Bioconjugation of tumor necrosis factor-alpha with the copolymer of divinyl ether and maleic anhydride increasing its antitumor potency.
To enhance the therapeutic usefulness of antitumor cytokines in vivo, we synthesized bioconjugated tumor necrosis factor-alpha (TNF-alpha) with divinyl ether and maleic anhydride copolymer (DIVEMA), which has intrinsic antitumor activity as a synthetic biological response modifier. The degree of modification could be controlled by the addition of 2,3-dimethylmaleic anhydride (DMMAn), which binds to amino groups of TNF-alpha by changing the pH. In addition, the specific activity of DIVEMA-TNF-alpha was hardly decreased in vitro. DIVEMA-TNF-alpha showed a marked antitumor effect compared to native TNF-alpha without any side effects such as sudden death, body-weight reduction, and decrease in platelet count on mice bearing solid tumors. These results suggest that DIVEMA is a useful polymeric modifier for-bioconjugation of TNF-alpha in order to increase its antitumor activity, and multifunctionally bioconjugated TNF-alpha may be a potentiated antitumor agent for therapeutic use.
Kaneda
Y
Y
Faculty of Pharmaceutical Sciences, Osaka University, Japan.
Yamamoto
Y
Y
Tsunoda
S
S
Kamada
H
H
Tsutsumi
Y
Y
Hirano
T
T
Mayumi
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002850:Chromatography, Gel; D006801:Humans; D008299:Maleic Anhydrides / Q000737:chemistry; D051379:Mice; D008956:Models, Chemical; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010976:Platelet Count / Q000187:drug effects; D011713:Pyran Copolymer / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D008299:Maleic Anhydrides; D014409:Tumor Necrosis Factor-alpha; D011713:Pyran Copolymer; C007474:2,3-dimethylmaleic anhydride