1990 Fiscal Year Annual Research Report

休止期細胞の動員と転移抑制効果を有する新合成制癌剤の探索

Research Project

Project/Area Number	02151021
Research Institution	Kanazawa University
Principal Investigator	佐々木琢磨金沢大学, がん研究所, 教授 (90109976)
Co-Investigator(Kenkyū-buntansha)	米田文郎京都大学, 薬学部, 教授 (80040327) 宮本謙一北陸大学, 薬学部, 教授 (30100514) 前田満和国立がんセンター, 研究所, 主任研究官 (60157146) 川添豊名古屋市立大学, 薬学部, 教授 (80106252) 兼松顕九州大学, 薬学部, 教授 (70023041)
Keywords	抗腫瘍性 / 癌転移抑制 / 休止期細胞 / 制癌剤耐性 / 合成制癌剤 / 2'ーシアノシチジン / 5ーデアザフラビン誘導体 / イソキノリン誘導体
Research Abstract	前年度に引続き2'ーdeoxycytidineの2'ーarabino位への置換基の導入を検討し、2'ーazido体(Cytarazid)の簡便、大量合成法を確立すると共に2'ーシアノ体(CNDAC)をラジカル反応を用いて新たに合成した。種々のヒト固型腫瘍由来細胞に対しCytarazid及びCNDACはともに強い増殖抑制効果を示した。また、podophyllotoxin型リグナン類の合成をDielsーAlder反応を用いて合成し、強い抗腫瘍活性を有する化合物を得ることができた。ブレオマイシンの細胞毒性は、ポリアクリル酸と撹拌すると増大するが、この時の細胞死は未知の致死機構によるものと考えられ、休止期細胞や耐性細胞にも同等に作用することを見出した。白金錯体を酸性多糖に結合させた高分子マトリックス型錯体を合成し、それらがB16ーF10メラノ-マの肺転移を抑制することを見出した。酸化還元代謝調節能を有するフラビンや5ーデアザフラビンの誘導体を合成した。これらの中でもNO_2基やCOOC_2H_5基を有するものが強い抗癌活性を示した。次に生元素の一つであるセレンを骨格内に導入した5ーデアザー10ーセレナフラビンを合成し、この化合物もかなり強い抗癌活性を有することを見出した。一方、ヒト腫瘍に対する簡便で能率の良い転移治療モデルとして、鶏卵胎児の転移多発臓器のおけるヒト腫瘍の微小転移巣に含まれるヒト腫瘍細胞の特定遺伝子をPolymerase Chain Reaction法により定量的に検出する我々独自の方法を用いて、転移抑制及び治療に有効な物質をスクリ-ニングした。その結果、本研究班で合成したDMDC(2'ーdeoxyー2'ーmethylidenecytidine)とCNDACがヒト線維肉腫HT1080の肝・肺の転移巣を顕著に抑制することがわかった。選択性の高いプロテインキナ-ゼ作用薬を得るために新しくデザインされたイソキノリン誘導体の細胞周期及び制癌剤多剤耐性に及ぼす影響を検討した結果、in vitroではあるが、P388/ADRの耐性解除作用の強い物質を見出した。

Research Products

(22 results)

All Other

All Publications (22 results)

[Publications] M.Maeda: "New antitumor platinum(II) complexes with both lipophilicity and water miscibility" Jpn.J.Cancer Res.81. 567-569 (1990)
[Publications] Y.Endo: "Specific detection of metastasized human tumor cells in embryonic chicks by the polymerase chain reaction" Jpn.J.Cancer Res.81. 723-726 (1990)
[Publications] A.Matsuda: "Synthesis and biological activities of 3'ーdeoxyー3'ーisocyano,ーisothiocyano,and ーisoselenocyanothymidines" Nucleosides & Nucleotides. 9. 587-597 (1990)
[Publications] A.Matsuda: "Synthesis of a new potent antitumor nucleoside,2'ーCーcyanoー2'ーdeoxyー1ーβーDーarabinofuranosylcytosine" Nucleic Acids Res.22. 51-52 (1990)
[Publications] M.Maeda: "Antitumor activity of bis(bilato)ー1,2ーcyclohexanediammineplatinum(II)complexes against pulmonary B16ーF10 melanoma cells in mice" Cancer Letters. 55. 143-147 (1990)
[Publications] K.Miyamoto: "Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMPーdependent protein kinase,Hー87" Cancer Letters. 51. 37-42 (1990)
[Publications] K.Miyamoto: "Changes in number of ーadrenergic receptor subtypes in hepatocytes from rats fed 3'ーmethylー4ーdimethylaminoazobenzene" Jpn.J.Cancer Res.81. 557-559 (1990)
[Publications] T.Yoshida: "Woodfordin C,a macroーring hydrolyzable tannin dimer with antitumor activity,and accompanying dimers from Woodfordia flowers" Chem.Pharm.Bull.38. 1211-1217 (1990)
[Publications] T.Suzuki: "Potentiation of bleomycin cytotoxicity in cultured mammalian cells by higher molecular weight polyacrylic acid" Anticancer Res.10. 1001-1004 (1990)
[Publications] T.Suzuki: "Potentiation of bleomycin cytotoxicity by polyhydric alcohols" Anticancer Res.10. 97-104 (1990)
[Publications] T.Ohーhara: "Lignified natural products as potential medicinal resources.I.Potentiation of hemolytic plaqueーforming cell production in mice" Chem.Pharm.Bull.38. 282-284 (1990)
[Publications] M.Maeda: "Synthesis and reactivities of 1ーmethylー2ーtrichloromethylー1,2ーdihydroquinolines" Chem.Pharm.Bull.39. 2577-2580 (1990)
[Publications] T.Kimachi: "First total synthesis of coenzyme factor 420" J.Chem.Soc.,Perkin Trans.253-256 (1990)
[Publications] 佐々木琢磨: "シンポジウム「癌化学療法の現状と展望」" 月刊薬事. 32. 2347-2351 (1990)
[Publications] A.Matsuda: "Nucleosides & Nucleotides.94.Radical deoxygenation of tertーalcohols in 1ー(2ーalkylpentofuranosyl)pyrimidines: Synthesis of(2'S)ー2'ーdeoxyー2'ーmethylcytidine,an antileukemic nucleoside" J.Med.Chem.(1991)
[Publications] A.Matsuda: "Nucleosides and Nucleotides.95.An improved synthesis of 1ー(2'ーazidoー2'ーdeoxyーβーDーarabinofuranosyl)ーcytosine (Cytarazid) andーthymine.The inhibitory spectrum of Cytarazid on the growth of various human tumor cells in vitro" J.Med.Chem.(1991)
[Publications] N.Minakawa: "Nucleosides and Nucleotides.96.Synthesis and antitumor activity of 5ーethynylー1ーβーDーribofuranosylimidazoleー4ーcarboxamide (EICAR) and its derivatives." J.Med.Chem.(1991)
[Publications] A.Matsuda: "Nucleosides and Nucleotides.97.Synthesis of a new broad spectrum of antineoplastic nucleosides,2'ーdeoxyー2'ーmethylidenecytidine (DMDC) and its derivatives" J.Med.Chem.(1991)
[Publications] N.Minakawa: "Nucleosides and Nucleotides.98.Synthesis and antitumor activities of 5ーethynylimidazoleー4ーcarboxamide and ーcarbonitrile derivatives" Nucleosides & Nucleotides. (1991)
[Publications] K.Yamagami: "Antitumor activity of 2'ーdeoxyー2'ーmethylidene,a new 2'ーdeoxycytidine derivative" Cancer Res.(1991)
[Publications] Y.Soneda: "A synthesis of lanosterol derivatives with 14ーfunctional group including an antineoplastic sterol,3βーhydroxylanostー7ーenー32ーoic acid." Chem.Pharm.Bull.(1991)
[Publications] S.Ohyama: "In vitro chemosensitivity test using collagen gel matrix for human gastric carcinomas" Jpn.J.Cancer Chemother.18. 101-105 (1991)

1990 Fiscal Year Annual Research Report

休止期細胞の動員と転移抑制効果を有する新合成制癌剤の探索

Principal Investigator

佐々木 琢磨 金沢大学, がん研究所, 教授 (90109976)

Research Products

[Publications] M.Maeda: "New antitumor platinum(II) complexes with both lipophilicity and water miscibility" Jpn.J.Cancer Res.81. 567-569 (1990)

[Publications] Y.Endo: "Specific detection of metastasized human tumor cells in embryonic chicks by the polymerase chain reaction" Jpn.J.Cancer Res.81. 723-726 (1990)

[Publications] A.Matsuda: "Synthesis and biological activities of 3'ーdeoxyー3'ーisocyano,ーisothiocyano,and ーisoselenocyanothymidines" Nucleosides & Nucleotides. 9. 587-597 (1990)

[Publications] A.Matsuda: "Synthesis of a new potent antitumor nucleoside,2'ーCーcyanoー2'ーdeoxyー1ーβーDーarabinofuranosylcytosine" Nucleic Acids Res.22. 51-52 (1990)

[Publications] M.Maeda: "Antitumor activity of bis(bilato)ー1,2ーcyclohexanediammineplatinum(II)complexes against pulmonary B16ーF10 melanoma cells in mice" Cancer Letters. 55. 143-147 (1990)

[Publications] K.Miyamoto: "Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMPーdependent protein kinase,Hー87" Cancer Letters. 51. 37-42 (1990)

[Publications] K.Miyamoto: "Changes in number of ーadrenergic receptor subtypes in hepatocytes from rats fed 3'ーmethylー4ーdimethylaminoazobenzene" Jpn.J.Cancer Res.81. 557-559 (1990)

[Publications] T.Yoshida: "Woodfordin C,a macroーring hydrolyzable tannin dimer with antitumor activity,and accompanying dimers from Woodfordia flowers" Chem.Pharm.Bull.38. 1211-1217 (1990)

[Publications] T.Suzuki: "Potentiation of bleomycin cytotoxicity in cultured mammalian cells by higher molecular weight polyacrylic acid" Anticancer Res.10. 1001-1004 (1990)

[Publications] T.Suzuki: "Potentiation of bleomycin cytotoxicity by polyhydric alcohols" Anticancer Res.10. 97-104 (1990)

[Publications] T.Ohーhara: "Lignified natural products as potential medicinal resources.I.Potentiation of hemolytic plaqueーforming cell production in mice" Chem.Pharm.Bull.38. 282-284 (1990)

[Publications] M.Maeda: "Synthesis and reactivities of 1ーmethylー2ーtrichloromethylー1,2ーdihydroquinolines" Chem.Pharm.Bull.39. 2577-2580 (1990)

[Publications] T.Kimachi: "First total synthesis of coenzyme factor 420" J.Chem.Soc.,Perkin Trans.253-256 (1990)

[Publications] 佐々木 琢磨: "シンポジウム「癌化学療法の現状と展望」" 月刊薬事. 32. 2347-2351 (1990)

[Publications] A.Matsuda: "Nucleosides & Nucleotides.94.Radical deoxygenation of tertーalcohols in 1ー(2ーalkylpentofuranosyl)pyrimidines: Synthesis of(2'S)ー2'ーdeoxyー2'ーmethylcytidine,an antileukemic nucleoside" J.Med.Chem.(1991)

[Publications] A.Matsuda: "Nucleosides and Nucleotides.95.An improved synthesis of 1ー(2'ーazidoー2'ーdeoxyーβーDーarabinofuranosyl)ーcytosine (Cytarazid) andーthymine.The inhibitory spectrum of Cytarazid on the growth of various human tumor cells in vitro" J.Med.Chem.(1991)

[Publications] N.Minakawa: "Nucleosides and Nucleotides.96.Synthesis and antitumor activity of 5ーethynylー1ーβーDーribofuranosylimidazoleー4ーcarboxamide (EICAR) and its derivatives." J.Med.Chem.(1991)

[Publications] A.Matsuda: "Nucleosides and Nucleotides.97.Synthesis of a new broad spectrum of antineoplastic nucleosides,2'ーdeoxyー2'ーmethylidenecytidine (DMDC) and its derivatives" J.Med.Chem.(1991)

[Publications] N.Minakawa: "Nucleosides and Nucleotides.98.Synthesis and antitumor activities of 5ーethynylimidazoleー4ーcarboxamide and ーcarbonitrile derivatives" Nucleosides & Nucleotides. (1991)

[Publications] K.Yamagami: "Antitumor activity of 2'ーdeoxyー2'ーmethylidene,a new 2'ーdeoxycytidine derivative" Cancer Res.(1991)

[Publications] Y.Soneda: "A synthesis of lanosterol derivatives with 14ーfunctional group including an antineoplastic sterol,3βーhydroxylanostー7ーenー32ーoic acid." Chem.Pharm.Bull.(1991)

[Publications] S.Ohyama: "In vitro chemosensitivity test using collagen gel matrix for human gastric carcinomas" Jpn.J.Cancer Chemother.18. 101-105 (1991)

佐々木琢磨金沢大学, がん研究所, 教授 (90109976)

[Publications] 佐々木琢磨: "シンポジウム「癌化学療法の現状と展望」" 月刊薬事. 32. 2347-2351 (1990)