1991 Fiscal Year Annual Research Report

新しい制がん剤耐性遺伝子群の解析と克服法の確立

Research Project

Project/Area Number	03151051
Research Institution	大分医科大学
Principal Investigator	桑野信彦大分医科大学, 医学部, 教授 (80037431)
Co-Investigator(Kenkyū-buntansha)	杉本芳一癌研究会癌化学療法センター, 基礎研究部, 研究員 (10179161) 西條長宏国立がんセンター研究所, 薬効試験部, 部長 (00215526) 植田和光京都大学, 農学部, 助手 (10151789) 稲葉実癌研究会癌化学療法センター, 基礎研究部, 主任研究員 (60085636) 石田良司愛知がんセンター研究所, 生化学部, 主任研究員 (50150214)
Keywords	抗癌剤耐性 / 耐性獲得機序 / 耐性克服剤開発 / 多剤耐性遺伝子 / Pー糖蛋白 / DNAトポイソメラ-ゼ / シスプラチン / 5ーフルオロウラシル
Research Abstract	1.制癌剤耐性遺伝子群に関して,我々は(1)多剤耐性遺伝子MDR1を制御するプロモ-タ-及びエンハンサ-結合蛋白について解析を進めた。さらに同遺伝子の発現は環境ストレスによって促進されるSOS遺伝子であることを提示した。他方,ヒト多剤耐性細胞に発現している85kDa蛋白の遺伝子構造を決定した。(2)乳癌,白血病,卵巣癌患者において再発した症例において,MDR1 mRNAの発現陽性率が治療前に較べて高いことがRTーPCR法を用いて観察された。他方,白血病の再発例においてNーras点突然変異の上昇もみられた。(3)5ーフルオロウラシル耐性のヒト胃癌や結腸癌細胞においてウリジンキナ-ゼ欠損をエトポシド耐性のヒト癌細胞においてDNAトポイソメラ-ゼII遺伝子発現の低下や細胞内蓄積が見出された。他方,シスプラチン耐性と関連する細胞膜局在の輸送蛋白及びDNA障害修復酵素の同定を進めた。2.耐性克服剤の開発に関して,(1)DNAと切断複合体を形成せずにトポイソメラ-ゼIIを阻害する新しいビペラジン誘導体ICRー193及びICRFー154は多剤耐性細胞に対して交差耐性を示さなかった。(2)Pー糖蛋白依存性の多剤耐性に対して交差耐性を示さないで優れた抗腫瘍活性を示すアンスラサイクリン抗生物質であるMX2,FAD104及びFTーADMを見出した。(3)Pー糖蛋白を標的とする新イソプレノイド剤はphasel研究において乳癌再発転移の症例でアドリアマイシンとの併用で改善した効果を示した。

Research Products

(30 results)

All Other

All Publications (30 results)

[Publications] Akira Kiue: "Reversal by two dihydroryridine compounds of resistance to multiple anticancer agents in mouse P388 leukemia in vivo and in vitro." Jpn.J.Cancer Res.81. 1057-1064 (1990)
[Publications] Akira Kiue: "Enhancement of antitumor activity of etoposide by dihydropyridines on drug-sensitive and drug resistant leukemia in mice." Brit.J.Cancer. 64. 221-226 (1991)
[Publications] Kazushi Tanabe: "Inhibition of topoisomerase II by antitumor agents bis(2,6-dioxopiperazine) derivatives." Cancer Res.51. 4903-4908 (1991)
[Publications] Ryoji Ishida: "Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives:mode of cell growth inhibition distinct from that of cleavable complez-forming type inhibitiors." Cancer Res.51. 4909-4916 (1991)
[Publications] Minoru Inaba: "Kinetic analysis of 5-fluorouracil action against various cancer cells." Jpn.J.Cancer Res.81. 1039-1044 (1990)
[Publications] Junko Mitsuhashi: "Mechanism for resistance to 5-fluorouracil i P388 leukemia cells." J.Pharmacobioo-Dyn.14. 577-581 (1991)
[Publications] Alfred M.Shimabuke: "Production of a site specifically cleavable Pーglycoproteinーβーgalactosidase fusion protein." Agric.Biol.Chem.55. 1075-1080 (1991)
[Publications] Tohru Sacki: "Expression of human P-glycoprotein in yeast cells-Effects of membrane component sterols on the activity of P-glycoprotein." Agric.Biol.Chem.55. 1859-1865 (1991)
[Publications] Masao Okumura: "Expression of H-related antigen on human megakeryocytes and megakaryocytic leukemia cells." Int.J.Haematol.54. 151-158 (1991)
[Publications] Hisashi Fukutani: "Treatment of myelodysplastic syndromes with orrally administrated N-(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine (Ubenimex)." Jpn.J.Clin.Oncol.21. 287-292 (1991)
[Publications] "Reversal by two dihydroryridine compounds of resistance to multiple anticancer agents in mouse P388 leukemia in vivo and in vitro." Jpn.J.Cancer Res.81. 1057-1064 (1990)
[Publications] Kimitoshi Kohno: "Induction of the transcription from the promoter of the human MDR1 gene by environmental stresses." Biochim.Biophys.Acta.
[Publications] Setsuko Kunimoto: "Biological activities of new anthracyclines containing fluorine,FAD104 and its metabolites." J.Antibiotics. 43. 556-565 (1990)
[Publications] K.R.Rox: "Sequence selective binding of ditrisarubicin B to DNA:Comparison with daunomycin." FEBS Lett.250. 323-327 (1989)
[Publications] Yasuhiro Fujiwara: "Detection of proteins that recognize platinum-modified DNA using gelmobility shift assay." Jpn.J.Cancer Res.81. 1210-1213 (1990)
[Publications] Yasutsuna Sasaki: "Phase I stury and pharmacological analysis of cis-diammine (glycolato)platinum (254-S;NSC 375101D) administered by 5-day continuous intravenuous intravenus infusion." Cancer Res.51. 1472-1477 (1991)
[Publications] Yoshikazu Sugimoto: "Elevated expression of DNA topoisomerase II in camptothecinresistant human tumor cell lines." Cancer Res.50. 7962-7965 (1990)
[Publications] Yoshikazu Sugimoto: "Suppression of experimental lung colonization of a metastatic variant of murine colon adenocarcinoma 26 by a monoclonal antibody 8F11 inhibiting tumor cell-induced platelet aggregation." Cancer Res.51. 921-925 (1991)
[Publications] Misako Ichikawa: "Interaction of organic chemicals with P-glycoprotein in the adrenal glad,kidney,and a multidrug-resistant KB cell." J.Biol.Chem.266. 903-908 (1991)
[Publications] Misako Ichikawa: "Glycosylation of P-glycoprotein in a multidrug-resistant KB cell line,and in the human tissue." Biochim.Biophys.Acta. 1073. 309-315 (1991)
[Publications] 向山雄人: "Cyclophosphamide,ThioーTEPA,Etoposideを用いた自家骨髄移植併用超大量化学療法の研究" 癌と化学療法. 17. 2207-2211 (1990)
[Publications] 向山雄人: "臨床におけるPー糖タンパクの発現と多剤耐性克服の試み" BIO medica. 6. 22-27 (1991)
[Publications] Michihiko Kuwano: "Circumvention of multidrug resistance (MDR) and regulation of the MDR gene in response to enviromental stimuli" Cancer Chemotherapy:Challenges for the Future ed.by K.Kimura,Excerpta Medica,Tokyo,7, (1992)
[Publications] 石田良司: "薬剤耐性細胞の分離ーアルキル化剤" 蛋白質核酸酵素, 30:195-198 (1991)
[Publications] 國元節子: "抗がん抗生物質ー最近の話題" バイオサイエンスとインダストリ-, 49:379-382 (1991)
[Publications] 木岡紀幸: "抗癌剤の耐性機序とその克服多剤耐性の分子機構" 腫瘍と感染, 3:443-450 (1990)
[Publications] Tomoki Naoe: "Polymerase chain reaction for the detection of the minimal residual B-cell clones usisng diversity of complementarity determining resion (CDR) III." Cancer Chemotherapy:Challenges for the future.(ed.by K.Kimura) Excerpta Medica, 6:54-59 (1991)
[Publications] Kimitoshi Kohno: "Drug resistance to DNA topoisomerase II-targeting agents and development of the reversal agents" DNA Topoisomerases in Chemotherapy.ed.by T.Andoh.CRC Press, (1992)
[Publications] Yoshikazu Sugimoto: "Development of multidrug resistance in rodent cell lines." "Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells".I.B.Roninson,ed.Plenum Press, 57-70 (1991)
[Publications] Taketo Mukaiyama: "High-Dose chemotherapy with autologous hematopoietic stem cell transplant for cancers." Cancer Chemotherapy:Challenges for the future (ed.by K.Kimura),Excepta Medica, 6:114-119 (1991)

1991 Fiscal Year Annual Research Report

新しい制がん剤耐性遺伝子群の解析と克服法の確立

Principal Investigator

桑野 信彦 大分医科大学, 医学部, 教授 (80037431)

Research Products

[Publications] Akira Kiue: "Reversal by two dihydroryridine compounds of resistance to multiple anticancer agents in mouse P388 leukemia in vivo and in vitro." Jpn.J.Cancer Res.81. 1057-1064 (1990)

[Publications] Akira Kiue: "Enhancement of antitumor activity of etoposide by dihydropyridines on drug-sensitive and drug resistant leukemia in mice." Brit.J.Cancer. 64. 221-226 (1991)

[Publications] Kazushi Tanabe: "Inhibition of topoisomerase II by antitumor agents bis(2,6-dioxopiperazine) derivatives." Cancer Res.51. 4903-4908 (1991)

[Publications] Ryoji Ishida: "Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives:mode of cell growth inhibition distinct from that of cleavable complez-forming type inhibitiors." Cancer Res.51. 4909-4916 (1991)

[Publications] Minoru Inaba: "Kinetic analysis of 5-fluorouracil action against various cancer cells." Jpn.J.Cancer Res.81. 1039-1044 (1990)

[Publications] Junko Mitsuhashi: "Mechanism for resistance to 5-fluorouracil i P388 leukemia cells." J.Pharmacobioo-Dyn.14. 577-581 (1991)

[Publications] Alfred M.Shimabuke: "Production of a site specifically cleavable Pーglycoproteinーβーgalactosidase fusion protein." Agric.Biol.Chem.55. 1075-1080 (1991)

[Publications] Tohru Sacki: "Expression of human P-glycoprotein in yeast cells-Effects of membrane component sterols on the activity of P-glycoprotein." Agric.Biol.Chem.55. 1859-1865 (1991)

[Publications] Masao Okumura: "Expression of H-related antigen on human megakeryocytes and megakaryocytic leukemia cells." Int.J.Haematol.54. 151-158 (1991)

[Publications] Hisashi Fukutani: "Treatment of myelodysplastic syndromes with orrally administrated N-(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl-L-leucine (Ubenimex)." Jpn.J.Clin.Oncol.21. 287-292 (1991)

[Publications] "Reversal by two dihydroryridine compounds of resistance to multiple anticancer agents in mouse P388 leukemia in vivo and in vitro." Jpn.J.Cancer Res.81. 1057-1064 (1990)

[Publications] Kimitoshi Kohno: "Induction of the transcription from the promoter of the human MDR1 gene by environmental stresses." Biochim.Biophys.Acta.

[Publications] Setsuko Kunimoto: "Biological activities of new anthracyclines containing fluorine,FAD104 and its metabolites." J.Antibiotics. 43. 556-565 (1990)

[Publications] K.R.Rox: "Sequence selective binding of ditrisarubicin B to DNA:Comparison with daunomycin." FEBS Lett.250. 323-327 (1989)

[Publications] Yasuhiro Fujiwara: "Detection of proteins that recognize platinum-modified DNA using gelmobility shift assay." Jpn.J.Cancer Res.81. 1210-1213 (1990)

[Publications] Yasutsuna Sasaki: "Phase I stury and pharmacological analysis of cis-diammine (glycolato)platinum (254-S;NSC 375101D) administered by 5-day continuous intravenuous intravenus infusion." Cancer Res.51. 1472-1477 (1991)

[Publications] Yoshikazu Sugimoto: "Elevated expression of DNA topoisomerase II in camptothecinresistant human tumor cell lines." Cancer Res.50. 7962-7965 (1990)

[Publications] Yoshikazu Sugimoto: "Suppression of experimental lung colonization of a metastatic variant of murine colon adenocarcinoma 26 by a monoclonal antibody 8F11 inhibiting tumor cell-induced platelet aggregation." Cancer Res.51. 921-925 (1991)

[Publications] Misako Ichikawa: "Interaction of organic chemicals with P-glycoprotein in the adrenal glad,kidney,and a multidrug-resistant KB cell." J.Biol.Chem.266. 903-908 (1991)

[Publications] Misako Ichikawa: "Glycosylation of P-glycoprotein in a multidrug-resistant KB cell line,and in the human tissue." Biochim.Biophys.Acta. 1073. 309-315 (1991)

[Publications] 向山 雄人: "Cyclophosphamide,ThioーTEPA,Etoposideを用いた自家骨髄移植併用超大量化学療法の研究" 癌と化学療法. 17. 2207-2211 (1990)

[Publications] 向山 雄人: "臨床におけるPー糖タンパクの発現と多剤耐性克服の試み" BIO medica. 6. 22-27 (1991)

[Publications] Michihiko Kuwano: "Circumvention of multidrug resistance (MDR) and regulation of the MDR gene in response to enviromental stimuli" Cancer Chemotherapy:Challenges for the Future ed.by K.Kimura,Excerpta Medica,Tokyo,7, (1992)

[Publications] 石田 良司: "薬剤耐性細胞の分離ーアルキル化剤" 蛋白質核酸酵素, 30:195-198 (1991)

[Publications] 國元 節子: "抗がん抗生物質ー最近の話題" バイオサイエンスとインダストリ-, 49:379-382 (1991)

[Publications] 木岡 紀幸: "抗癌剤の耐性機序とその克服多剤耐性の分子機構" 腫瘍と感染, 3:443-450 (1990)

[Publications] Tomoki Naoe: "Polymerase chain reaction for the detection of the minimal residual B-cell clones usisng diversity of complementarity determining resion (CDR) III." Cancer Chemotherapy:Challenges for the future.(ed.by K.Kimura) Excerpta Medica, 6:54-59 (1991)

[Publications] Kimitoshi Kohno: "Drug resistance to DNA topoisomerase II-targeting agents and development of the reversal agents" DNA Topoisomerases in Chemotherapy.ed.by T.Andoh.CRC Press, (1992)

[Publications] Yoshikazu Sugimoto: "Development of multidrug resistance in rodent cell lines." "Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells".I.B.Roninson,ed.Plenum Press, 57-70 (1991)

[Publications] Taketo Mukaiyama: "High-Dose chemotherapy with autologous hematopoietic stem cell transplant for cancers." Cancer Chemotherapy:Challenges for the future (ed.by K.Kimura),Excepta Medica, 6:114-119 (1991)

桑野信彦大分医科大学, 医学部, 教授 (80037431)

[Publications] 向山雄人: "Cyclophosphamide,ThioーTEPA,Etoposideを用いた自家骨髄移植併用超大量化学療法の研究" 癌と化学療法. 17. 2207-2211 (1990)

[Publications] 向山雄人: "臨床におけるPー糖タンパクの発現と多剤耐性克服の試み" BIO medica. 6. 22-27 (1991)

[Publications] 石田良司: "薬剤耐性細胞の分離ーアルキル化剤" 蛋白質核酸酵素, 30:195-198 (1991)

[Publications] 國元節子: "抗がん抗生物質ー最近の話題" バイオサイエンスとインダストリ-, 49:379-382 (1991)

[Publications] 木岡紀幸: "抗癌剤の耐性機序とその克服多剤耐性の分子機構" 腫瘍と感染, 3:443-450 (1990)