title: A novel recombinant tumor necrosis factor-alpha mutant with increased anti-tumor activity and lower toxicity.
abstract: We prepared a novel recombinant tumor necrosis factor-alpha (TNF) mutant (mutant 471), in which 7 N-terminal amino-acids were deleted and Pro8Ser9Asp10 was replaced by ArgLysArg, and compared its biological activity with that of wild-type recombinant TNF. Mutant 471 had a 7-fold higher anti-tumor activity against murine L-M cells in vitro, and a higher binding activity to TNF receptors on L-M cells, than wild-type TNF. Furthermore, mutant 471 showed a higher anti-tumor effect on murine Meth A-HM tumors transplanted into BALB/c mice, with complete regression of the tumors being observed in the animals. The possible cachectin activity of mutant 471 was almost the same as that of wild-type TNF. The acute lethal toxicity of mutant 471 in beta-D-galactosamine-sensitized C3H/HeJ mice was 18 times lower than that of wild-type TNF. These results suggest that mutant 471 might be a more promising anti-cancer agent than wild-type TNF.
authors.affiliation: Biotechnology Research Laboratories, Teijin Limited, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Masegi
authors.forename: M
authors.initials: M
authors.lastname: Fukuoka
authors.forename: K
authors.initials: K
authors.lastname: Kitai
authors.forename: H
authors.initials: H
authors.lastname: Ogawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: M
authors.initials: M
authors.lastname: Maeda
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000473:pathology; D007739:L Cells / Q000166:cytology / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008071:Lipoprotein Lipase