免疫賦活を目的としたα-N-アセチルガラクトサミニダーゼ阻害剤の制がん剤分子設計

• 研究課題/領域番号: 10672090
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 医薬分子機能学
• 研究機関: 徳島大学
• 研究代表者: 堀 均 徳島大学, 工学部, 教授 (90119008)
• 研究分担者: 紺世 秀子 (永沢 秀子) 徳島大学, 工学部, 講師 (90207994)
• 研究期間 (年度): 1998 – 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 3,300千円 (直接経費: 3,300千円); 1999年度: 900千円 (直接経費: 900千円); 1998年度: 2,400千円 (直接経費: 2,400千円)
• キーワード: -N-アセチルガラクトサミニダーゼ / 酵素阻害剤 / 免疫賦活剤 / 分子設計 / 制がん剤 / α-N-アセチルガラクトサミニダーゼ / 阻害活性 / 制がん剤分子設計 / がん細胞

研究概要

がん患者の免疫抑制の機構として,血中に増加するα-N-アセチルガラクトサミニダーゼ(α-NaGalase)によってマクロファージ活性化因子(GcMAF)前駆体が分解することが提唱されている.(Yamamoto,N.et al.,1998)このような機構を検証するため,種々のがん細胞におけるα-NaGalase酵素活性について解析を行った.さらにがん患者の免疫賦活を目的として,α-NaGalase阻害剤設計を検討した.
1)がん細胞としてHCT116,HepG2細胞と正常細胞としてChung Liver細胞及びラットhepatocytesを用いて,α-NaGalase活性を測定したところ,がん細胞において活性が有意に上昇していた.この際,がん細胞中のα-NaGalaseが,endo型であるか,exo型であるかについてそれぞれのPNP基質を用いて調べたところ,endo型活性は認められなかった.がん患者血清中のα-NaGalaseに関しても同様に検討したところ,endo活性は認められなかった.これより,GcMAF前駆体であるGcProteinのα-NaGalaseによる糖鎖分解の機構(endo型切断)について再検討を要することがあきらかになった.一方,血清より精製したGcProteinからin situで得られたGcMAFによるマクロファージの0^-_2産生能の上昇が認められた.
2)mannosidaze阻害剤でアザ糖であろスワンソニンに免疫賦活作用があることから,これをリード化合物として,その水酸基の2面角をコントロールして阻害するグリコシダーゼの種類を制御することを目的にsp2炭素の導入に基づく分子設計を行い,合成ルートの確立を検討した.その結果エナミン誘導体の合成に成功した.これらについてα-NaGalaseを含む各種グリコシダーゼ阻害活性について現在検討中である.

研究成果

• [文献書誌] Zhu,J-W,H Nagasawa,H Hori et al.: "Elucidation of Strict Structural Requirements of Brefeldin A as an lnducer of Differentiation and Apoptosis"Bioorg.Med.Chem.. 8. 455-463 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Nagasawa,H.,H.Hori et al.: "Apoptosis induction in HCT116 cells by cytochalasins isolated from the fungus Daldinia vernicosa"Phytomedicine. 6. 403-409 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] A-Z,Medhat,H Hori et al.: "Studies of methy 2-nitroimidazole-1-acetohydroxamate (KIN-804)1.Effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 190-194 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] A-Z,Medhat,H Hori et al.: "Studies of methy 2-nitroimidazole-1-acetohydroxamate (KIN-804)2.Effect on certain antioxidant enzyme system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 195-198 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Inomata,T,H Nagasawa,H Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804 and KIN-844"Oncology Reports. 6(6). 1209-1212 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Masunaga,S,K Ono,H Hori et al.: "Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermina:reference to effect on quiescent tumor cells"Int.J.Hyperthermia. 15(1). 7-16 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] T.Inomata,S.Yoshida,H.Nagasawa,H.Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in conmparison with its Analogs KIN-804A@and KIN-844"Oncology Reports. 6. 1209-1212 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] I.Shimizu,Y.Mizobuchi,F.liu,T.Miura,H.Hori et al.: "Effects of sho-saiko-to, a japanese herbal medicine,on hepatic fibrosis in rats"Hepatology. 29. 49-60 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] H.Hori,M.Ishibashi,H.Nagasawa,Y.Uto,et al.: "Enhancement effect of methyl a-D-glucoside for inhibitory effects of antioxidants on ADP/Fe2+-induced lipid perox idation in rat liver mitochondria"Adv.Mxp.Med.Biol.(Oxygen Transport Tissue XXI). XXI. 395-402 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] T.Inomata,S.Kariya,H.Nagasawa,H.Hori,et al.: "The Effects of the Lung Metastasis Suppressioh of the Bifunctional New Radiosensitizer KIN-806"Int.J.Mol.Med.. 4. 257-260 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.Masunaga,H.Hori,H.Nagasawa,Y.Uto et al.: "Potentially lethal damage repair by total and quiscent tumor cells following various DNA-damaging treatments"Radiation Medicine. 17. 259-264 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] K Ohkura,H Hori: "Analysis of structure-permeability of correlation of nitrophenol analogues in newborn rat abdominal skin using semiempirical moleular orbital calculation"Bioorg.Med.Chem.. 7. 309-314 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kasai,S.,Nagasawa,H.,H.Hori et al.: "TX-1877:Design,Synthesis,and Biological Aeitivities as a BRM-functional Hypoxic Cell Radiosensitizer"Int.J.Radiation Oncology Biol.Phys. 42(4). 799-802 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Masunage,S,K Oho,H Hori et al.: "Enhancement of cisplatin sensitivity of quiescent cells in solid tumors by combined treantment with tirapazamine and low-temperature hyperthermia"Radiation Medicine. 16(6). 441-448 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Masunaga,S,K Ono,Y Sakurai,H Hori et al.: "Applicability of Combination with Tirapazamine in Boron Meutron Capture Therapy"Jpn.J.Cancer Res.89(7):768-774(1998). 87(7). 768-774 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Goto,S,K-X Chen,S Oda,H Hori,and H Terada: "Dynamic Structural Features of Macrocyclic Cytochalasin Analogues Responsible for Their Hexose Transport Inhibiton"J.Am.Chem.Soc.. 120. 2457-2463 (1998)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Zhu, J-W, H Nagasawa, and H Hori et al.: "Elucidation of Strict Structural Requirements of Brefeldin A as an Inducer of Differentiation and Apoptosis."Bioorg Med. Chem.. 8. 455-463 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Nagasawa. H., H. Hori et al.: "Apoptosis induction in HCT116 cells by cytochalasins isolated from the fungus Daldinia vernicosa."Phytomedicine. 6(6). 403-409 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] A-Z, Medhat, H Hori, H Nagasawa et al.: "Studies of methyl 2-nitroimidazole- 1- acetohydroxamate (KIN-804) 1. Effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma."Biol. Pharm. Bull.. 23(2). 190-194 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] A-Z, Medhat, H Hori, H Nagasawa et al.: "Studies of methyl 2-nitroimidazole- 1- acetohydroxamate (KIN-804) 2. Effect on certain antioxidant enzyme system in mice bearing Ehrlich ascites carcinoma."Biol. Pharm. Bull.. 23(2). 195-198 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Ohkura, K and H Hori: "Analysis of structure-permeability of correlation of nitrophenol analogues in newborn rat abdominal skin using semiempirical molecular orbital calculation."Bioorg. Med. Chem.. 7. 309-314 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shimizu, I, Y.-R. Ma, Y Mizobuchi, F Liu, T Miura, Y Nakai, M Yasuda, M Shiba, T Horie, S Amagaya, N Kawada, H Hori, and S Ito: "Effects of sho-saiko-to, a japanese herbal medicine, on hepatic fibrosis in rats."Hepatology. 29(1). 49-60 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Hori, H., M. Ishibashi, S. B. Mohamad, H. Nagasawa, Y. Uto, H. Sakamaki, N. Pan, K. Ohkura, and S. Nishibe: "Enhancement effect of methyl α-D-glucoside for inhibitory effects of antioxidants on ADP/FeィイD12+ィエD1-induced lipid peroxidation in rat liver mitochondria."Adv. Exp. Med. Bio. (Oxygen Transport to Tissue XXI). 395-402 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Inomata, H Nagasawa, H Hori et al.: "The Effects of the Lung Metastasis Suppression of the Bifunctional New Radiosensitizer KIN-806."Int. J. Mol. Med. 4(3). 257-260 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Inomata, T, H Nagasawa, H Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804 and KIN-844."Oncology Reports. 6(6). 1209-1212 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Masunaga, S, K Ono, H Hori et al.: "Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermina : reference to effect on quiescent tumor cells."Int. J. Hyperthermia. 15(1). 7-16 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Masunaga, S, K Ono, H Hori et al.: "Potentially lethal damage repair by total and quiscent tumor cells following various DNA-damaging treatments."Radiation Medicine. 17(4). 259-264 (1999)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Kasai, S., H. Nagasawa, H. Hori et al.: "TX-1877 : Design, Synthesis, and Biological Activities as a BRM-functional Hypoxic Cell Radiosensitizer."Int. J. Badiation Oncology Biol. Phys. 42(4). 799-802 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Masunaga, S, K Ono, H Hori et al.: "Enhancement of cisplatin sensitivity of quiescent cells in solid tumors by combined treatment with tirapazamine and low-temperature hyperthermia."Badiation Medicine. 16(6). 441-448 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Masunaga, S, K Ono, Y Sakurai, H Hori et al.: "Applicability of Combination with Tirapazamine in Boron Neutron Capture Therapy."Jpn. J. Pancer Res.. 89(7). 768-774 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Goto, S, K.-X Chen, S Oda, H Hori, and H Terada: "Dynamic Structural Features of Macro-cyclic Cytochalasin Analogues Responsible for Their Hexose Taansport Inhibition."J. Am. Chem. Soc.. 120. 2457-2463 (1998)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Zhu,J-W,H Nagasawa,H Hori et al.: "Elucidation of Strict Structural Requirements of Brefeldin A as an Inducer of Differentination and Apoptosis."Bioorg.Med.Chem.. 8. 455-463 (2000)
• [文献書誌] Nagasawa,H.,H.Hori et al.: "Apoptosis induction in HCT116 cells by cytochalasins isolated from the fungus Daldinia vernicosa."Phytomedicine. 6. 403-409 (2000)
• [文献書誌] A-Z,Medhat,H Hori et.al.: "Studies of methyl2-nitroimidazole-1-acetohydroxamate(KIN-804)1.Effect on free radical scavenging system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 190-194 (2000)
• [文献書誌] A-Z,Medhat,H Hori et.al.: "Studies of methyl2-nitroimidazole-2-acetohydroxamate(KIN-804)1.Effect on certain antioxidant enzyme system in mice bearing Ehrlich ascites carcinoma"Biol.Pharm.Bull.. 23(2). 195-198 (2000)
• [文献書誌] Inomata,T,H Nagasawa,H Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804 and KIN-844."Oncology Reports. 6(6). 1209-1212 (1999)
• [文献書誌] Masunaga,S,K Ono,H Hori et al.: "Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermina:reference to effect on quiescent tumor cells."Int.J.Hyperthermia.. 15(1). 7-16 (1999)
• [文献書誌] T.Inomata,S.Yoshida,H,Nagasawa,H.Hori et al.: "The immunopotentiation Effects of the Bifunctional Radiosensitizer KIN-806 in comparison with its Analogs KIN-804Å@ and KIN-844."Oncology Reports. 6. 1209-1212 (1999)
• [文献書誌] I.Shimizu,Y.Mizobuchi,F.Liu,T.Miura,H.Hori et al.: "Effects of sho-saiko-to,a japanese herbal medicine,on hepatic fibrosis in rats"Hepatalogy. 29. 49-60 (1999)
• [文献書誌] H.Hori,M.Ishibashi,H.Nagasawa,Y.Uto,et al.: "Enhancement effect of methyl a-D-glucoside for inhibitory effects of antioxidants on ADP/Fe2+-induced lipid perox idation in rat liver mitochondria"Adv.Exp.Med.Biol.(Oxygen Transport to Tissue XXI). XXI. 395-402 (1999)
• [文献書誌] T.Inomata,S.Kariya,H.Nagasawa,H.Hori,et al.: "The Effects of the Lung Metastasis Suppression of the Bifunctional New Radiosensitizer KIN-806"Int.J.Mol.Med.. 4. 257-260 (1999)
• [文献書誌] S.Masunaga,H.Hori,H.Nagasawa,Y.Uto et al.: "Potentially lethal damage repair by total and quiscent tumor cells following various DNA-damaging treatments"Radiation Medicine. 17. 259-264 (1999)
• [文献書誌] K.Ohkura,H.Hori: "Analysis of structure-permeability of correlation of nitrophenol analogues in newborn at abdominal skin using semiempirical molecular orbital calculation"Bioorg.Med.Chem.. 7. 309-314 (1999)
• [文献書誌] Goto,S.,Chen,K.X.,Oda,S.,Hori,H.et al.: "Dynamic structural features of macrocyclic cytochalasin analogues responsible for their hexose transport inhibition." J.Am.Chem.Soc.120. 2457-2463 (1998)
• [文献書誌] Kasai,S.,Nagasawa,H.,& Hori,H.et al.: "TX-1877:design,synthesis,and biological actibities as a BRM-functional hypozic cell radiosensitizer." Int.J.Radiation Oncology Biol.Phys.42(4). 799-802 (1998)
• [文献書誌] Masunaga,S-1,Ono,K.,Hon,H.et al.: "Wnhancement ofcisplatin sensitibity of quiescent cells in solid tumors by combined treatment with tirapazamine and low-temperature hyperthermia." Radiation Medicine. 16(6). 441-448 (1998)
• [文献書誌] Masunaga,S.i-.,Ono,K.,Sakurai,Y.,Hori,H.,et al.: "Applicability of Combination with Tirapazamine in Boron Neutron Capture Therapy." Jpn.J.Cancer Res.89(7). 768-774 (1998)
• [文献書誌] MIsobuchi,Y.,Shimizu,I.,Yasuda,M.,Hori,et al.: "Retinyl palmitate reduces hepatic fibrosis in rats induced by dimethylnitrosamine or pig serum." J.Hepatology. 29(6). 933-943 (1998)
• [文献書誌] Masunaga,S.-I.,Ono,K.,Hori,H.et al.: "Modification of tirapazamine-induced cytotoxicity in combination with mild hyperthermina:reference to effect on quiescent tumor cells." Int.J.Hyoertheermia. 15(1). 7-16 (1999)
• [文献書誌] Shimizu,I.,Ma,Y.R.,Mizobuchi,Y.Hori,H.,et al.: "Effects of sho-saiko-to,a jaoanese herbal medicine,on hepatic fibrosis in rats." Hepatology. 29(1). 49-60 (1999)
• [文献書誌] Ohkura,K.,& Hori,H.: "Analysis of structure-oermeability of correlation of nitrophenol analogues in newborn rat abdominal skin using semiempirical moleular orbital calculation." Bioorg.Med.Chem.6(in press). (1999)