title: Molecular design of hybrid tumour necrosis factor alpha with polyethylene glycol increases its anti-tumour potency.
abstract: This study was conducted to increase the anti-tumour potency and reduce the toxic side-effects of tumour necrosis factor alpha (TNF-alpha). Natural human TNF-alpha was chemically conjugated with monomethoxy polyethylene glycol (PEG) using succinimidyl coupling of lysine amino groups of TNF-alpha. The number-average molecular weight of PEG-modified TNF-alpha (PEG-TNF-alpha) increased with an increase in the reaction time and the initial molar ratio of PEG relative to TNF-alpha. The resulting modified TNF-alpha was separated into fractions of various molecular weights. The specific activity of separated PEG-TNF-alpha s relative to that of native TNF-alpha gradually decreased with an increase in the degree of PEG modification, but the plasma half-life was drastically increased with the increase in molecular weight of modified TNF-alpha. PEG-TNF-alpha s, in which 29% and 56% of lysine residues were coupled to PEG, had anti-tumour activity approximately 4 and 100 times greater than unmodified TNF-alpha in the murine Meth-A fibrosarcoma model. Extensive PEG modification did not increase its in vivo activity. A high dose of unmodified TNF-alpha induced toxic side-effects, but these were not observed with the modified TNF-alpha s. Optimal PEG modification of TNF-alpha markedly increased its bioavailability and may facilitate its potential anti-tumour therapeutic use.
authors.affiliation: Faculty of Pharmaceutical Sciences, Osaka University, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutsumi
authors.forename: T
authors.initials: T
authors.lastname: Kihira
authors.forename: S
authors.initials: S
authors.lastname: Tsunoda
authors.forename: T
authors.initials: T
authors.lastname: Kanamori
authors.forename: S
authors.initials: S
authors.lastname: Nakagawa
authors.forename: T
authors.initials: T
authors.lastname: Mayumi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols