2001 Fiscal Year Annual Research Report

部位指向性代謝制御剤設計による抗がん剤副作用軽減法開発

Research Project

Project/Area Number	13218114
Research Institution	Osaka City University
Principal Investigator	井上正康大阪市立大学, 大学院・医学研究科, 教授 (80040278)
Co-Investigator(Kenkyū-buntansha)	佐藤英介大阪市立大学, 大学院・医学研究科, 助手 (60211942)
Keywords	シスプラチン / 活性酸素 / カルニチン / スーパーオキシドディスムターゼ / 腎臓
Research Abstract	発癌の重要因子である活性酸素は、癌治療における主要な作用因子でもあり、シスプラチン腎症を初めとする各種の副作用も活性酸素毒性によるものが多い。癌化学療法の限界と患者のQOL低下を克服するには、化学療法により誘起される正常組織での酸化傷害を部位特異的に阻止軽減することが不可欠である。本研究は、腎と消化器で活性酸素毒性を選択的に阻止軽減する薬剤を開発し、癌化学療法のアキレス腱である副作用を除去する新治療法の確立を目的とする。長時間循環型SOD、内皮指向性SOD、あるいは糸球体で積極的に濾過されて近位尿細管刷子縁膜のプロテオグリカンに結合し、速やかに尿細管細胞内に取り込まれる腎指向性SOD(AH-SOD)などを開発し、本年度は、以下のことを明らかにした。(1)シスプラチンが腎や消化管組織のミトコンドリアゲノム(mtDNA)を速やかかつ選択的に酸化障害し、内膜機能の崩壊とアポトーシスを誘起することを明らかにした。(2)腎指向性AH-SODが近位尿細管細胞のmtDNAを特異的に保護し、シスプラチン腎症を阻止軽減すること、及びこれによりシスプラチンで治療した担癌動物の約50%の生存率が著明に延長することが判明した。(3)シスプラチンの毒性発現にはプラチナ部位の還元再生反応が不可欠であり、両組織にこの様な代謝特性が局在する必要がある。本年度の研究により、両組織でのGSHレドックスサイクル系の存在とその代謝特性を明らかにした。さらに、本レドックス系がシスプラチンの連続的再活性化に関与していることが示唆された。(4)シスプラチンの再活性化によりPhospholipase A2依存性のミトコンドリア障害が誘起されること、及び本障害がβ-酸化を促進するカルニチンで阻止されることが判明した。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] M.Kashiba, J.Oka, R.Ichikawa, A.Kageyama, T.Inayama, H.Kageyama, T.Ishikawa, M.Nishikimi, M.Inoue, S.Inoue: "Impaired reductive regeneration of ascorbic acid in the Goto-Kakizaki diabetic rat"Biochem.J.. 351. 313-318 (2001)
[Publications] M.Tomita, E.Sato, M.Nishikawa, Y.Yamano, M.Inoue: "Nitric oxide regulates mitochondrial respiration and functions of articular chondrocytes"Arthritis & Rheumatism. 44. 96-104 (2001)
[Publications] M.Tsuchiya, A.Asada, K.Maeda, Y.Ueda, E.Sato, M.Shindo, M.Inoue: "Propofol versus midazolam regarding their antioxidant a ctivities"Am J Respir Crit Care Med. 163. 1-6 (2001)
[Publications] M.Nishikawa, H.Nagatomi, Bao-Jun Cang, E.Sato, M.Inoue: "Targeting Superoxide Dismutase to Renal Proximal Tubule Cells Inhibits Mitochondrial Injury and Renal Dysfunction induced by Cisplatin"Archives of Biochemistry and Biophysics. 387・1. 78-84 (2001)
[Publications] M.Nishikawa, S.Nishiguchi, S.Shiomi, A.Tamori, N.Kon, T.Takeda, S.Kubo, K.Hirohashi, E.Sato, M.Inoue: "Somatic Mutation of Mitochondrial DNA in Canncerous and Nomcancerous Liver Tissue in Individuals with Hepatocellar Carcinoma"CANCER RESEARCH. 61. 1843-1845 (2001)
[Publications] M.Inoue, E.Sato, A.Park, N.Nahikawa, E.Kasahara, M.Miyoshi, A.Ochi, K.Utumi: "Cross-Talk Between NO and Oxyradicals,a Supesystem that Regulates Enegy Metabolism and Survival of Animals"Free Rad.Res. 33. 757-770 (2001)
[Publications] A.Nishikimi, Y.Kira, E.Kasahawa, E.Sato, T.Kanno, K.Utumi, M.Inoue: "Tributyltin interacts With mitochondria and induces cytochrome c release"Biochem J. 356. 621-626 (2001)
[Publications] K.Katsuragi, S.Takemura, Y.Minamiyama, H.Tanaka, M.Inoue, H.Kinoshita: "Combined use of adenosine and amrinoe inhibits reperfusion injury of ratliver"Pathophysiology. 8. 29-34 (2001)
[Publications] T.Furuno, T.Kanno, K.Arita, M.Asami, T.Utaumi, Y.Doi, M.Inoue, K.Utsumi: "Roles of long chain fatty acidis and carnitine in mitochondrial membrane permeability transition"Biochem Pharmacol. 62. 1037-1046 (2001)
[Publications] H.Ohnaka, K.Ukita, S.Yamamasu, M.Inue, M.Imanaka, O.Ishiko, S.Ogita: "Effects of Cocaine and Ethanol on Mouse Fetuses"Osaka City Med.J.. 47. 83-93 (2001)
[Publications] Y.Wang, M.Kashida, E.Kasahara, M.Tsuchiya, EF.Sato, K.Urumi, M.Inoue: "Metabolic cooperation of Ascorbic Acid and Glutathione in Normal and Vitamin C-deficient ODS Rats"Physiol.Chem.Phys.& Med.NMR. 33. 29-39 (2001)
[Publications] Y.Minamiyama, S.Imaoka, S.Takemura, S.Okada, M.Inoue, Y.Funae: "Escape from tolerance of organic nitrate by induction of cytochrome P450"Free Radical Biology & Medicine. 31. 1498-1508 (2001)
[Publications] M.Inoue: "Protective Mechanisms Against Reactive Oxygen Species"The Liver:Biology and Pathobiology. 281-290 (2001)
[Publications] M.Nishikawa, H.Nagatomi, B.J.Chang, E.Sato, M.Inoue: "Targeting Superoxide Dismutase to Renal Proximal Tubule Cells Inhibits Mitochondrial Injury and Renal Dysfunction Induced by Cisplatin"Archives of Biochemistry and Biophysics. 387. 78-84 (2001)
[Publications] M.Tuchiya, A.Asada, E.Kasahara, E.Sato, M.Shindo, M.Inoue: "Antioxidant Protection of Propofol and Its Recycling in Erythrocyte Membranes"Am J Respir Crit Care Med. 165. 54-60 (2002)
[Publications] I.Imada, EF.Sato, Y.Ichimori, Y.Aramaki, M.Inoue: "L-012:An Ultrasensitive Reagent for Detecting Cellular Generation of Reactive Oxygen Species"CRC Press LLC. 279-286 (2002)

2001 Fiscal Year Annual Research Report

部位指向性代謝制御剤設計による抗がん剤副作用軽減法開発

Principal Investigator

井上 正康 大阪市立大学, 大学院・医学研究科, 教授 (80040278)

Research Products

[Publications] M.Kashiba, J.Oka, R.Ichikawa, A.Kageyama, T.Inayama, H.Kageyama, T.Ishikawa, M.Nishikimi, M.Inoue, S.Inoue: "Impaired reductive regeneration of ascorbic acid in the Goto-Kakizaki diabetic rat"Biochem.J.. 351. 313-318 (2001)

[Publications] M.Tomita, E.Sato, M.Nishikawa, Y.Yamano, M.Inoue: "Nitric oxide regulates mitochondrial respiration and functions of articular chondrocytes"Arthritis & Rheumatism. 44. 96-104 (2001)

[Publications] M.Tsuchiya, A.Asada, K.Maeda, Y.Ueda, E.Sato, M.Shindo, M.Inoue: "Propofol versus midazolam regarding their antioxidant a ctivities"Am J Respir Crit Care Med. 163. 1-6 (2001)

[Publications] M.Nishikawa, H.Nagatomi, Bao-Jun Cang, E.Sato, M.Inoue: "Targeting Superoxide Dismutase to Renal Proximal Tubule Cells Inhibits Mitochondrial Injury and Renal Dysfunction induced by Cisplatin"Archives of Biochemistry and Biophysics. 387・1. 78-84 (2001)

[Publications] M.Nishikawa, S.Nishiguchi, S.Shiomi, A.Tamori, N.Kon, T.Takeda, S.Kubo, K.Hirohashi, E.Sato, M.Inoue: "Somatic Mutation of Mitochondrial DNA in Canncerous and Nomcancerous Liver Tissue in Individuals with Hepatocellar Carcinoma"CANCER RESEARCH. 61. 1843-1845 (2001)

[Publications] M.Inoue, E.Sato, A.Park, N.Nahikawa, E.Kasahara, M.Miyoshi, A.Ochi, K.Utumi: "Cross-Talk Between NO and Oxyradicals,a Supesystem that Regulates Enegy Metabolism and Survival of Animals"Free Rad.Res. 33. 757-770 (2001)

[Publications] A.Nishikimi, Y.Kira, E.Kasahawa, E.Sato, T.Kanno, K.Utumi, M.Inoue: "Tributyltin interacts With mitochondria and induces cytochrome c release"Biochem J. 356. 621-626 (2001)

[Publications] K.Katsuragi, S.Takemura, Y.Minamiyama, H.Tanaka, M.Inoue, H.Kinoshita: "Combined use of adenosine and amrinoe inhibits reperfusion injury of ratliver"Pathophysiology. 8. 29-34 (2001)

[Publications] T.Furuno, T.Kanno, K.Arita, M.Asami, T.Utaumi, Y.Doi, M.Inoue, K.Utsumi: "Roles of long chain fatty acidis and carnitine in mitochondrial membrane permeability transition"Biochem Pharmacol. 62. 1037-1046 (2001)

[Publications] H.Ohnaka, K.Ukita, S.Yamamasu, M.Inue, M.Imanaka, O.Ishiko, S.Ogita: "Effects of Cocaine and Ethanol on Mouse Fetuses"Osaka City Med.J.. 47. 83-93 (2001)

[Publications] Y.Wang, M.Kashida, E.Kasahara, M.Tsuchiya, EF.Sato, K.Urumi, M.Inoue: "Metabolic cooperation of Ascorbic Acid and Glutathione in Normal and Vitamin C-deficient ODS Rats"Physiol.Chem.Phys.& Med.NMR. 33. 29-39 (2001)

[Publications] Y.Minamiyama, S.Imaoka, S.Takemura, S.Okada, M.Inoue, Y.Funae: "Escape from tolerance of organic nitrate by induction of cytochrome P450"Free Radical Biology & Medicine. 31. 1498-1508 (2001)

[Publications] M.Inoue: "Protective Mechanisms Against Reactive Oxygen Species"The Liver:Biology and Pathobiology. 281-290 (2001)

[Publications] M.Nishikawa, H.Nagatomi, B.J.Chang, E.Sato, M.Inoue: "Targeting Superoxide Dismutase to Renal Proximal Tubule Cells Inhibits Mitochondrial Injury and Renal Dysfunction Induced by Cisplatin"Archives of Biochemistry and Biophysics. 387. 78-84 (2001)

[Publications] M.Tuchiya, A.Asada, E.Kasahara, E.Sato, M.Shindo, M.Inoue: "Antioxidant Protection of Propofol and Its Recycling in Erythrocyte Membranes"Am J Respir Crit Care Med. 165. 54-60 (2002)

[Publications] I.Imada, EF.Sato, Y.Ichimori, Y.Aramaki, M.Inoue: "L-012:An Ultrasensitive Reagent for Detecting Cellular Generation of Reactive Oxygen Species"CRC Press LLC. 279-286 (2002)

井上正康大阪市立大学, 大学院・医学研究科, 教授 (80040278)