This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaneda, Y. Articles by Mayumi, T. Search for Related Content PubMed Articles by Kaneda, Y. Articles by Mayumi, T.

Antitumor Activity of Tumor Necrosis Factor Conjugated with Divinyl Ether and Maleic Anhydride Copolymer on Solid Tumors in Mice¹

Faculty of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565, Japan [Y. K., Y. Y., H. K., S-i. T., Y. T., T. M.], and National Institute of Bioscience and Human Technology, I-1 Tsukuba-higashi, Ibaraki 305, Japan [T. H.]

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 (TNF-) by conjugation in vivo. We synthesized TNF- 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- 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- (+) synthesized with DMMAn was hardly decreased in vitro. However, DIVEMA-TNF- (-), which is conjugated without blocking by DMMAn, had a markedly diminished specific activity. DIVEMA-TNF- (+) caused a dramatic hemorrhagic necrotic effect on the tumor when compared to native TNF- 24 h after i.v. injection into mice bearing Sarcoma-180 solid tumors. In addition, DIVEMA-TNF- (+) 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- and that could induce complete regression in all five mice bearing Meth-A solid tumors without any apparent side effects. Because neither DIVEMA alone nor a mixture of TNF- and DIVEMA caused antitumor activity with i.v. administration, the increase in antitumor potency of TNF- may be caused by the covalent conjugation with DIVEMA. DIVEMA-TNF- at low dose revealed dramatic antitumor potency. Because TNF- injected in vivo is extremely low-dose, concentration of intrinsic TNF- in vivo is not influenced. Therefore, the cytokine network in vivo is not destroyed. These results suggest that DIVEMA is a useful polymeric modifier for conjugation of TNF- to increase its antitumor activity.

¹ This work was supported in part by a grant from the Uehara Memorial Foundation, and in part by Grants-in-Aid for Cancer Research and for Scientific Research from the Ministry of Education, Science and Culture of Japan.

² To whom requests for reprints should be addressed, at Faculty and Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565, Japan. Phone: 81-6-879-8175; Fax: 81-6-879-8179; E-mail: mayumi@phs.osaka-u.ac.jp.

Received 8/ 6/97. Accepted 11/11/97.

This article has been cited by other articles:

				H. Shibata, Y. Yoshioka, S. Ikemizu, K. Kobayashi, Y. Yamamoto, Y. Mukai, T. Okamoto, M. Taniai, M. Kawamura, Y. Abe, et al. Functionalization of Tumor Necrosis Factor-{alpha} Using Phage Display Technique and PEGylation Improves Its Antitumor Therapeutic Window Clin. Cancer Res., December 15, 2004; 10(24): 8293 - 8300. [Abstract] [Full Text] [PDF]

				L. Panaitescu and R. M. Ottenbrite Biological Effects and Antitumor Activity Induced by Benzocaine Conjugated Anionic Polymers Journal of Bioactive and Compatible Polymers, September 1, 2002; 17(5): 357 - 374. [Abstract] [PDF]

				H. Kamada, Y. Tsutsumi, Y. Yamamoto, T. Kihira, Y. Kaneda, Y. Mu, H. Kodaira, S.-i. Tsunoda, S. Nakagawa, and T. Mayumi Antitumor Activity of Tumor Necrosis Factor-{{alpha}} Conjugated with Polyvinylpyrrolidone on Solid Tumors in Mice Cancer Res., November 1, 2000; 60(22): 6416 - 6420. [Abstract] [Full Text]

				S. Tsunoda, T. Ishikawa, Y. Yamamoto, H. Kamada, K. Koizumi, J. Matsui, Y. Tsutsumi, T. Hirano, and T. Mayumi Enhanced Antitumor Potency of Polyethylene Glycolylated Tumor Necrosis Factor-alpha : A Novel Polymer-Conjugation Technique with a Reversible Amino-Protective Reagent J. Pharmacol. Exp. Ther., July 1, 1999; 290(1): 368 - 372. [Abstract] [Full Text]