2000 Fiscal Year Annual Research Report

慢性感染に伴うフリーラジカル産生と発がん

Research Project

Project/Area Number	12213113
Research Institution	Kumamoto University
Principal Investigator	前田浩熊本大学, 医学部, 教授 (90004613)
Co-Investigator(Kenkyū-buntansha)	宮本洋一熊本大学, 医学部, 助手 (20295132) 澤智裕熊本大学, 医学部, 助手 (30284756) 赤池孝章熊本大学, 医学部, 助教授 (20231798) 小川道雄熊本大学, 医学部, 教授 (30028691)
Keywords	フリーラジカル / NO / パーオキシナイトライト / 遺伝子変異 / ウイルス感染病態 / 発癌
Research Abstract	固型癌のうち、胃癌、肝癌、子宮癌などの原因が細菌やウイルスによることが次第に明らかになってきた。さらに、胆管や胆のう癌、食道癌も何らかの感染症に起因する容疑が濃くなってきた。これらの感染症と発癌に共通の事象として、それが長期にわたる慢性炎症を伴うこと、また活性酸素(スーパーオキサイドやH_2O_2、あるいはHOCl)や一酸化窒素(NO)などのフリーラジカル関連分子種が宿主の炎症反応に伴い、感染局所で過剰に生成していることである。さらに重要なことは、これらのラジカル分子種はDNAを容易に障害することである。そこで本研究では、微生物感染・炎症にともない生成するフリーラジカルと核酸成分との反応を特に遺伝子変異との関係から解析した。また、センダイウイルス肺炎モデルを作製し、in vivoでの遺伝子変異におけるフリーラジカルの役割を検討した。その結果、過酸化脂質がミオグロビン等のヘム鉄存在下に生じる過酸化脂質ラジカルが、2本鎖DNAに対して変異原性のある脱塩基部位の形成をもたらした。また、上記ウイルス感染においては、スーパーオキサイドラジカル(O_2^-)と一酸化窒素(NO)の過剰生成がおこることを明らかにしたが、この両者はすみやかに反応してより反応性の強いパーオキシナイトライト(ONOO^-)となる。ONOO^-とDNAやRNAとの反応では、グアニン残基のニトロ化が効率良くおこり、さらに生じたニトログアノシンがチトクロム還元酵素の作用によりO_2^-を生じることが分かった。このONOO^-がin vivo,in vitroいずれにおいてもウイルス遺伝子に対して強力な遺伝子変異をもたらすことを、NO合成酵素(NOS)ノックアウトマウスやNOS強制発現細胞を用いて明らかにし、上記の知見が正しいことを確認した。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Akaike,T.,et al.: "Viral mutation accelarated by nitric oxide production during infection in vivo"FASEB J.. 14. 1447-1454 (2000)
[Publications] Sawa,T.,et al: "Tyrosine nitration by peroxynitrite formed from nitric oxide and superoxide generated by xanthine oxidase"J.Biol.Chem.. 275. 32467-32474 (2000)
[Publications] Akaike,T.,and Maeda,H.: "Nitric oxide and virus infection"Immunol.. 101. 300-308 (2000)
[Publications] Ikebe,N.,et al.: "Protective effect of S-nitrosylated alphal-protease inhibitor on hepatic ischemia-reperfusion injury"J.Pharmacol.Exp.Therap.. 295. 904-911 (2000)
[Publications] Akizuki,E.,et al.: "Role of nitric oxide and superoxide in acute cardiac allograft rejection in rats"Proc.Soc.Exp.Biol.Med.. 225. 151-159 (2000)
[Publications] Kanazawa,A.,et al.: "Formation of abasic sites in DNA by t-butyl peroxyl radicals:implication for potent genotoxicity of lipid peroxyl radicals"Cancer Letters. 156. 51-55 (2000)
[Publications] Kanazawa,A.,et al.: "Generation of lipid peroxyl radicals from edible oils and their biological activities:a need for consideration for anti-radical components and purification processing"BioFactors. 13. 187-193 (2000)
[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)
[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)
[Publications] Kuwahara,H.,et al.: "Helicobacter pylori urease suppresses bactericidal activity of peroxynitrite via carbon dioxide production"Infect.Immun.. 68. 4378-4383 (2000)
[Publications] Miyamoto,Y.,et al: "S-nitrosylated human alphal-protease inhibitor"Biochim.biophys.Acta. 1477. 90-97 (2000)
[Publications] Miyamoto,Y.,et al.: "Novel functions of human alphal-protease inhibitor after S-nitrosylation:inhibition of cysteine protease and antibacterial activity"Biochem.Biophys.Res. Commun.. 267. 918-923 (2000)
[Publications] Maeda,H.,et al: "Tumor vascular permeability and the EPR effect in macromolecular therapeutics:a review"J.Control.Rel.. 65. 271-284 (2000)
[Publications] Maeda,H.,et al: "Mechanism of tumor-targeted delivery of macromolecular drugs,including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS"J.Control.Rel.. (in press). (2001)
[Publications] Maeda,H.: "The enhanced permeability and retention(EPR)effect in tumor vasculature::the key role of tumor-selective macromolecular drug targeting"Adv.Enzyme Regul.. (in press). (2001)
[Publications] Akaike,T.,and Maeda,H.: "Nitric Oxide:Biology and Pathobiology,L.J.Ignarro(Ed.)"Academic Press,San Diego. 12 (2000)

2000 Fiscal Year Annual Research Report

慢性感染に伴うフリーラジカル産生と発がん

Principal Investigator

前田 浩 熊本大学, 医学部, 教授 (90004613)

Research Products

[Publications] Akaike,T.,et al.: "Viral mutation accelarated by nitric oxide production during infection in vivo"FASEB J.. 14. 1447-1454 (2000)

[Publications] Sawa,T.,et al: "Tyrosine nitration by peroxynitrite formed from nitric oxide and superoxide generated by xanthine oxidase"J.Biol.Chem.. 275. 32467-32474 (2000)

[Publications] Akaike,T.,and Maeda,H.: "Nitric oxide and virus infection"Immunol.. 101. 300-308 (2000)

[Publications] Ikebe,N.,et al.: "Protective effect of S-nitrosylated alphal-protease inhibitor on hepatic ischemia-reperfusion injury"J.Pharmacol.Exp.Therap.. 295. 904-911 (2000)

[Publications] Akizuki,E.,et al.: "Role of nitric oxide and superoxide in acute cardiac allograft rejection in rats"Proc.Soc.Exp.Biol.Med.. 225. 151-159 (2000)

[Publications] Kanazawa,A.,et al.: "Formation of abasic sites in DNA by t-butyl peroxyl radicals:implication for potent genotoxicity of lipid peroxyl radicals"Cancer Letters. 156. 51-55 (2000)

[Publications] Kanazawa,A.,et al.: "Generation of lipid peroxyl radicals from edible oils and their biological activities:a need for consideration for anti-radical components and purification processing"BioFactors. 13. 187-193 (2000)

[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)

[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)

[Publications] Kuwahara,H.,et al.: "Helicobacter pylori urease suppresses bactericidal activity of peroxynitrite via carbon dioxide production"Infect.Immun.. 68. 4378-4383 (2000)

[Publications] Miyamoto,Y.,et al: "S-nitrosylated human alphal-protease inhibitor"Biochim.biophys.Acta. 1477. 90-97 (2000)

[Publications] Miyamoto,Y.,et al.: "Novel functions of human alphal-protease inhibitor after S-nitrosylation:inhibition of cysteine protease and antibacterial activity"Biochem.Biophys.Res. Commun.. 267. 918-923 (2000)

[Publications] Maeda,H.,et al: "Tumor vascular permeability and the EPR effect in macromolecular therapeutics:a review"J.Control.Rel.. 65. 271-284 (2000)

[Publications] Maeda,H.,et al: "Mechanism of tumor-targeted delivery of macromolecular drugs,including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS"J.Control.Rel.. (in press). (2001)

[Publications] Maeda,H.: "The enhanced permeability and retention(EPR)effect in tumor vasculature::the key role of tumor-selective macromolecular drug targeting"Adv.Enzyme Regul.. (in press). (2001)

[Publications] Akaike,T.,and Maeda,H.: "Nitric Oxide:Biology and Pathobiology,L.J.Ignarro(Ed.)"Academic Press,San Diego. 12 (2000)

前田浩熊本大学, 医学部, 教授 (90004613)