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The invention of the intellectualization cytokine using a synthetic biological response modifier.

Research Project

Project/Area Number 11672259
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionOsaka University

Principal Investigator

KUBO Kazuyoshi  Graduate School of Pharmaceutical Sciences Osaka University Associate Professor, 薬学研究科, 助教授 (00028846)

Co-Investigator(Kenkyū-buntansha) NAKAGAWA Shinsaku  Graduate School of Pharmaceutical Sciences Osaka University Associate Professor, 薬学研究科, 助教授 (70207728)
MAYUMI Tadanori  Graduate School of Pharmaceutical Sciences Osaka University Professor, 薬学研究科, 教授 (00098485)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsAntineoplastic-Agents / Drug-Carriers / Maleic-Anhydrides / Tumor-Necrosis-Factor / 抗腫瘍作用 / DMMAn
Research 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-INF-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 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-alpha and DIVEMA caused antitumor activity with i.v. administration, the increase in antitumor potency of TNF-alpha may be caused by the covalent conjugation with DIVEMA.DIVEMA-TNF-alpha at low dose revealed dramatic antitumor potency. Because TNF-alpha injected in vivo is extremely low-dose, concentration of intrinsic TNF-alpha 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-alpha to increase its antitumor activity.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Kamada H.: "Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidoneonsolid tumors in mice"Cancer Res.. 60. 6416-6420 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mu Y.: "Bioconjugation of bioactive peptide : synthetic peptide YIGSR conjugated with poly (styrene co-maleic acid) enhanced its inhibitory effect on lung metastasis of B16BL6 melanoma cells."Drug Delivery System. 14. 129-135 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsunoda S.: "Enhanced antitumor potency of PEGylated tumor necrosis factor-a : a novel polymer-conjugation technique with a reversible amino-protective reagent."J.Pharmacol.Exp.Ther.. 290. 368-372 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mu Y.: "Bioconjugation of Laminin-Related Peptide YIGSR with Polyvinyl Pyrrolidone Increases its Antimetastatic Effect Due to a linger Plasma Half-Life."Biochem.Biophys.Res.Comm.. 264. 763-767 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kamada H.et al.: "Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice."Cancer Res.. 60. 6416-6420 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mu Y.et al.: "Bioconjugation of bioactive peptide : synthetic peptide YIGSR conjugated with poly (styrene co-maleic acid) enhanced its inhibitory effect on lung metastasis of B16BL6 melanoma cells."Drug Delivery System. 14. 129-135 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsunoda S.et al.: "Enhanced antitumor potency of PEGylated tumor necrosis factor-a : a novel polymer-conjugation technique with a reversible amino-protective reagent."J.Pharmacol.Exp.Ther.. 290. 368-372 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Mu Y.et al.: "Bioconjugation of Laminin-Related Peptide YIGSR with Polyvinyl Pyrrolidone Increases its Antimetastatic Effect Due to a linger Plasma Half-Life."Biochem.Biophys.Res.Comm.. 264. 763-767 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kamada H: "Antitumor activity of tumor necrosis factor-alpha conjugated with polyvinylpyrrolidone on solid tumors in mice"Cancer Res.. 60. 6416-6420 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Tsunoda: "Enhanced antitumor potency of PEGylated tumor necrosis factor-alpha: a novel polymer-conjugation technique with a reversible amino-protective reagent"J. Pharmacol. Exp. Ther.. 290(1). 368-372 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yu Mu: "Bioconjugation of bioactive peptide: synthetic peptide YIGSR conjugated with poly (styrene co-maleic acid) enhanced its inhibitory effect on lung metastasis of B16BL6 melanoma cells"Drug Delivery System. 14(2). 129-135 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Haruhiko Kamada: "Molecular design of conjugated tumor necrosis factor-alpha; Synthesis and characteristics of polyvinyl pyrrolidone modified tumor necrosis facyor-alpha"Biochem. Biophys. Res. Commun.. 257(2). 448-453 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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