1990 Fiscal Year Annual Research Report

固型腫瘍における血管透過性亢進とキニン産生系の活性化

Research Project

Project/Area Number	02151050
Research Institution	Kumamoto University
Principal Investigator	前田浩熊本大学, 医学部, 教授 (90004613)
Co-Investigator(Kenkyū-buntansha)	今野俊光熊本大学, 医学部附属病院, 講師 (60117348) 山本哲郎熊本大学, 医学部, 助教授 (60112405) 加藤久雄国立循環器病センター研究所, 室長 (80029959) 川口隆憲福島県立医科大学, 講師 (10045685) 鈴木磨郎東北大学, 抗酸菌病研究所, 教授 (90006081)
Keywords	腫瘍血管 / 腫瘍血管透過性 / ブラジキニン / キニン分解酵素阻害剤 / 高分子制癌剤 / 油性制癌剤 / EPR効果 / 癌性腹水
Research Abstract	腫瘍局所は血管透過亢進因子産生系の亢進により血管の漏出性が亢進していることを、高分子のモデル化合物の放射化アルブミンやスマンクスあるいは油剤を用いて証明した。その現象はアンジオテンシンIIによる昇圧剤投与下に正常圧下よりもさらに約2倍ほど高められることを明らかにした。つぎに重要なことは、このとき上記とは逆に正常の骨髄へのデリバリ-が約50%抑制されることである。この現象は高分子に特徴的のようであり、低分子のモデル化合物の[ ^<14>C]メチルグルコ-スを用いた場合はこのようには行かない。腫瘍血管の透過性亢進の理由の一つが、腫瘍局所で産生されるブラジキニンによることから、その分解をキニン分解酵素阻害剤(カプトプリルなど)の投与後に昇圧下に薬剤を静注するとどうなるかを検討した。すなわち、ヒト腸癌を移植した。ヌ-ドマウスモデルに、A7ーモノクモ-ナル抗体結合NCSを投与すると、デリバリ-が2〜3倍促進されることを認めた。これは、キニナ-ゼ阻害剤非投与よりも有意に高かった。以上より、キニン分解阻害剤投与下に、昇圧し、高分子制癌剤を投与することは骨髄毒性の軽減に加えて、腫瘍集積性の大巾な増強が期待され、通常の方法の3〜4倍のメリットがあると思われる。今後の課題としては、実際の高分子制癌剤のスマンクスやピランーアドリアマイシンを用いた、動物における検証が必要である。

Research Products

(27 results)

All Other

All Publications (27 results)

[Publications] M.Suzuki,K.Hori,S.Saito,S.Tanda,I.Abe,H.Sato^1 and H.Sato^2: "Functional characteristics of tumor vessels:Selective increase in tumor blood flow." Sci.Rep.Res.Inst.Tohoku Univ.,ーC,. 36. 37-45 (1989)
[Publications] T.Yokota,E.Otsuji,A.Noguchi,T.Yamaguchi,K.Sawai and T.Takahashi: "Antigenic modulation and internalization of monoclonal antibody to human colonic carcinoma cells detected by enzymeーlinked immunosorbent assay" Int.J.Cancer. 44. 1095-1099 (1989)
[Publications] T.Kawaguchi,M.Kawaguchi,T.M.Lembo and G.L.Nicolson: "Differential tumor growth of bloodーborne B16 melanoma variants in cerebral dura mater is related to tumorーhost cell reactions." Clin.Exp1.Metastasis.7. 1-14 (1989)
[Publications] T.Kawaguchi,K.Watanabe,T.Sugino,A.Sakuma,S.Igarashi,T.Ono,et al.: "Establishment & Characterization of metastatic ascites hepatoma variants with different adhesive proterties to substrate <in vitro>___ー." Recent Progress of Life Science Technology in Japan. 267-279 (1989)
[Publications] H.Kato and K.Enjyoji: "Purification and proterties of inhibitors for contact activation of factor XII and prekallikrein from bovine plasma." Thromb.Haemostas.62. 16 (1989)
[Publications] T.Konno: "Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium." Cancer. 66. 1897-1903 (1990)
[Publications] Y.Matsumura,H.Maeda,and H.Kato: "Degradation pathway of kinins in tumor ascites and inhibition by kininase inhibitors:Analysis by HPLC." Agents and Actions. 29. 172-180 (1990)
[Publications] T.Akaike,M.Ando,T.Oda,T.Doi,S.Ijiri,S.Araki and H.Maeda: "Dependence on O_2 generation by xanthine oxidase of pathogenesis of influenza virus infection in mice." J.Clin.Invest.85. 739-745 (1990)
[Publications] K.Oka,Y.Miyamoto,Y.Matsumura,S.Tanaka,T.Oda,F.Suzuki and H.Maeda: "Enhanced intestinal absorption of a hydrophobic polymerーconjugated proteinーdrug smancs,in an oily formulation." Pharmaceut.Res.7. 852-855 (1990)
[Publications] Y.Miyamoto,T.Oda,and H.Maeda: "Comparison of the cytotoxic effects of the highーand lowーmolecularーweight anticancer agents on multidrugーresistant Chinese hamster ovary cells <in vitro>___ー." Cancer Res.50. 1571-1575 (1990)
[Publications] F.Suzuki,R.B.Pollard,S.Uchimura,T.Munakata and H.Maeda: "Role of natural killer cells and macrophages on the nonspecific resistance to tumors in mice stimulated with Smancs,a polymerーconjugated derivative of neocarzinostatin." Cancer Res.50. 3897-3904 (1990)
[Publications] H.Yamamoto,T.Miki,T.Oda,T.Hirano,Y.Sera,M.Akagi and H.Maeda: "Reduced bone marrow toxicity of neocazinostatin by conjugation with divinyl etherーmaleic acid copolymer." Europ.J.Cancer. 28. 236-260 (1990)
[Publications] K.Hori,M.Suzuki,S.Tanda and S.Saito: "In vivo analysis of tumor vascularization in the rat." Jpn.J.Cancer Res.81. 279-288 (1990)
[Publications] K.Kitamura,T.Takahashi,K.Takashina,T.Yamaguchi,A.Noguchi,H.Tsurumi et al.: "Polyethylene glycol modification of the monoclonal antibody A7 enhances its tumor localization." Biochem.Biophys.Res.Commun.28. 1387-1394 (1990)
[Publications] E.Otsuji,T.Takahashi,T.Yamaguchi,N.Yamaguchi,and J.Imanishi: "Specific cytotzxic effect of neocarzinostatin conjugated to monoclonal antibody A7 on human pancreatic carcinoma" The Japanses Society of Gastroenterology. 25. 244-248 (1990)
[Publications] K.Kitamura,T.Takahashi,T.Yamaguchi,S.Kitai,T.Amagai and J.Imanishi: "Monoclonal antibody A7 tumor localization enhancement by its F(ab')_2 fragments to colon carcinoma xenografts in nude mice." Jpn.J.Clin.Oncol.20. 139-144 (1990)
[Publications] S.Sugihara,T.Yamamoto,J.Tsuruta,J.Tanaka,T.Hiraoka,S.Tashiro,et al: "Enzymeーinduced aggregation and disaggregation of tumor cells via cell surface glycocalyx in association with deoxyribonucleic acid." Acta.Pathol.Jpn.41. (1990)
[Publications] S.Sugihara,T.Yamamoto,J.Tsuruta,T.Tanaka,T.Kambara,T.Hirano et al.: "Serine proteaseーinduced enhancement of bloodーborne metastasis of rat ascites tumour cells and its prevention with deoxyribonuclease." Br.J.Cancer.62. 607-613 (1990)
[Publications] 佐藤春彦,漆山昌伸,杉山克郎,石塚圭一,星正彦,涌井昭: "昇圧化学療法における胃癌治療効果と用量強度" 癌と化学療法. 17. 564-569 (1990)
[Publications] K.Kromizu,O.Abe and H.Maeda: "Location of the disulfide bonds in antitumor protein,neocarzinostatin." Arch.Biochem.Biophys.(1990)
[Publications] H.Maeda: "SMANCS and polymerーconjugated macromolecular drugs:Advantages in cancer chemotherapy." Adv.Drug Delivery Rev.(1991)
[Publications] Y.Miyamoto and H.Maeda: "Enhanced effect of neocarzinostatin by verapamil on multidrug resistant Chinese hamster ovary cell:Possible release of nonprotein chromophore in cells." Jpn.J.Cancer Res.82. (1991)
[Publications] Y.Matsumura,K.Maruo,M.Kimura,T.Yamamoto and H.Maeda: "Kininーgeneration cascade in cancer:Clinical and <in vitro>___ー study." Jpn.J.Cancer Res.(1991)
[Publications] K.Hori,M.Suzuki,S.Tanda and S.Saito: "Characterization of heterogeneous distribution of tumor blood flow in the rat." Jpn.J.Cancer Res.82. 109-117 (1991)
[Publications] 木村正美,今野俊光,前田浩: "制がん剤の体腔がんへのタ-ゲティングと骨髄集積の回避" 細胞工学. 10. (1991)
[Publications] H.Maeda: "Protein drugs tailored with synthetic polymers:Enhanced plasmaーhalfーlife and efficient delivery to tumor and inflammatory site.<in>___ー High Performance Biomaterials;A Comprehensive Guide to Medical and Pharmacoutical Applications" Technomic Pub.Co.Inc.Lancaster,P.A.,
[Publications] 前田浩,宮本洋一: "DDSの開発及び実用化の現状と問題点,4,高分子医薬品と油性化製剤の特徴と問題点.嘉悦勲編「DDS技術の進歩,薬物ー高分子ハイブリッドの展開" (社)日本工業技術振興協会, 14 (1990)

1990 Fiscal Year Annual Research Report

固型腫瘍における血管透過性亢進とキニン産生系の活性化

Principal Investigator

前田 浩 熊本大学, 医学部, 教授 (90004613)

Research Products

[Publications] M.Suzuki,K.Hori,S.Saito,S.Tanda,I.Abe,H.Sato^1 and H.Sato^2: "Functional characteristics of tumor vessels:Selective increase in tumor blood flow." Sci.Rep.Res.Inst.Tohoku Univ.,ーC,. 36. 37-45 (1989)

[Publications] T.Yokota,E.Otsuji,A.Noguchi,T.Yamaguchi,K.Sawai and T.Takahashi: "Antigenic modulation and internalization of monoclonal antibody to human colonic carcinoma cells detected by enzymeーlinked immunosorbent assay" Int.J.Cancer. 44. 1095-1099 (1989)

[Publications] T.Kawaguchi,M.Kawaguchi,T.M.Lembo and G.L.Nicolson: "Differential tumor growth of bloodーborne B16 melanoma variants in cerebral dura mater is related to tumorーhost cell reactions." Clin.Exp1.Metastasis.7. 1-14 (1989)

[Publications] T.Kawaguchi,K.Watanabe,T.Sugino,A.Sakuma,S.Igarashi,T.Ono,et al.: "Establishment & Characterization of metastatic ascites hepatoma variants with different adhesive proterties to substrate <in vitro>___ー." Recent Progress of Life Science Technology in Japan. 267-279 (1989)

[Publications] H.Kato and K.Enjyoji: "Purification and proterties of inhibitors for contact activation of factor XII and prekallikrein from bovine plasma." Thromb.Haemostas.62. 16 (1989)

[Publications] T.Konno: "Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium." Cancer. 66. 1897-1903 (1990)

[Publications] Y.Matsumura,H.Maeda,and H.Kato: "Degradation pathway of kinins in tumor ascites and inhibition by kininase inhibitors:Analysis by HPLC." Agents and Actions. 29. 172-180 (1990)

[Publications] T.Akaike,M.Ando,T.Oda,T.Doi,S.Ijiri,S.Araki and H.Maeda: "Dependence on O_2 generation by xanthine oxidase of pathogenesis of influenza virus infection in mice." J.Clin.Invest.85. 739-745 (1990)

[Publications] K.Oka,Y.Miyamoto,Y.Matsumura,S.Tanaka,T.Oda,F.Suzuki and H.Maeda: "Enhanced intestinal absorption of a hydrophobic polymerーconjugated proteinーdrug smancs,in an oily formulation." Pharmaceut.Res.7. 852-855 (1990)

[Publications] Y.Miyamoto,T.Oda,and H.Maeda: "Comparison of the cytotoxic effects of the highーand lowーmolecularーweight anticancer agents on multidrugーresistant Chinese hamster ovary cells <in vitro>___ー." Cancer Res.50. 1571-1575 (1990)

[Publications] F.Suzuki,R.B.Pollard,S.Uchimura,T.Munakata and H.Maeda: "Role of natural killer cells and macrophages on the nonspecific resistance to tumors in mice stimulated with Smancs,a polymerーconjugated derivative of neocarzinostatin." Cancer Res.50. 3897-3904 (1990)

[Publications] H.Yamamoto,T.Miki,T.Oda,T.Hirano,Y.Sera,M.Akagi and H.Maeda: "Reduced bone marrow toxicity of neocazinostatin by conjugation with divinyl etherーmaleic acid copolymer." Europ.J.Cancer. 28. 236-260 (1990)

[Publications] K.Hori,M.Suzuki,S.Tanda and S.Saito: "In vivo analysis of tumor vascularization in the rat." Jpn.J.Cancer Res.81. 279-288 (1990)

[Publications] K.Kitamura,T.Takahashi,K.Takashina,T.Yamaguchi,A.Noguchi,H.Tsurumi et al.: "Polyethylene glycol modification of the monoclonal antibody A7 enhances its tumor localization." Biochem.Biophys.Res.Commun.28. 1387-1394 (1990)

[Publications] E.Otsuji,T.Takahashi,T.Yamaguchi,N.Yamaguchi,and J.Imanishi: "Specific cytotzxic effect of neocarzinostatin conjugated to monoclonal antibody A7 on human pancreatic carcinoma" The Japanses Society of Gastroenterology. 25. 244-248 (1990)

[Publications] K.Kitamura,T.Takahashi,T.Yamaguchi,S.Kitai,T.Amagai and J.Imanishi: "Monoclonal antibody A7 tumor localization enhancement by its F(ab')_2 fragments to colon carcinoma xenografts in nude mice." Jpn.J.Clin.Oncol.20. 139-144 (1990)

[Publications] S.Sugihara,T.Yamamoto,J.Tsuruta,J.Tanaka,T.Hiraoka,S.Tashiro,et al: "Enzymeーinduced aggregation and disaggregation of tumor cells via cell surface glycocalyx in association with deoxyribonucleic acid." Acta.Pathol.Jpn.41. (1990)

[Publications] S.Sugihara,T.Yamamoto,J.Tsuruta,T.Tanaka,T.Kambara,T.Hirano et al.: "Serine proteaseーinduced enhancement of bloodーborne metastasis of rat ascites tumour cells and its prevention with deoxyribonuclease." Br.J.Cancer.62. 607-613 (1990)

[Publications] 佐藤 春彦,漆山 昌伸,杉山 克郎,石塚 圭一,星 正彦,涌井 昭: "昇圧化学療法における胃癌治療効果と用量強度" 癌と化学療法. 17. 564-569 (1990)

[Publications] K.Kromizu,O.Abe and H.Maeda: "Location of the disulfide bonds in antitumor protein,neocarzinostatin." Arch.Biochem.Biophys.(1990)

[Publications] H.Maeda: "SMANCS and polymerーconjugated macromolecular drugs:Advantages in cancer chemotherapy." Adv.Drug Delivery Rev.(1991)

[Publications] Y.Miyamoto and H.Maeda: "Enhanced effect of neocarzinostatin by verapamil on multidrug resistant Chinese hamster ovary cell:Possible release of nonprotein chromophore in cells." Jpn.J.Cancer Res.82. (1991)

[Publications] Y.Matsumura,K.Maruo,M.Kimura,T.Yamamoto and H.Maeda: "Kininーgeneration cascade in cancer:Clinical and <in vitro>___ー study." Jpn.J.Cancer Res.(1991)

[Publications] K.Hori,M.Suzuki,S.Tanda and S.Saito: "Characterization of heterogeneous distribution of tumor blood flow in the rat." Jpn.J.Cancer Res.82. 109-117 (1991)

[Publications] 木村 正美,今野 俊光,前田 浩: "制がん剤の体腔がんへのタ-ゲティングと骨髄集積の回避" 細胞工学. 10. (1991)

[Publications] H.Maeda: "Protein drugs tailored with synthetic polymers:Enhanced plasmaーhalfーlife and efficient delivery to tumor and inflammatory site.<in>___ー High Performance Biomaterials;A Comprehensive Guide to Medical and Pharmacoutical Applications" Technomic Pub.Co.Inc.Lancaster,P.A.,

[Publications] 前田 浩,宮本 洋一: "DDSの開発及び実用化の現状と問題点,4,高分子医薬品と油性化製剤の特徴と問題点.嘉 悦勲 編「DDS技術の進歩,薬物ー高分子ハイブリッドの展開" (社)日本工業技術振興協会, 14 (1990)

前田浩熊本大学, 医学部, 教授 (90004613)

[Publications] 佐藤春彦,漆山昌伸,杉山克郎,石塚圭一,星正彦,涌井昭: "昇圧化学療法における胃癌治療効果と用量強度" 癌と化学療法. 17. 564-569 (1990)

[Publications] 木村正美,今野俊光,前田浩: "制がん剤の体腔がんへのタ-ゲティングと骨髄集積の回避" 細胞工学. 10. (1991)

[Publications] 前田浩,宮本洋一: "DDSの開発及び実用化の現状と問題点,4,高分子医薬品と油性化製剤の特徴と問題点.嘉悦勲編「DDS技術の進歩,薬物ー高分子ハイブリッドの展開" (社)日本工業技術振興協会, 14 (1990)