Intravenous administration of polyethylene glycol-modified tumor necrosis factor-alpha completely regressed solid tumor in Meth-A murine sarcoma model.
Complete regression of solid tumors was achieved by plural intravenous (i.v.) administrations of polyethylene glycol (PEG)-modified tumor necrosis factor-alpha (TNF-alpha), prepared by covalently modifying natural human TNF-alpha with N-succinimidyl succinate PEG. The anti-tumor efficacy of PEG-modified TNF-alpha (MPEG-TNF-alpha), in which 56% of the TNF-alpha-lysine residues were coupled with PEG, was compared with that of native TNF-alpha in the Meth-A murine fibrosarcoma model. MPEG-TNF-alpha and native TNF-alpha were given as i.v. injections twice a week for 2 weeks. The anti-tumor activity of MPEG-TNF-alpha was dose-dependent and was far superior to that of native TNF-alpha. Complete regression was observed in 3 of the 8 mice administered native TNF-alpha at the dose of 10,000 JRU (Japan reference unit), but 4 of the 5 remaining mice died during the therapeutic period. At 5,000 JRU of native TNF-alpha, no case of complete regression was observed. By contrast, complete regression was obtained in all 10 mice given 200 JRU of MPEG-TNF-alpha. No side-effects were observed at the dose of 500 JRU of MPEG-TNF-alpha, which was 2.5 times the minimal dose (200 JRU) of MPEG-TNF-alpha required for complete regression in all treated mice. MPEG-TNF-alpha appears to have potential as a candidate anti-tumor therapeutic agent.
Faculty of Pharmaceutical Sciences, Osaka University, Suita.
Y
Y
Tsutsumi
T
T
Kihira
S
S
Tsunoda
K
K
Kubo
M
M
Miyake
T
T
Kanamori
S
S
Nakagawa
T
T
Mayumi
D000818:Animals; D000951:Antigens, Neoplasm; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy*; D006649:Histocompatibility Antigens; D007275:Injections, Intravenous; D051379:Mice; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D012074:Remission Induction; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use*
D000951:Antigens, Neoplasm; D006649:Histocompatibility Antigens; C092033:PEG-modified tumor necrosis factor-alpha; D014409:Tumor Necrosis Factor-alpha; C029237:tumor-associated transplantation antigen; D011092:Polyethylene Glycols