Chemical modification of natural human tumor necrosis factor-alpha with polyethylene glycol increases its anti-tumor potency.
Natural human tumor necrosis factor-alpha (TNF-alpha) was chemically modified with an active ester of monomethoxy polyethylene glycol (PEG). The molecular weight of PEG-modified TNF-alpha depended on the reaction time as well as the initial molar ratio of PEG to TNF-alpha. The specific activity of modified TNF-alpha was gradually reduced with increase in the degree of PEG-modification, but the plasma half-life of TNF-alpha was increased by up to 40-fold. Modified TNF-alpha showed approximately 100 times greater anti-tumor potency than unmodified TNF-alpha. Covalent attachment of PEG to TNF-alpha thus increased the bioavailability of TNF-alpha, and may facilitate its potential therapeutic use.
Tsutsumi
Y
Y
Faculty of Pharmaceutical Sciences, Osaka University.
Kihira
T
T
Yamamoto
S
S
Kubo
K
K
Nakagawa
S
S
Miyake
M
M
Horisawa
Y
Y
Kanamori
T
T
Ikegami
H
H
Mayumi
T
T
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
C092033:PEG-modified tumor necrosis factor-alpha; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols