title: N-acetylneuraminic acid coupled human recombinant TNFalpha exhibits enhanced anti-tumor activity against Meth-A fibrosarcoma and reduced toxicity.
abstract: In order to study the effect of glycosylation on its biological activities and to develop tumor necrosis factor alpha (TNFalpha) with less deleterious effects, N-acetylneuraminic acid (NeuAc) with a C9 spacer was chemically coupled to human recombinant TNFalpha. NeuAc-coupled TNFalpha (NeuAc-TNFalpha) exhibited reduced activities in vitro by about threefold compared to native TNFalpha. In this study, we examined a variety of TNFalpha activities in vivo. NeuAc-TNFalpha reduced activities in the up-regulation of serum levels of IL-6 and NOx, but comparable activity as native TNFalpha in the down-regulation of the serum level of glucose. However, NeuAc-TNFalpha was more potent than TNFalpha in the up-regulation of the serum level of serum amyloid A (SAA). NeuAc-TNFalpha was less toxic to mice. In addition, NeuAc-TNFalpha exhibited an augmented anti-tumor activity against Meth-A fibrosarcoma without hemorrhagic necrosis. These results indicate that coupling with NeuAc enabled us to develop neoglycoTNFalpha with selective activities in vivo, including enhanced anti-tumor activity but reduced toxicity.
authors.affiliation: Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe, Mizuho, Nagoya 467-8603, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayashi
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.forename: Taku
authors.initials: T
authors.lastname: Chiba
authors.forename: Satoshi
authors.initials: S
authors.lastname: Sasayama
authors.forename: Kikuo
authors.initials: K
authors.lastname: Onozaki
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005354:Fibrosarcoma / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000378:metabolism* / Q000633:toxicity; D009569:Nitric Oxide / Q000097:blood; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000378:metabolism* / Q000633:toxicity*; D000685:Serum Amyloid A Protein / Q000032:analysis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000633:toxicity
chemical_list: D001786:Blood Glucose; D015850:Interleukin-6; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019158:N-Acetylneuraminic Acid