1989 年度実績報告書

耐性および癌遺伝子研究の進展に基づく制癌剤の開発研究

研究課題

研究課題/領域番号	01010019
研究機関	東京大学
研究代表者	鈴木日出夫東京大学, 応用微生物研究所, 助教授 (50013321)
研究分担者	国元節子微生物化学研究所, 主任研究員 (10161655) 稲葉実癌研, 癌化療センター, 主任研究員 (60085636) 小河原宏明治薬科大学, 薬学部, 教授 (00097198) 桑野信彦大分医科大学, 医学部, 教授 (80037431) 中村昭四郎広島大学, 医学部, 教授 (40013304)
キーワード	多剤耐性 / 耐性克服 / 耐性機構 / P糖タンパク / 癌遺伝子
研究概要	多剤耐性の原因であるP糖タンパクを特異的に認識するマウス由来モノクローナル抗体MRK16を耐性癌の診断、治療などの臨床応用に用いるべく、遺伝子工学的手段によってマウスのV領域とヒトのC領域を持つキメラ抗体の作成を試み、MH162抗体を得た。MH162は、ヒトのeffector cellを用いた場合のADCCによる殺細胞効果がMRK16に比べて優れており、ヒトの多剤耐性癌に対する治療剤としても期待が持たれる。ヒトの多剤耐性遺伝子のプロモーター及びエンハンサー領域を単離することに成功した。ハムスター細胞由来のシスプラチン耐性細胞株は、グルタチオンSトランスフェラーゼ(GST)活性が著明に上昇しており、GSTーpiのmRNAレベルも数倍に上昇していた。多剤耐性を克服する薬剤として多くのdihy dropyridine系薬剤をスクリーニングし、カルシウム拮抗作用が小さく、P糖タンパクに親和性の高い薬剤を見いだした。これは経口投与でも有効であった。多剤耐性克服剤AHC-52はADMやVCRが効きにくいヒトの胃癌、結腸癌などの培養系においてVCRの効果を大幅に増強した。多剤耐性克服のみならず幅広い抗癌剤の活性を増強させる合成イソプレノイドNー1379は、特にブレオマイシン系抗癌剤に対して強い相乗作用を示した。ペプロマイシン(PEP)とNー1379を1時間作用させただけで、PEPによるDNA鎖切断活性は大きく増強しており、PEPとNー1379との併用によって、ADN耐性性L5178Y細胞を移植してマウスの生存日数を延長した。多剤耐性癌細胞に有効な新規抗癌剤FAD104は糖の2位にフッ素を持ったアンスラサイクリン抗生物質であるが、生体内で代謝を受けたFTーADMがさらに強力な抗腫瘍活性を有することが分かった。微生物の代謝産物をスクリーニングし、新規に、Resorthiomycin,OH-1049物質及びKO3599物質を見いだした。癌遺伝子の一種HrasでトランスホームしたNRK細胞の形態を正常に戻すものとしてアセトキシシクロヘキシミドを単離した。

研究成果

(18件)

すべてその他

すべて文献書誌 (18件)

[文献書誌] HIDEO SUZUKI: "Resorthiomycin,a novel antitumor antibiotic.I.Taxonomy,isolation and biological activity." J.Antibiotics. 43. 129-134 (1990)
[文献書誌] MAKOTO TAHARA: "Resorthiomycin,a novel antitumor antibiotics.III.Potentiation of antitumor drugs and its mechanism of action." J.Antibiotics. 43. 138-142 (1990)
[文献書誌] HIDEO SUZUKI: "Cytocidal activity of synthetic isoprenoid,SDB-ethylenediamine,and its potentiation of antitumor drugs against multidrug-resistant and sensitive cells in vitro." Jpn.J.Cancer Res.81. (1990)
[文献書誌] ICHIRO NOGAE: "Analysis of structural features of dihydropyridine analogs needs to reverse multidrug-resistance and inhibit photoaffinity labeling of P-glycoprotein." Biochem.Pharmacol.38. 519-527 (1989)
[文献書誌] KUNI-ICHI ASOH: "Potentiation of some anticancer agents by dipyridamole against drug-sensitive and drug-resistant cell lines." Jpn.J.Cancer Res.80. 475-481 (1989)
[文献書誌] YOSHIO SABURI: "Increased expression of glutathione S-transferase gene in cis-diamminedichloroplatinum(II)-resistant variants of a Chinese hamster ovary cell line." Cancer Res.49. 7020-7025 (1989)
[文献書誌] OMURA SATOSHI: "Studies of a novel antitumor antibiotic,phenazinomycin:Taxonomy,fermentation,isolation,and physicochemical and biological characteristics." J.Antibiotics. 42. 1037-1042 (1989)
[文献書誌] HIROSHI OGAWARA: "Inhibition of tyrosine protein kinase activity by synthetic isoflavones and flavones." J.Antibiotics. 42. 340-343 (1989)
[文献書誌] HIROSHI OGAWARA: "Acetoxycycloheximide and cycloheximide convert transformed morphology of ras-transformed cells to normal morphology." J.Antibiotics. 42. 1530-1533 (1989)
[文献書誌] YOLSHIMASA UEHARA: "Mechanism of reversion of Rous sarcoma virus transformation by herbimycin A:Reduction of total phosphotyrosine levels due to reduced kinase activity and increased turnover of p60^<v-src>." Cancer Res.49. 780-785 (1989)
[文献書誌] YOSHIMASA UEHARA: "Irreversible inhibition of v-src tyrosine kinase activity by herbimycin A and its abrogation by sulfhydryl compounds." Biochem.Biophys.Res.Commun.163. 803-809 (1989)
[文献書誌] HIROSHI KANAMARU: "MDR1 RNA levels in human renal cell carcinomas:Correlation with grade and prediction of reversal of doxorubicin resistance by quinidine in tumor explants." J.National Cancer Institute. 81. 844-849 (1989)
[文献書誌] YUKINORI TAKE: "Biological properties of streptonigrin derivtives.III.In vitro and in vivo antiviral and antitumor activities." J.Antibiotics. 42. 968-976 (1989)
[文献書誌] YASUSHI ISHIDA: "Multidrug resistance in cultured human leukemia and lymphoma cell lines detected by a monoclonal antibody,MRK16." Jpn.J.Cancer Res.80. 1006-1013 (1989)
[文献書誌] ISAMU SUGAWARA: "Further characterization of the human adrenal-derived P-glycoprotein recognized by monoclonal antibody MRK16 reacting with only human P-glycoprotein." Jpn.J.Cancer Res.80. 1199-1205 (1989)
[文献書誌] TAKASHI TSURUO: "Inhibition of multidrug-resistant human tumor growth in athymic mice by anti-P-glycoprotein monoclonal antibodies." Jpn.J.Cancer Res.80. 627-631 (1989)
[文献書誌] HIROTAKA SHINODA: "In vivo circumvention of vincristine resistance in mice with p388 liukemia using a novel compound,AHJC-52." Cancer Res.49. 1722-1726 (1989)
[文献書誌] SETSUKO KUNIMOTO: "Biological activities of new anthracyclines containing fluorine,FAD104 and its metabolites." J.Antibiotics. 43. (1990)

1989 年度 実績報告書

耐性および癌遺伝子研究の進展に基づく制癌剤の開発研究

研究代表者

鈴木 日出夫 東京大学, 応用微生物研究所, 助教授 (50013321)

研究成果

[文献書誌] HIDEO SUZUKI: "Resorthiomycin,a novel antitumor antibiotic.I.Taxonomy,isolation and biological activity." J.Antibiotics. 43. 129-134 (1990)

[文献書誌] MAKOTO TAHARA: "Resorthiomycin,a novel antitumor antibiotics.III.Potentiation of antitumor drugs and its mechanism of action." J.Antibiotics. 43. 138-142 (1990)

[文献書誌] HIDEO SUZUKI: "Cytocidal activity of synthetic isoprenoid,SDB-ethylenediamine,and its potentiation of antitumor drugs against multidrug-resistant and sensitive cells in vitro." Jpn.J.Cancer Res.81. (1990)

[文献書誌] ICHIRO NOGAE: "Analysis of structural features of dihydropyridine analogs needs to reverse multidrug-resistance and inhibit photoaffinity labeling of P-glycoprotein." Biochem.Pharmacol.38. 519-527 (1989)

[文献書誌] KUNI-ICHI ASOH: "Potentiation of some anticancer agents by dipyridamole against drug-sensitive and drug-resistant cell lines." Jpn.J.Cancer Res.80. 475-481 (1989)

[文献書誌] YOSHIO SABURI: "Increased expression of glutathione S-transferase gene in cis-diamminedichloroplatinum(II)-resistant variants of a Chinese hamster ovary cell line." Cancer Res.49. 7020-7025 (1989)

[文献書誌] OMURA SATOSHI: "Studies of a novel antitumor antibiotic,phenazinomycin:Taxonomy,fermentation,isolation,and physicochemical and biological characteristics." J.Antibiotics. 42. 1037-1042 (1989)

[文献書誌] HIROSHI OGAWARA: "Inhibition of tyrosine protein kinase activity by synthetic isoflavones and flavones." J.Antibiotics. 42. 340-343 (1989)

[文献書誌] HIROSHI OGAWARA: "Acetoxycycloheximide and cycloheximide convert transformed morphology of ras-transformed cells to normal morphology." J.Antibiotics. 42. 1530-1533 (1989)

[文献書誌] YOLSHIMASA UEHARA: "Mechanism of reversion of Rous sarcoma virus transformation by herbimycin A:Reduction of total phosphotyrosine levels due to reduced kinase activity and increased turnover of p60^<v-src>." Cancer Res.49. 780-785 (1989)

[文献書誌] YOSHIMASA UEHARA: "Irreversible inhibition of v-src tyrosine kinase activity by herbimycin A and its abrogation by sulfhydryl compounds." Biochem.Biophys.Res.Commun.163. 803-809 (1989)

[文献書誌] HIROSHI KANAMARU: "MDR1 RNA levels in human renal cell carcinomas:Correlation with grade and prediction of reversal of doxorubicin resistance by quinidine in tumor explants." J.National Cancer Institute. 81. 844-849 (1989)

[文献書誌] YUKINORI TAKE: "Biological properties of streptonigrin derivtives.III.In vitro and in vivo antiviral and antitumor activities." J.Antibiotics. 42. 968-976 (1989)

[文献書誌] YASUSHI ISHIDA: "Multidrug resistance in cultured human leukemia and lymphoma cell lines detected by a monoclonal antibody,MRK16." Jpn.J.Cancer Res.80. 1006-1013 (1989)

[文献書誌] ISAMU SUGAWARA: "Further characterization of the human adrenal-derived P-glycoprotein recognized by monoclonal antibody MRK16 reacting with only human P-glycoprotein." Jpn.J.Cancer Res.80. 1199-1205 (1989)

[文献書誌] TAKASHI TSURUO: "Inhibition of multidrug-resistant human tumor growth in athymic mice by anti-P-glycoprotein monoclonal antibodies." Jpn.J.Cancer Res.80. 627-631 (1989)

[文献書誌] HIROTAKA SHINODA: "In vivo circumvention of vincristine resistance in mice with p388 liukemia using a novel compound,AHJC-52." Cancer Res.49. 1722-1726 (1989)

[文献書誌] SETSUKO KUNIMOTO: "Biological activities of new anthracyclines containing fluorine,FAD104 and its metabolites." J.Antibiotics. 43. (1990)

1989 年度実績報告書

鈴木日出夫東京大学, 応用微生物研究所, 助教授 (50013321)