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Study of cellular trafficking and membrane permeability of antisense DNA

Research Project

Project/Area Number 06454252
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 内科学一般
Research InstitutionSt.Marianna University School of Medicine

Principal Investigator

SHIMADA Jingoro  St.Marianna University School of Medicine Professor, 医学部, 教授 (50056701)

Co-Investigator(Kenkyū-buntansha) SHOJI Yoko  St.Marianna University School of Medicine Assistant Professor, 医学部, 助手 (00235714)
MIZUSHIMA Yutaka  Institute of Medical science, St.Marianna University School of Medicine Professo, 難病治療研究センサ, 教授 (40010409)
Project Period (FY) 1994 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 1996: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1995: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1994: ¥2,900,000 (Direct Cost: ¥2,900,000)
Keywordsantisense DNA / phosphorothioate / cationic liposomes / cellular distribution / geraniol / ゲラニオール / カチオン性リポソーム / リポフェクチン / DOTAP / transfectam / VEGF / HUVEC / S-オリゴ / FITC標識S-オリゴ / 拡散チャンバー / 単純ヘルペスウイルスI型 / S-oligo / 共焦点レーザー蛍光顕微鏡システム
Research Abstract

Summary
We synthesized antisense DNA toward to immediate early pre-mRNA 4/5 (IE pre-mRNA4/5) of herpes simplex virus type1 (HSV-1) and evaluated anti-herpetic activity both in vitro and in vivo system. We clarified sequence specificity of antisense DNA,membrane delivery effects, and enhancement of biological activity by using drug delivery system (DDS). Since sequence non-specific activity of antisense DNA could not be neglected, anti-HIV activity of antisense DNA containing consecutive G sequence were evaluated.
We observed from this study following points ; 1) Phosphorothioate oligonucleotide possessed most potent anti-herpetic activity, which was paralleled with intercellular amount. 2) Cellular distribution of antisense DNA in infected cells were obviously different from that in non-infected cells. From this results, it was suggested that virus infection may enhance the delivery efficiency of antisense DNA.3) We found that antisense DNA targeted limited splicing site revealed potent anti-herpetic activity. 4) Sequence specific activity of antisense DNA can be delineated from calculation based on the thermodynamics and kinetics of base-pairing. 5) 5'end modification with geraniol enhanced anti-herpetic activity of antisense DNA in a sequence specific manncr. Homogeneous cellular distribution of geranil modified antisense DNA may reflect on anti-herpetic activity. 6) Cationic liposomes altered subcellular distribution of antisense DNA.7) Sequence non-specific biological activity was recognized. Sequence containing consecutive G sequence showed potent anti-HIV activity. 8) Inhibition of virus replication by antisense DNA was recognized on rabbit herpes cornea keratitis.

Report

(4 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] 東海林洋子、嶋田甚五郎: "オリゴヌクレオチドのDDS." 臨床薬理の進歩. 16. 9-19 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Shoji Y.,Shimada J.,et al: "Cellular uptake and biological effects of antisense oligodeoxynucleotides analogs targeted to herpes simplex virus." 40. 1996. (1670-1675)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 岩谷若夫、東海林洋子、田村信也、乗松美貫、嶋田甚五郎、水島裕: "抗HSV活性を有するアンチセンス・オリゴDNAの安定性およびウイルス感染細胞における動態の検討。" Drug Delivery System. 11. 427-434 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Shoji,Shimade,et al.: "Anti-HIV activity of phosphorothioate oligodeoxynucleotides containing consecutive G sequences" Int.J.Immunotherapy. XII(1/2). 1-9 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Shoji,J.Shimada,et al.: "Enhancement of anti-herpetic activity of antisense phosphorothioate oligonucleotides 5' end modified with geraniol." Drug Targeting. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 東海林洋子、松原司、大内信香、舟橋恵子、嶋田甚五郎、水島裕: "VEGF mRNAに対するアンチセンスDNAのヒトさい帯静脈の管腔形成抑制効果をカチオン性リポソームが増強。" Drug Delivery System. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] N.Tamura, W.Iwatani, Y.Shoji, M.Norimatsu, J.Shimada, Y.Mizushima.: "Antiviral effects of phosphorothioate oligonucleotides complementary to 3' splice region of herpes simplex virus immediate early pre-mRNA5." Nucleic Acids Symposium Series. 31. 73-74 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] N.Tamura, W.Iwatani, Y.Shoji, J.Shimada, and Y.Mizushima: "Aptameric inhibition of in vitro DNA polymerization by phosphorothioate oligonucleotides." Nucleic Acids Symposium Series. 34. 93-94 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Shoji Y., Shimaa J., Mizuhshima Y., Iwasawa A., Nakamura Y., Inouye K., Azuma T., Sakurai M., and Nishimura T.: "Cellular uptake and biological effects of antisense oligodeoxynucleotides analogs targeted to herpes simplex virus." Antimicrob.Agents Chem.40. 1670-1675 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Shoji, H.Nakashima, W.Iwatani, N.Tamura, M.Norimatsu, J.Shimada, Y.Mizushima: "Anti-HIV activity of phosphorothioate oligodeoxynucleotides containing consecutive G sequences" Int.J.Immunotherapy. XII (1/2). 1-9 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Y.Shoji, J.Shimada, et al.: "Enhancement of anti-herpetic activity of antisense phosphorothioate oligonucleotides 5' end modified with geraniol." Drug Targeting. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] 東海林洋子、他: "アンチセンスオリゴヌクレオチドの家兎ヘルペス角膜炎に対する効果の基礎的検討。" Jpn Clin Pharmacol Ther. 27. 309-310 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shoji Y.,et al.: "Cellular uptake and biological effects of antisense oligodeoxynucleotides analogs targeted to herpes simplex virus." Antimicrob. Agents Chem.40. 1670-1675 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] 岩谷若夫、東海林洋子、他: "抗HSV活性を有するアンチセンス・オリゴDNAの安定性およびウイルス感染細胞における動態の検討。" Drug Delivery System. 11. 427-434 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Y.Shoji,et al.: "Anti-HIV activity of phosphorothioate oligodeoxynucleotides containing consecutive G sequences" Int. J. Immunotherapy. XII (1/2). 1-9 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shoji Y.et al.: "Enhancement of anti-herpetic activity of antisense phosphorothioate oligonucleotides 5' end modified with geraniol." Drug Targeting. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] 東海林洋子、他: "VEGF mRNAに対するアンチセンスDNAのヒトさい帯静脈の管腔形成抑制効果をカチオン性リポソームが増強。" Drug Delivery System. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Nobuya Tamura, Wakao Iwatani, Yoko Shoji, Jingoro Shimada, et al.: "Aptameric inhibition of in virto DNA polymerization by phosphorothioate oligonucleotides." Nucleic Acids Symposium Series.34. 93-94 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 東海林洋子、嶋田甚五郎: "オリゴヌクレオチドのDDS" 臨床薬理の進歩. 16. 9-19 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 東海林洋子、嶋田甚五郎、水島裕.: "アンチセンスDNAの細胞内分布に及ぼす要因" Drug Delivery System. 10. 85-90 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hideki Nakashima, Yoko Shoji, Sang-Gum Kim, Jingoro Shimada, et al.: "Anti-human immunodeficiency virus type 1 activity of phosphorotohioate analogs of oligodeoxynucleotides: penetration and localization of oligodeoxynucleotides in HIV-1-infected MOLT-4 cells." Nucleic Acids Res.22. 5004-5010 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nobuya Tamura, Wakao Iwatani, Jingoro Shimada, et al.: "Antiviral effects of phosphorothioate oligonucleotides complementary to 3' splice region of herpes simplex virus immediate early pre-mRNA5." Nucleic-Acids Symposium Series. 31. 73-74 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] 東海林 洋子,道券 一浩,嶋田 甚五郎,水島 裕.: "チオール化アンチセンスDNAのCH^RC5細胞における取り込み機能と細胞内分布." Drug Delivery System. 9. 19-24 (1994)

    • Related Report
      1995 Annual Research Report
  • [Publications] 東海林洋子、嶋田甚五郎 他: "チオール化アンチセンスDNAのCH^RC5細胞における取り込み機構と細胞内分布" Drug Delivery System. 9. 19-24 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] N.Tamura,J.Shimada,et al.: "Antiviral effects of phosphorothioate oligonucleotides complementary to 3′splice region of herpes simplex virus immediate early pre-mRNA5" Nucleic Acids Symposium Series. 31. 73-74 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] H.Nakashima,J,Shimada,et al.: "Anti-human immunodeficiency virus type 1 activity of phosphrothioate analogs of oligodeoxynucleotides:penetration and localization of oligodeoxynucleotides in HIV-infected MOLT-4 cells." Nucleic Acids Res.22. 5004-5010 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 東海林洋子、嶋田甚五郎 他: "アンチセンスDNAの細胞内分布に及ぼす要因" Drug Delivery System. (印刷中).

    • Related Report
      1994 Annual Research Report
  • [Publications] S-G.Kim,J.Shimada,et al.: "Synthesis and anti-HIV activities of 5′-linked lipid-oligodeoxynucleotide derivatives." Biochem.Biophys.Res.Commun.(in press).

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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