Kaneda Y, Yamamoto Y, Tsunoda S, Kamada H, Tsutsumi Y, Hirano T, Mayumi T
Faculty of Pharmaceutical Sciences, Osaka University, Japan.
Biochem Biophys Res Commun. 1997 Oct 9;239(1):160-5. doi: 10.1006/bbrc.1997.7330.
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.
为提高抗肿瘤细胞因子在体内的治疗效用，我们用二乙烯基醚和顺丁烯二酸酐共聚物（DIVEMA）合成了生物共轭肿瘤坏死因子-α（TNF-α），DIVEMA作为一种合成生物反应调节剂具有内在抗肿瘤活性。修饰程度可通过添加2,3-二甲基马来酸酐（DMMAn）来控制，DMMAn通过改变pH值与TNF-α的氨基结合。此外，DIVEMA-TNF-α在体外的比活性几乎没有降低。与天然TNF-α相比，DIVEMA-TNF-α对荷实体瘤小鼠显示出显著的抗肿瘤作用，且无任何副作用，如猝死、体重减轻和血小板计数减少。这些结果表明，DIVEMA是一种用于TNF-α生物共轭的有用聚合物修饰剂，可增强其抗肿瘤活性，多功能生物共轭TNF-α可能是一种有潜力的治疗用抗肿瘤药物。
