:ADP Ribose Transferases; D006528:Carcinoma, Hepatocellular / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002678:Chimera; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics; D005098:Exotoxins / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008113:Liver Neoplasms / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology; D016133:Polymerase Chain Reaction; D011971:Receptors, Immunologic / Q000378:metabolism; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects / Q000276:immunology
D005098:Exotoxins; C064195:IL-6-PE40 protein, chimeric; D015850:Interleukin-6; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D036002:ADP Ribose Transferases