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Free radical generation in chronic infection and its implication in carcinogenesis

Research Project

Project/Area Number 11138244
Research Category

Grant-in-Aid for Scientific Research on Priority Areas (A)

Allocation TypeSingle-year Grants
Research InstitutionKumamoto University

Principal Investigator

MAEDA Hiroshi  Kumamoto Univ.Sch.Med., Professor, 医学部, 教授 (90004613)

Co-Investigator(Kenkyū-buntansha) MIYAMOTO Youichi  Kumamoto Univ.Sch.Med., Research Associate, 医学部, 助手 (20295132)
SAWA Tomohiro  Kumamoto Univ.Sch.Med., Research Associate, 医学部, 助手 (30284756)
AKAIKE Takaaki  Kumamoto Univ.Sch.Med., Associate Professor, 医学部, 助教授 (20231798)
OGAWA Michio  Kumamoto Univ.Sch.Med., Professor, 医学部, 教授 (30028691)
Project Period (FY) 1999
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1999: ¥7,500,000 (Direct Cost: ¥7,500,000)
Keywordsfree radical / nitric oxide / peroxynitrite / genomic mutation / viral pathogenesis / carcinogenesis / nitroguanosine
Research Abstract

Excessive production of free radicals such as superoxide (O_2^<・->) and nitric oxide (NO) as well as their reaction product, peroxynitrite (ONOO^-) are known to occur during infection and inflammation. These reactive species cause oxidation and nitration of vital molecules including DNA, and hence may involve in mutagenesis and carcinogenesis. In the present study, we investigated the reaction between ONOO- and nucleic acid, particularly the products of damaged nucleic acids. We further studied the impact of ONOO^- on genomic mutation by using Sendai virus (SeV) constracted green fluorescent protein (GFP) as a marker of mutation. High performance liquid chromatography analysis showed that ONOO^- clearly nitrates guanine residues in nucleoside, RNA and DNA.Efficacy of guanine nitration in RNA was as high as that in nucleoside, and 10 times higher than that in DNA.Interestingly, nitroguanosine thus formed was found to produce O_2^<・-> to a significant extent, comparably higher than that by mitomycin C, catalyzed by cytochrome reductase system. These findings suggest that nitration of guanosine by ONOO^- further enhance cellular oxidative stress due to its potential to produce O_2^<・->. Exposure of GFP/SeV to physiologically releavant concentration of ONOO^- (0.8 μM) markedly facilitated the mutation rate of GFP/SeV compared to control GFP/SeV without ONOO^- exposure. Furthermore, in vivo mutation rate of GFP/SeV was also found to depend on NO production during infection as revealed by using NO synthase knock-out mice model. All these findings suggest that reactive nitrogen species may play an important role in infection-associated carcinogensis due to, at least in part, its genotoxic potentials.

Report

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

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Sawa,T., et al.: "Alkylperoxyl radical-scavenging activity of various flavonoids and other phenolic compounds : Implications for the anti-tumor-promoter effect of vegetables"J.Agric.Food Chem.. 42. 397-402 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujii,S., et al: "Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats"Virology. 256. 203-212 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Glover,R.E., et al.: "Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea"Mol.Pharmacol.. 55. 1006-1010 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Doi,K., et al.: "Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumour growth"Br.J.Cancer. 80. 1945-1954 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue,K., et al.: "Nitrosothiol formation catalyzed by ceruloplasmin : Implication for cytoprotective mechanism in vivo"J.Biol.Chem.. 274. 27069-27074 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maeda,H., et al.: "Free radical generation from heterocyclic amines by cytochrome b5 reductase in the presence of NADH"Cancer Letters. 143. 117-121 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maeda,H., et al.: "Kallikrein-kinin in infection and cancer"Immunopharmacology. 43. 115-128 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sawa,T., et al.: "Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue"Cancer Res.. 60. 666-671 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hori,K., et al.: "Tumor-selective blood flow decrease induced by an angiotensin converting enzyme imhibitor, temocapril hydrochloride"Jpn.J.Cancer Res.. 91. 261-269 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akaike,T., et al.: "Viral mutation accelerated by nitric oxide production during infection in vivo"FASEB J.. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akaike,T., and Maeda,H.: "Nitric Oxide and Infection (ed.F.C.Fang)"Kluwer Academic/Plenum Publishing Co., New York. 19 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akaike,T., and Maeda,H.: "Nitric Oxide (ed.L.J.Ignarro)"Academic Press, San Diego (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maeda, H., Sawa, T., Yubisui, T.and Akaike, T.: "Free radical generation from heterocyclic amines by cytochrome b5 reductase in the presense of NADH"Cancer Letters. 143. 117-121 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sawa, T., Nakao, M., Akaike, T., Ono, K., and Maeda, H.: "Alkylperoxyl radical-scavenging activity of various flavonoids and other polyphenolic compounds : Implications for the anti-tumor-promoter effect of vegetables"J.Agric. Food Chem.. 42. 397-402 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fujii, S., Akaike, T., and Maeda, H.: "Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats"Virology. 256. 203-212 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Inoue, K., Akaike, T., Miyamoto, Y., Okamoto, T., Sawa, T., Otagiri, M., Suzuki, S., Yoshimura, T.and Maeda, H.: "Nitrosothiol formation catalyzed by ceruloplasmin : Implication for cytoprotective mechanism in vivo"J.Biol.Chem.. 274. 27069-27075 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Doi, K., Akaike, T., Fujii, S., Tanaka, S., Ikebe, N., Beppu, T., Shibahara, S., Ogawa, M., and Maeda, H.: "Induction of haem oxygenase-1 by nitric oxide and ischemia in experimental solid tumours and implications for tumour growth"Br.J.Cancer. 80. 1945-1954 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Glover, R.E., Ivy, E.D., Orringer, E.P., Maeda, H., Mason, R.P.: "Detection of nitrosyl hemoglobin in venous blood in the treatment of sicle cell anemia with hydroxyurea"Mol.Pharmacol.. 55. 1006-1010 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akaike, T.and Maeda, H.: "Nitric oxide in influenza"Nitric Oxide and Infection (ed.F.C.Fang). Kluwer Academic/Plenum Publishing Co., New York. 397-415 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hori, K., Saito, S., Takahashi, H., Sato, H., Maeda, H., Sato, Y.: "Tumor-selective blood flow decrease induced by an angiotensin concerting enzyme inhibitor, temocapril hydrochloride"Jpn.J.Cancer Res.. 91. 261-269 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akaike, T.and Maeda, H.: "Pathophysiological effects of high-output production of nitric oxide"Nitric Oxide (ed.L.J.Ignarro). Academic Press, San Diego. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Maeda, H., Wu, J., Okamoto, T., Maruo, K., and Akaike, T.: "Kallikrein-kinin in infection and cancer"Immunopharmacology. 43. 115-128 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sawa, T., Wu, J., Akaike, T., and Maeda, H.: "Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue"Cancer Res.. 60. 666-671 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Akaike, T., Fujii, S., Kato, A., Yoshitake, J., Miyamoto, Y., Sawa, T., Okamoto, S., Suga, M., Asakawa, M., Nagai, Y.and Maeda, H.: "Viral mutation accelarated by nitric oxide production during infection"FASEB J.. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sawa,T.,et al.: "Alkylperoxyl radical-scavenging activity of various flavonoids and other phenolic compounds:Implications for the anti-tumor-promoter effect of vegetables"J.Agric.Food Chem.. 42. 397-402 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fujii,S.,et al.: "Role of nitric oxide in pathogenesis of herpes simplex virus encephalitis in rats"Virology. 256. 203-212 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Glover,R.E.,et al.: "Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea"Mol.Pharmacol.. 55. 1006-1010 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Doi,K.,et al.: "Induction of haem oxygenase-1 by nitric oxide and ischaemia in experimental solid tumours and implications for tumor growth"Br.J.Cancer.. 80. 1945-1954 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Inoue,K.,et al.: "Nitrosothiol formation catalyzed by ceruloplasmin:Implication for cytoprotective mechanism in vivo"J.Biol.Chem.. 274. 27069-27074 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Maeda,H.,et al.: "Free radical generation from heterocyclic amines by cytochrome b5 reductase in the presence of NADH"Cancer Letters. 143. 117-121 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Maeda,H.,et al.: "Kallikrein-kinin in infection and cancer"Immunopharmacology. 43. 115-128 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sawa,T.,et al.: "Tumor-targeting chemotherapy by a xanthine oxidase-polymer conjugate that generates oxygen-free radicals in tumor tissue"Cancer Res.. 60. 666-671 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hori,K.,et al.: "Tumor-selective blood flow decrease induced by an angiotensin converting enzyme imhibitor,temocapril hydrochloride"Jpn.J.Cance Res.. 91. 261-269 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akaike,T.,et al.: "Viral mutation accelerated by nitric oxide production during infection in vivo"FASEB J.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akaike,T.,and Maeda,H.: "Nitric Oxide and Infection(ed.F.C.Fang)"Kluwer Academic/Plenum Publishing Co.,New York. 19 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akaike,T.,and Maeda,H.: "Nitric Oxide(ed.L.J.Ignarro)"Academic Press,San Diego(in press). (2000)

    • Related Report
      1999 Annual Research Report

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

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