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Control of Membrane Permeability by External ATP in Animal Cells And its Application to Cancer Chemotherapy

Research Project

Project/Area Number 63571072
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research Institution国立予防衛生研究所

Principal Investigator

KITAGAWA Takayuki  Natl. Inst. Hlth, Dept. Chem., Section Chief, 化学部, 化学療法剤室長 (80092188)

Co-Investigator(Kenkyū-buntansha) AMANO Fumio  Natl. Inst. Hlth, Dept. Chem., Chief investigator, 化学部, 主任研究員 (90142132)
AKAMATSU Yuzuru  Natl. Inst. Hlth, Dept. Chem. Dept Hand, 化学部, 部長 (00072900)
Project Period (FY) 1988 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1990: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1989: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1988: ¥1,300,000 (Direct Cost: ¥1,300,000)
KeywordsMembrane permeability / ATP effect / Membrane variant / Calmodulin antagonists / Transformed cells / Cancer chemotherapy / がん化学療法 / 膜透過性修飾 / 抗癌剤作用の増強 / 細胞膜透過性
Research Abstract

External ATP causes the passive permeability change in several transformed cells but not in untransformed cells. The mechanism by which external ATP controls the permeability change and possible application of this phenomenon for the in vivo cancer chemotherapy have been examined in this research, and the following results were obtained :
1) The newly synthesized sulfonamide derivatives, which inhibit calmodulin-dependent phosphodiesterase activity, enhanced the ATP-dependent passive permeability change in CHO-K1 cells and B16 melanoma cells. The effective concentrations of these drugs were wider than those of previously known antagonists such as trifluoperazine and W7, suggesting the usefulness of the new drugs for pharmacological use.
2) Modulation of the membrane permeability with external ATP have been made in mildly alkaline Tris-buffered saline. Such increased membrane permeability with the ATP was also observed in B16 melanoma cells at pH 7.4 in a growth medium containing calf ser … More um and divalent ions at normal concentrations. Prolonged exposure of the transformed cells to the ATP in this medium led to cell lysis.
3) Studies on the two ATP-requiring enzyme activities, protein kinase and ATPase, present on the cell surface of CHO-K1 cells demonstrate that these ecto-enzymes are not directly associated with the ATP-dependent permeability change. However, several phosphorylated proteins were detected when the cells were permeabilized by external ATP and these protein phosphorylations were not observed in an ATP-resistant CHO clone. Further characteristics of these phosphoproteins are investigated.
4) Therapeutic effects of antitumor agents such as 5-FU and adriamycin against Ehrlich ascites cells grown in mouse ascites cavity or under the back skin were significantly enhanced by combined treatment with ATP. Similar results were also obtained with B16 melanoma cells. These results indicate the great usefulness of added ATP in the cancer chemotherapy management in vivo. Less

Report

(4 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • 1988 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] 北川 隆之: "動物細胞表面膜の細胞外ATPの透過性調節と化学療法への応用" 薬学雑誌. 108. 604-612 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 北川 隆之: "物質透過性変化:特集「細胞測定法マニュアル」" 生体の科学. 39. 440-442 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Takayuki Kitagawa,et al.: "External ATPーinduced passive permeability change and cell lysis:Action in serumーcontaining media." Biochim.Biophys.Acta(Biomembranes). 941. 257-263 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Takayuki Kitagawa,et al.: "Inhibitory effects of newly synthesized sulfonamide derivatives on calmodulinーdependent phosphodiesterase activities and their modulation of ATPーdependent permeability change in mammalian cells." Biochim.Biophys.Acta(Biomembranes). 987. 235-238 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Takayuki Kitagawa,et al.: "Regulation of glucose transport activity and expression of glucose transporter mRNA by serum,growth factors and phorbol ester in mouse fibroblasts." Biochim.Biophys.Acta(Biomembranes). 980. 100-108 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Masaaki Iwaki,et al.: "Cytotoxic effects of aflatoxin Bl and its association with cellular components in chicken primary cultured cells." Biochim.Biophys.Acta(General subjects). 1035. 146-153 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 北川 隆之: "動物細胞の増殖調節機構に関与する遺伝子の解析:増殖因子による糖輸送・輸送体遺伝子発現の調節機構." ビオメディカ. 5. 76-81 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Takayuki Kitagawa,et al.: "Transforming growth factor Bl stimulates glucose transport and expression of glucose transporter mRNA in quiescent mouse fibroblasts." (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Nobuo Yokoo,et al.: "Enhancing effect of external ATP on in vivo cytotoxicity of antitumor drugs for tranformed cells." (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] 北川 隆之,他(共訳): "生体膜:分子構造と機能(ロバ-トB.ゲニス著:Biomembranes)" シュプリンガ-フェアラ-ク社, 526 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T.: "Control of membrane permeability by external ATP in animal cells and its application to chemotherapy." Yakugaku Zasshi. 108(7). 604-612 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T.: "Changes in membrane permeability in animal cells." Seitai-no-Kagaku. 39 (5). 440-442 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T., Amano , E. and Akamatsu, Y.: "External ATP-induced passive permeability change and cell lysis. Action in serum-containing media." Biochim. Biophys. Acta. 941. 257-263 (1988)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T., et al.: "Inhibitory effects of newly synthesized sulfonamide derivatives on calmodulin dependent phosphodiestrase activities and their modulation of ATP-dependent permeability change in mammalian cells." Biochim. Biophys. Acta. 987. 235-238 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T., et al.: "Regulation of glucose transport activity and expression of glucose transporter mRNA by serum, growth factors and phorbol ester in mouse fibroblasts." Biochim. Biophys. Acta. 980. 100-108 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Iwaki, M., Kitagawa, T., et al.: "Cytotoxic effects of aflatoxin B1 and its association with cellular components in chicken primary cultured cells." Biochim. Biophys. Acta. 1035. 146-153 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T.: "Studies on cellular genes associated with growth control of animal cells. Control of glucose transport and the transporter gene expression by growth factors." Biomedical. 5 (10). 76-81 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kitagawa, T., et al.: "Transforming growth factor B1 stimulates glucose transport and expression of glucose transporter mRNA in quiescent mouse fibroblasts." (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yokoo, N., Kitagawa, T., et al.: "Enhancing effect of the in vivo cytotoxicity of antitumor drugs for transformed cells." (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] M.Iwaki,et al.: "Cytotoxic effects of aflatoxin B1 and its association with cellular components in chicken primary cultured cells." Biochim.Biophys.Acta. 1035. 146-153 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] T.Kitagawa,et al.: "Transforming growth factorβ1 stimulates glucose transport and expression of glucose transporter mRNA in quiescent mouse 3T3 cells." (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 北川 隆之: "動物細胞の増殖調節機構に関与する遺伝子の解析:増殖因子による糖輸送・輸送体遺伝子発現の調節機構." ビオメディカ. 5. 76-81 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Takayuki Kitagawa,et al.: "Regulation of glucose transport activity and expression of glucose transporter mRNA by growth factors in mouse fibroblasts." Biochim.Biophys.Acta(Biomembranes). 980. 100-108 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Takayuki Kitagawa,et al.: "Inhibitory effects of newly synthesized sulfonamide derivatives on calmodulinーdependent phosphodiesterase activity and their modulation of ATPーdependent permeability change in mammalian cells." Biochim.Biophys.Acta(Biomembranes). 987. 235-238 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Masaki Iwaki,et al.: "Cytotoxic effects of aflatoxin Bl and its association with cellular components in chiken primary cultured cells." Biochim.Biophys.Acta(General subjects). (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] 北川隆之: "動物細胞の増殖と糖輸送の制御" 蛋白質核酸酵素.

    • Related Report
      1989 Annual Research Report
  • [Publications] 北川隆之他共著: "生体膜(邦訳):R.B.Genis著"Biomembranes"" シュプリンガ-フェアラ-ク社, (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Takayuki Kitagawa,;Fumio Amano,;Yuzuru Akamatsu.: Biochimica et Biophysica Acta(Biomembranes). 941. 257-263 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Takayuki Kitagawa,;Mariko Tanaka,;Yuzuru Akamatsu.: Biochimica et Biophysica Acta(Biomembranes). (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] 北川隆之: 薬学雑誌. 108. 604-612 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] 北川隆之: 生体の科学. 39. 440-442 (1988)

    • Related Report
      1988 Annual Research Report

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Published: 1988-04-01   Modified: 2016-04-21  

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