1997 Fiscal Year Annual Research Report

部位指向性酵素分子設計による抗ガン剤副作用軽減法の開発

Research Project

Project/Area Number	09255254
Research Institution	Osaka City University
Principal Investigator	井上正康大阪市立大学, 医学部, 教授 (80040278)
Co-Investigator(Kenkyū-buntansha)	佐藤英介大阪市立大学, 医学部, 助手 (60211942)
Keywords	活性酸素 / 一酸化窒素 / 制ガン剤 / 副作用 / SOD / 酸素毒性 / 腎障害 / シスプラチン
Research Abstract	各種抗ガン剤の副作用は活性酸素毒性が主体であり、これが薬剤使用量の制限因子となっている。抗ガン剤に起因する活性酸素障害はスーパーオキシドの発生亢進を介して病態を増悪させるので、局所効果を増強すると同時に、腫瘍外組織の活性酸素病態を阻止軽減することが重要である。本研究は、特定の組織細胞局所で活性酸素を選択的に消去する部位指向性SOD誘導体を開発すると同時に、スーパーオキシドと反応するNOの抗腫瘍作用を増強する新たな癌化学療法を確立することを目的として行われた。解析の結果、腎近位尿細管上皮細胞SOD誘導体群を開発し、各組識細胞局所のスーパーオキシドを選択的に不均化することにより、シスプラチンの腎毒性が著明に軽減できることが判明した。また、スーパーオキシドにより不活化される一酸化窒素(NO)の活量を増加させることが、その生物作用増強に重要であることが判明した。さらに、NOはミトコンドリア電子伝達系のcytochrome C oxidaseを可逆的に阻害し、癌細胞のアポトーシスを誘起する事および、癌細胞周辺の酸素分圧が低いほど抗腫瘍作用が増強することが判明した。ヘモグロビンや赤血球が本阻害反応を瞬時に解除することから、血管新生がNOの抗腫瘍作用を激減させる事が判明した。腫瘍の新生血管は栄養供給を介して癌細胞増殖を促進するが、これにはNOの抗腫瘍作用減弱効果も関与することが判明した。これらの所見から、腫瘍局所の酸素分圧、NO産生、およびスーパーオキシド産生を有効に制御することが癌化学療法に重要であることが判明した。

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] Minamiyama,Y.;Takemura,S.;Kawada,N.;Inoue,M.: "Role of nitric oxide in extracellular nucleotide-induced contractile status of assorted vessels including parts of portal vasculature" J.Hepatology. 28:314-319. 314-319 (1998)
[Publications] Nishikawa,M.;Sato,EF.;Kuroki,T.;Utsumi,K.Inoue,M.: "Role of glutathione in energy metabolism of tumor cells" Hepatology. (in press). (1998)
[Publications] Nakanishi,K.;Nishi,Y.;Sato,EF;Ishii,M.;Hamada,T.;Inoue,M.: "Termal injury induces thymoyte apoptosis in the rat" J.Trauma. (in press). (1998)
[Publications] Nakahara,H.;Sato,EF.;Ishihara,R.;Yabuki,M.;Inoue,M.;Utsumi,K.: "Biochemical properties of human neutrophils" Free Radic.Res.(in press). (1998)
[Publications] Nishikawa,M.;Takeda,K.;Sato,EF.;Kuroki.T.;Inoue,M.: "Nitric oxide regulates energy metabolism and bcl-2 expression in rat intestional epithelial cells" Am.J.Physiol.(in press). (1998)
[Publications] Morishita,S.;Sato,EF,;Takahashi,YP.;Manabe,M.;Inoue,M.: "Hypoglycemia-induced apoptosis in rat thymocytes in vivo" Dyabetes Res.Clin.Prac.(in press). (1998)
[Publications] Nagata,K.;Yu,H.;Sato,EF.;Kasahiba,M.;Tamura,T.;Inoue,M.: "Irreversible inhibition of respiration of Helicobacter pylori by nitric oxide" J.Biol.Chem.(in press). (1998)
[Publications] Kawada,N.;Seki,S.;Inoue,M.;Kuroki,T.: "Effect of Antioxidants,resveratol,quercetin and N-acetyl cysteine on the function of hepatic stellate cells and Kupffer cells" Hepatology. (in press). (1998)
[Publications] Dunlap,WC.;Yamamoto,Y.;Inoue,M.;Kashiba,M.;Yamaguchi,M.;Tomita,K.: "Uric acid photo-oxidation assay:in vitro comparison of sunscreening agents" Int.I.Cosmetic Sci.20:1-8. 1-8 (1998)
[Publications] I.Shiraishi.;E.F.Sato.;M.Nishikawa.;F.Sendo.;M.Inoue: "Mechanism of hypotensive shock induced by anti-neutrophil monoclonal antibody" Pathopysiology. 4:197-204. 197-204 (1997)
[Publications] H.Yu.;E.F.Sato.;T.Arakawa.;K.Kobayashi,.;M.Inoue: "Protective action of lipopolysaccharide against stress-induced gastric mucosal injury" Digestion. 58:311-318. 311-318 (1997)
[Publications] Hirai,A.;Minamiyam,Y.;Hamada,T.;Ishii,M.;Inoue,M.: "Dynamic aspects of glutathione metabolism in mice with hapten-induced allergic and irritant contact" J.Invest.Dermatol.109:314-318. 314-318 (1997)
[Publications] Minamiyam,Y.;Takemura,S.;Inoue,M.: "Effect of thiol status on nitric oxide metabolism in the circulation" Arch.Biochem.Biophys.341:186-192. 186-192 (1997)
[Publications] Yabuki,M.;Inai,Y.;Yoshioka,T.;Hamazaki,K.;Yasuda,T.;Inoue,M.;Utsumi.K.: "Oxygen-dependent fragmentation of cellular DNA by nitric oxide" Free Rad.Res.26:245-255. 245-255 (1997)
[Publications] Uno,H.;Arakawa,T.;Fukuda,T.;Yu,H.;Fujiwara,Y.;Higuchi,K.;Inoue,M.;Kobayashi,K.: "Nitric oxide stimulates prostaglandin synthesis in cultured rabbit gastric cells" Prostaglandins. 53:153-162. 153-162 (1997)
[Publications] Yu.H.;Sato.EF.;Nagata,K.;Nishikawa,M.;Kashiba,M.;Arakawa,T.;Kobayashi,K.;Inoue.M.: "Oxygen-dependent regulation of the respiration and growth of Escherichia coli by nitric oxide" FEBS Letters. 409:161-165. 161-165 (1997)
[Publications] Yamamasu,S.;Sato,EF.;Ogita,S.;Inoue.M.: "Role of glutathione metabolism and apoptosis in the regression of liver hemopoiesis" Free Radical Biol. & Med.23:100-109. 100-109 (1997)
[Publications] Kashiba,M.;Miyamoto,M.;Inoue,M.: "Effect of nitric oxide on the ligand binding activity of albumin" Arch. Biochem. Biophys.345:237-242. 237-242 (1997)
[Publications] Morishita,S.;Nishi,Y.;Sato,EF.;Yamaoka,K.;Manabe,M.;Inoue,M.: "Cold-stress induces thymocyte apoptosis in the rat" Pathophysiology. 4:213-219. 213-219 (1997)
[Publications] Hanada,H.;Kashiwagi,A.;Takehara,Y.;Kanno,T.;Yabuki,M.;Sasaki,J.;Inoue.M.;Utsumi.K.: "Do reactive oxygen species underlie the mechanism of apoptosis in the tadpole tail?" Free Radical Biol. & Med.23:294-301. 294-301 (1997)
[Publications] Nishikawa,M.;Sato,EF.;Kuroki,T.;Inoue,M.: "Role glutathione in the energy metabolism of mitochondria" FEBS Letters. 415:341-345. 341-345 (1997)
[Publications] Kashiba,M.;Kitoh,K.;Yu,H.;Kasahara,E.;Nishikawa,M.;Matsuo,M.;Inoue.M.: "Ascorbic Acid and reducing agents regulates the fates and functions of S-nitrospthiols" J. Biochem.122:1208-1214. 1208-1214 (1997)
[Publications] Minamiyama,Y.;Takemura,S.;Imaoka,S.;Funae,Y.;Tanimoto,Y.;Inoue,M.: "Irreversible inhibition of cytochrome P450 by nitric oxide" J. Phaemacol. Exp. Ther.283:1479-1485. 1479-1485 (1997)
[Publications] Yamada,T.;Yukioka,H.;Asada,A.;Inoue,M.: "Effect of inhaled nitric oxide on platelet-activating factor induced pulmonary hypertension in dogs" Acta Anesthesiol. Scand.41. (1997)
[Publications] Kashiba-Iwatsuki.M.,Kitoh.K.,Nishikawa.M.,Sato.EF.Inoue M.: "Oxygen Homeostasis and its dynamics" Springer-Verlag,Tokyo(Ishimura,Y.,Suematsu,M.,Shimada,H.), 7 (1998)
[Publications] Utsumi.K.,Takehara,Y.,Inai.Y,.Yabuki.M.,Kanno,T.,Nishikawa,M.,Sato,EF.,Inoue.M.: "Mitochondria,Oxidants,and Aging" Academic Press(L.Packer Cadenas)(in press), (1998)

1997 Fiscal Year Annual Research Report

部位指向性酵素分子設計による抗ガン剤副作用軽減法の開発

Principal Investigator

井上 正康 大阪市立大学, 医学部, 教授 (80040278)

Research Products

[Publications] Minamiyama,Y.;Takemura,S.;Kawada,N.;Inoue,M.: "Role of nitric oxide in extracellular nucleotide-induced contractile status of assorted vessels including parts of portal vasculature" J.Hepatology. 28:314-319. 314-319 (1998)

[Publications] Nishikawa,M.;Sato,EF.;Kuroki,T.;Utsumi,K.Inoue,M.: "Role of glutathione in energy metabolism of tumor cells" Hepatology. (in press). (1998)

[Publications] Nakanishi,K.;Nishi,Y.;Sato,EF;Ishii,M.;Hamada,T.;Inoue,M.: "Termal injury induces thymoyte apoptosis in the rat" J.Trauma. (in press). (1998)

[Publications] Nakahara,H.;Sato,EF.;Ishihara,R.;Yabuki,M.;Inoue,M.;Utsumi,K.: "Biochemical properties of human neutrophils" Free Radic.Res.(in press). (1998)

[Publications] Nishikawa,M.;Takeda,K.;Sato,EF.;Kuroki.T.;Inoue,M.: "Nitric oxide regulates energy metabolism and bcl-2 expression in rat intestional epithelial cells" Am.J.Physiol.(in press). (1998)

[Publications] Morishita,S.;Sato,EF,;Takahashi,YP.;Manabe,M.;Inoue,M.: "Hypoglycemia-induced apoptosis in rat thymocytes in vivo" Dyabetes Res.Clin.Prac.(in press). (1998)

[Publications] Nagata,K.;Yu,H.;Sato,EF.;Kasahiba,M.;Tamura,T.;Inoue,M.: "Irreversible inhibition of respiration of Helicobacter pylori by nitric oxide" J.Biol.Chem.(in press). (1998)

[Publications] Kawada,N.;Seki,S.;Inoue,M.;Kuroki,T.: "Effect of Antioxidants,resveratol,quercetin and N-acetyl cysteine on the function of hepatic stellate cells and Kupffer cells" Hepatology. (in press). (1998)

[Publications] Dunlap,WC.;Yamamoto,Y.;Inoue,M.;Kashiba,M.;Yamaguchi,M.;Tomita,K.: "Uric acid photo-oxidation assay:in vitro comparison of sunscreening agents" Int.I.Cosmetic Sci.20:1-8. 1-8 (1998)

[Publications] I.Shiraishi.;E.F.Sato.;M.Nishikawa.;F.Sendo.;M.Inoue: "Mechanism of hypotensive shock induced by anti-neutrophil monoclonal antibody" Pathopysiology. 4:197-204. 197-204 (1997)

[Publications] H.Yu.;E.F.Sato.;T.Arakawa.;K.Kobayashi,.;M.Inoue: "Protective action of lipopolysaccharide against stress-induced gastric mucosal injury" Digestion. 58:311-318. 311-318 (1997)

[Publications] Hirai,A.;Minamiyam,Y.;Hamada,T.;Ishii,M.;Inoue,M.: "Dynamic aspects of glutathione metabolism in mice with hapten-induced allergic and irritant contact" J.Invest.Dermatol.109:314-318. 314-318 (1997)

[Publications] Minamiyam,Y.;Takemura,S.;Inoue,M.: "Effect of thiol status on nitric oxide metabolism in the circulation" Arch.Biochem.Biophys.341:186-192. 186-192 (1997)

[Publications] Yabuki,M.;Inai,Y.;Yoshioka,T.;Hamazaki,K.;Yasuda,T.;Inoue,M.;Utsumi.K.: "Oxygen-dependent fragmentation of cellular DNA by nitric oxide" Free Rad.Res.26:245-255. 245-255 (1997)

[Publications] Uno,H.;Arakawa,T.;Fukuda,T.;Yu,H.;Fujiwara,Y.;Higuchi,K.;Inoue,M.;Kobayashi,K.: "Nitric oxide stimulates prostaglandin synthesis in cultured rabbit gastric cells" Prostaglandins. 53:153-162. 153-162 (1997)

[Publications] Yu.H.;Sato.EF.;Nagata,K.;Nishikawa,M.;Kashiba,M.;Arakawa,T.;Kobayashi,K.;Inoue.M.: "Oxygen-dependent regulation of the respiration and growth of Escherichia coli by nitric oxide" FEBS Letters. 409:161-165. 161-165 (1997)

[Publications] Yamamasu,S.;Sato,EF.;Ogita,S.;Inoue.M.: "Role of glutathione metabolism and apoptosis in the regression of liver hemopoiesis" Free Radical Biol. & Med.23:100-109. 100-109 (1997)

[Publications] Kashiba,M.;Miyamoto,M.;Inoue,M.: "Effect of nitric oxide on the ligand binding activity of albumin" Arch. Biochem. Biophys.345:237-242. 237-242 (1997)

[Publications] Morishita,S.;Nishi,Y.;Sato,EF.;Yamaoka,K.;Manabe,M.;Inoue,M.: "Cold-stress induces thymocyte apoptosis in the rat" Pathophysiology. 4:213-219. 213-219 (1997)

[Publications] Hanada,H.;Kashiwagi,A.;Takehara,Y.;Kanno,T.;Yabuki,M.;Sasaki,J.;Inoue.M.;Utsumi.K.: "Do reactive oxygen species underlie the mechanism of apoptosis in the tadpole tail?" Free Radical Biol. & Med.23:294-301. 294-301 (1997)

[Publications] Nishikawa,M.;Sato,EF.;Kuroki,T.;Inoue,M.: "Role glutathione in the energy metabolism of mitochondria" FEBS Letters. 415:341-345. 341-345 (1997)

[Publications] Kashiba,M.;Kitoh,K.;Yu,H.;Kasahara,E.;Nishikawa,M.;Matsuo,M.;Inoue.M.: "Ascorbic Acid and reducing agents regulates the fates and functions of S-nitrospthiols" J. Biochem.122:1208-1214. 1208-1214 (1997)

[Publications] Minamiyama,Y.;Takemura,S.;Imaoka,S.;Funae,Y.;Tanimoto,Y.;Inoue,M.: "Irreversible inhibition of cytochrome P450 by nitric oxide" J. Phaemacol. Exp. Ther.283:1479-1485. 1479-1485 (1997)

[Publications] Yamada,T.;Yukioka,H.;Asada,A.;Inoue,M.: "Effect of inhaled nitric oxide on platelet-activating factor induced pulmonary hypertension in dogs" Acta Anesthesiol. Scand.41. (1997)

[Publications] Kashiba-Iwatsuki.M.,Kitoh.K.,Nishikawa.M.,Sato.EF.Inoue M.: "Oxygen Homeostasis and its dynamics" Springer-Verlag,Tokyo(Ishimura,Y.,Suematsu,M.,Shimada,H.), 7 (1998)

[Publications] Utsumi.K.,Takehara,Y.,Inai.Y,.Yabuki.M.,Kanno,T.,Nishikawa,M.,Sato,EF.,Inoue.M.: "Mitochondria,Oxidants,and Aging" Academic Press(L.Packer Cadenas)(in press), (1998)

井上正康大阪市立大学, 医学部, 教授 (80040278)