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Development of the therapy for oral cancer by transduction of iNOS gene in combination with radiotherapy

Research Project

Project/Area Number 12557176
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Surgical dentistry
Research InstitutionThe University of Tokushima

Principal Investigator

SATO Mitsunobu  The University of Tokushima, School of Dentistry, Professor, 歯学部, 教授 (00028763)

Co-Investigator(Kenkyū-buntansha) OKAMOTO Masato  The University of Tokushima, School of Dentistry, Research Associate, 歯学部, 助手 (10243718)
AZUMA Masayuki  The University of Tokushima, School of Dentistry Hospital, Assistant Professor, 歯学部附属病院, 講師 (20144983)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥10,400,000 (Direct Cost: ¥10,400,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2001: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2000: ¥6,100,000 (Direct Cost: ¥6,100,000)
Keywordsoral cancer / iNOS gene / NO / radiotherapy / OK-432 / lipoteichoic acid-related molecule / Th1-type cytokine / anti-tumor effect / iNos遺伝子 / 口腔扁平上皮癌 / 口腔小唾液腺癌 / iNOS / IFN-γ / TIL / NK
Research Abstract

1. Transfection of human oral squamous cell carcinoma cells (B88) with the gene encoding inducible nitric oxide synthase (INOS) resulted in the suppression of cell growth and NO production in vitro or in nude mice. The effect of overexpression of iNOS gene on B88 cells was augmented by irradiation, while down-regulation of iNOS gene in B88 cells caused significantly the enhancement of cell growth.
2. In transfection of iNOS gene to B88 cells, bystander effect on the tumor cells without expression of iNOS gene was detected.
3. We have already reported the high effectiveness of the therapy for oral squamous cell carcinoma by UFT and OK-432 in combination with radiotherapy. When we examined immunohistochemically the expression of iNOS in the biopsy materials taken at the first visit to our clinic, group with complete remission showed the strong expression of iNOS in the inflammatory cells infiltrating into the subepithellal region.
4. We found that a lipoteichoic acid-related molecule (OK-PSA) prepared from streptococcal agent, OK-432 is a potent inducer of Th1-type cytokines.
5. When human salivary cancer (HSG) ?bearing nude mice were administered OK-PSA peritumorally, production of Th1 type cytokines such as IFN-γ, , TNF-α, IL-2, IL-12 or IL-18 as well as of nitrite/nitrate was detected in the blood, in which radiotherapy augmented production of the cytokines and NO.6. Treatment with OK-PSA of human peripheral blood mononuclear cells, U937 cells, human gingival fibroblasts or human oral squamous carcinoma cells (BHY) resulted in production of N0_2^-.
7. Cultivation of B88 cells under the presence of NO donor (NOC18 ; 0.01-1mg/ml) caused potent induction of apoptosis.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (57 results)

All Other

All Publications (57 results)

  • [Publications] Masato Okamoto: "Induction of Th1-type cytokines by lipoteichoic acid-related prepara isolated from OK-432, a penicillin-killed streptococcal agent"Immunopharmacology. 49(3). 363-370 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Cytokine-inducing activity and antitumor effect of a liposome-incorporated interferon-γ-inducing molecule derived from OK-432, a streptococcal preparation"J.Immunother.. 23(1). 94-103 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Induction of cytokines and killer cell activities by cisplatin and 5-fluorouracil in head and neck cancer patients"Anti-Cancer Drugs. 11(3). 165-173 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Keiko Aota: "5-Fluorouracil induces apoptosis through the suppression of NF-kB activity in human salivary gland cancer cells"Biochem.Biophys.Res.Commun.. 273(3). 1168-1174 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Mechanism for bone invasion of oral cancer cells mediated by interleukin 6 in vitro and in vivo"Cancer. 89(9). 1966-1975 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Daisuke Uchida: "Overexpression of TSC-22(TGF-β stimulated clone 22) markedly enhances 5-fluorouracil-induced apoptosis in a human salivary gland cancer cell line"Lab.Invest.. 80(6). 955-963 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Enhancement of anti-cancer immunity by lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptococcus"Cancer Immunol Immunother. 50(8). 408-418 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Go Ohe: "Th1-cytokine induction and anti-tumor effect of 55kd protein isolated from Aeginetia indica L, a parasitic plant"Cancer Immunol Immunother. 50(5). 251-259 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Comparison of cytokine-inducing activity in lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptocuccus and from the untreated bacteria"Int Immunopharmacol. 1(11). 1957-1968 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Severe impairment of anti-cancer effect of lioteichoic acid-related ~molecule isolated from a penicillin-killed Streptocuccus pyogenes in toll-like receptor 4 deficient mice"Int Immunopharmacol. 1(9-10). 1789-1795 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masayuki Azuma: "5-Fluorouracil suppression of NF-kB is mediated by the inhibition of IkB kinase activity in human salivary gland cancer cells"Biochem.Biophys.Res.Commun.. 282(1). 292-296 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Daisuke Uchida: "Low-dose retinoic acid enhances in vitro invasiveness of human oral squamous cell-carcinoma cell lines"Br J Cancer. 85(1). 122-128 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Involvement of toll-like receptor 4 signaling in interferon-γ production and antitumor effect by streptococcal agent OK-432"J.Nat.Cancer Inst.. 95・4. 316-326 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Enhancement of anti-tumor immunity by lipoteichoic acid-related molecule isolated from OK-432, a streptococcal agent, in athymic nude mice bearing human salivary adenocarcinoma:Role of natural killer cells"Anticancer Res.. 22・6A. 3229-3240 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koji Harada: "Low p27^<Kip1> expression is associated with poor prognosis in oral squamous cell carcinoma"Anticancer Res.. 22・5. 2985-2990 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Keiko Aota: "Stable inhibition of NF-kB in salivary gland cells does not enhance sentitivity to TNF-α-induced apoptosis due to upregulation of TRAF-1 expression"Exp.Cell Res.. 276・1. 111-119 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Satoshi Hino: "Cytoplasmic TSC-22 (transforming growth factor-β-stimulated clone-22) markedly enhances the ratiation sensitivity of salivary gland cancer cells"Blochem.Biophys.Res.Commun.. 292・4. 957-963 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Supriatno: "Overexpression of p27^<Kip1> growth arrest and apoptosis in an oral cancer cell line"Oral Oncol.. 38・7. 730-736 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 佐藤光信: "口腔外科 YEAR BOOK "癌の遺伝子治療の最近の進歩 頭頸部癌""クインテッセンス出版株式会社. 4 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Ohe G, Oshikawa T, Nishikawa H, Furuichi S, Yoshida H, Matsuno T, Saito M, and Sato M: "Induction of Th1-type cytokines by lipoteichoic acid-related preparation isolated from OK-432, a penicillin-killed streptococcal agent."Immunopharmacology. 49(3). 363-376 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Gohda H, Ohe G, Yoshida H, Matsuno T, Saito M, and Sato M: "Cytokine-inducing activity and antitumor effect of a liposome-incorporated interferon-γ-inducing molecule derived from OK-432, a streptococcal preparation."J Immunother. 23(1). 94-103 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Ohe G, Oshikawa T, Nishikawa H, Furuichi S, Yoshida H, and Sato M: "Induction of cytokines and killer cell activities by cisplatin and 5-fluorouracil in head and neck cancer patients."Anti-Cancer Drugs. 11(3). 165-173 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aota K, Azuma M, Yamashita T, Tamatani T, Motegi K, Ishimaru N, Hayashi Y, And Sato M: "5-Fluorouracil induces apoptosis through the suppression of NF-kB activity in human salivary gland cancer cells."Biochem Biophys Res Commun. 273(3). 1168-1174 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Hiura K, Ohe G, Ohba Y, Terai K, Oshikawa T, Furuichi S, Nishikawa H, Moriyama K, Yoshida H, and Sato M: "Mechanism for bone invasion of oral cancer cells mediated by interleukin 6 in vitro and in vivo."Cancer. 89(9). 1966-1975 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchida D, Kawamata H, Omotehara F, Miwa Y, Hino S, Begum NM, Yoshida H, and Sato M: "Overexpression of TSC22 (TGF-β stimulated clone 22) markedly enhances 5-fluorouracil-induced apoptosis in a human salivary gland cancer cell line."Lab Invest. 80(6). 955-963 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Ohe G, Oshikawa T, Furuichi S, Nishikawa H, Tano T, Ahmed SU, Yoshida H, Moriya Y, Saito M, and Sato M: "Enhancement of anti-cancer immunity by lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptococcus."Cancer Immunol Immunother. 50(8). 408-418 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohe G, Okamoto M, Oshikawa T, Furuichi S, Nishikawa H, Tano T, Uyama K, Bando T, Yoshida H, Sakai T, Himeno K, Sato M, and Ohkubo S: "Th1-cytokine induction and antitumor effect of 55kD protein isolated from Aeginetia indica L, a parasitic plant."Cancer Immunol Immunother. 50(5). 251-259 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Oshikawa T, Ohe G, Furuichi S, Nishikawa H, Tano T, Bando T, Yoshida H, Matsubara S, Matsuno T, Saito M, and Sato M: "Comparison of cytokine-inducing activity in lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptococcus and from the untreated bacteria."Int Immunopharmacol. 1(11). 1957-1968 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Oshikawa T, Ohe G, Nishikawa H, Furuichi S. Tano T, Moriya Y, Saito M, and Sato M: "Severe impairment of anti-cancer effect of lipoteichoic acid-related molecule isolated from a penicillin-killed Streptococcus pyogenes in toll-like receptor 4-deficient mice."Int Immunopharmacol. 1(9-10). 1789-1795 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Azuma M, Yamashita T, Aota K, Tamatani T, and Sato M: "5-Fluorouracil suppression of NF-kB is mediated by the inhibition of IkB kinase activity in human salivary gland cancer cells."Biochem Biophys Res COMMUN. 282(1). 292-296 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchida D, Kawamata H, Nakashiro K, Omotehata F, Hino S, Hoque MO, Begum NM, Yoshida H, Sato M, and Fujimori T: "****dose retinoic acid enhances in vitro invasiveness of human oral squamous cell-carcinoma cell lines."Br J Cancer. 85(1). 122-128 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Oshikawa T, Tano T, Ohe G, Furuichi S, Nishikawa H, Ahmed SU, Akashi S, Miyake K, Takeuchi O, Akira S, Moriya Y, Matsubara S. Ryoma Y, Saito M, and Sato M: "Involvement of toll-like receptor 4 signaling in interferon-γ production and antitumor effect by streptococcal agent OK-432."J Nat cancer Inst. 95(4). 316-326 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okamoto M, Ohe G, Furuichi S. Nishikawa H, Oshikawa T, Tano T, Ahmed SU, Yoshida H, Moriya Y, Matsubara S, Ryoma Y, Saito M, and Sato M: "Enhancement of anti-tumor immunity by lipoteichoic acid-related molecule isolated from OK-432, a streptococcal agent, in athymic nude mice bearing human salivary adenocarcinoma : role of natural killer cells."Anticancer Res. 22(6A). 3229-3240 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Harada K, Supriatno, Yoshida H, and Sato M: "Low p27Kip1 expression is associated with poor prognosis in oral squamous cell carcinoma."Anticancer Res. 22(5). 2985-2990 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aota K, Azuma M, Tamatani T, Yamashita T, Ashida Y, and Sato M: "Stable inhibition of NF-kB in salivary gland cells does not enhance sensitivity to TNF-α-induced apoptosis due to upregulation of TRAF-1 expression."Exp Cell Res. 276(1). 111-119 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hino S, Kawamata H, Omotehara F, Uchida D, Miwa Y, Begum NM, Yoshida H, Sato M, and Fujimori T: "Cytoplasmic TSC-22 (transforming growth factor-β-stimulated clone-22) markedly enhances the radiation sensitivity of salivary gland cancer cells."Biochem Biophys Res Commun. 292(4). 957-963 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Supriatno, Harada K, Hoque MO, Bando T, Yoshida H, and Sato M: "Overexpression of p27 (Kip1) induces growth arrest and apoptosis in an oral cancer cell line."Oral Oncol. 38(7). 730-736 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mitsunobu Sato, Masato Okamoto, and Koji Harada: "Current Progress of Human Cancer Gene Therapy-Head and Neck Cancer in Oral Surgery YEAR BOOK"127-130 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masato Okamoto: "Involvement of toll-like receptor 4 signaling in interferon-γ production and antitumor effect by streptococcal agent OK-432"J. Nat. Cancer Inst.. 95・4. 316-326 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masato Okamoto: "Enhancement of anti-cancer immunity by lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptococcus agent, mathymic nude mice bearing human salivary adenocarcinoma : role of natural killer cells"Anticancer Res.. 22・6A. 3229-3240 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koji Harada: "Low p27^<kipl> expression is associated with poor prognosis in oral squamous cell carcinoma"Anticancer Res.. 22・5. 2985-2990 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Keiko Aota: "Stable inhibition of NF-kB in salivary gland cells does not enhance sentitivity to TNF-α-induced apoptosis due to upregulation of TRAF-1 expression"Exp. Cell Res.. 276・1. 111-119 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Satoshi Hino: "Cytoplasmic TSC-22 (transforming growth factor-β-stimulated clone-22) markedly enhances the ratiation sensitivity of salivary gland cancer cells"Biochem. Biophys. Res. Commun.. 292・4. 957-963 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Supriatno: "Overexpression of p27^<Kipl> growth arrest and apoptosis in an oral cancer cell line"Oral Oncol.. 38・7. 730-736 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 佐藤光信: "口腔外科 YEAR BOOK "癌の遺伝子治療の最近の進歩 頭頸部癌""クインテッセンス出版株式会社. 4 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masato Okamoto: "Enhancement of anti-cancer immunity by lipoteichoic acid-related molecule isolated from a penicillin-killed group A Streptococcus"Cancer Immunol Immunother. 50(8). 408-418 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Go Ohe: "Th1-cytokine induction and anti-tumor effect of 55kd protein isolated from Aeginetia indica L, a parasitic plant"Cancer Immunol Immunother. 50(5). 251-259 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masato Okamoto: "Comparison of cytokine-inducing activity in lipoteichoic acidrelated molecule isolated from a penicillin-killed group A Streptocuccus and from the untreated bacteria"Int Immunopharmacol. 1(11). 1957-1968 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masato Okamoto: "Severe impairment of anti-cancer effect of lioteichoic acid-related molecule isolated from a penicillin-killed Streptocuccus pyogenes"Int Immunopharmacol. 1(9-10). 1789-1795 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masayuki Azuma: "5-Fluorouracil suppression of NF-kB is mediated by the inhibition of IkB kinase activity in human salivary gland cancer cells"Biochem. Biophys. Res. Commun.. 282(1). 292-296 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Daisuke Uchida: "Low-dose retinoic acid enhances in vitro invasiveness of human oral squamous cell-carcinoma cell lines"Br J Cancer. 85(1). 122-128 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masato Okamoto: "Induction of Th1-type cytokines by lipoteichoic acid-related preparation isolated from OK-432, a penicillin-killed streptococcal agent."Immunopharmacology. 49(3). 363-370 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masato Okamoto: "Cytokine-inducing activity and antitumor effect of a liposome-incorporated interferon-γ-inducing molecule derived from OK-432, a streptococcal preparation.,"J.Immunother.. 23(1). 94-103 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masato Okamoto: "Induction of cytokines and killer cell activities by cisplatin and 5-fluorouracil in head and neck cancer patients."Anti-Cancer Drugs. 11(3). 165-173 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Keiko Aota: "5-Fluorouracil induces apoptosis through the suppression of NF-kB activity in human salivary gland cancer cells."Biochem.Biophys.Res.Commun.. 273(3). 1168-1174 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Masato Okamoto: "Mechanism for bone invasion of oral cancer cells mediated by interleukin 6 in vitro and in vivo."Cancer. 89(9). 1966-1975 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Daisuke Uchida: "Overexpression of TSC-22 (TGF-β stimulated clone 22) markedly enhances 5-fluorouracil-induced apoptosis in a human salivary gland cancer cell line."Lab.Invest.. 80(6),. 955-963 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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