PMID: 9443407Jan 27, 1998Paper

Antitumor activity of tumor necrosis factor alpha conjugated with divinyl ether and maleic anhydride copolymer on solid tumors in mice

Cancer Research
Y KanedaT Mayumi

Abstract

The purpose of this study is to further explore the usefulness of conjugation with functional polymeric modifiers for clinical application of bioactive proteins and to increase the therapeutic efficacy of tumor necrosis factor alpha (TNF-alpha) by conjugation in vivo. We synthesized TNF-alpha conjugated with the copolymer of divinyl ether and maleic anhydride (DIVEMA), which has intrinsic antitumor activity as a synthetic biological response modifier. The synthesis of DIVEMA-TNF-alpha could be controlled by the addition of 2,3-dimethylmaleic anhydride (DMMAn), which binds to or separates from amino groups when the pH is changed. The specific activity of DIVEMA-TNF-alpha (+) synthesized with DMMAn was hardly decreased in vitro. However, DIVEMA-TNF-alpha (-), which is conjugated without blocking by DMMAn, had a markedly diminished specific activity. DIVEMA-TNF-alpha (+) caused a dramatic hemorrhagic necrotic effect on the tumor when compared to native TNF-alpha 24 h after i.v. injection into mice bearing Sarcoma-180 solid tumors. In addition, DIVEMA-TNF-alpha (+) at a dose of only 100 Japan reference units per mouse revealed a dramatic antitumor effect that is approximately 100 times greater than native TNF-alpha and that could i...Continue Reading

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