1992 Fiscal Year Annual Research Report

腫瘍・宿主条件の系統的解析に基づく癌化学療法の最適化設計

Research Project

Project/Area Number	04151033
Research Institution	Kyoto University
Principal Investigator	橋田充京都大学, 薬学部, 教授 (20135594)
Co-Investigator(Kenkyū-buntansha)	内藤幹彦東京大学, 応用微生物研究所, 助手 (00198011) 谷川允彦福井医科大学, 助教授 (00111956) 田代田鶴子 (財)癌研究会癌化学療法センター, 研究員 (50085635) 西條長宏国立がんセンター研究所, 部長 (00215526) 加藤哲郎秋田大学, 医学部, 助教授 (40004642)
Keywords	癌化学療法 / 腫瘍・宿主条件 / 薬物送達システム / ファーマコキネティクス / 多剤耐性 / 化学塞栓療法 / モノクローナル抗体 / メタロチオネイン
Research Abstract	本研究では、癌化学療法の効果を決定する腫瘍・宿主側因子として、腫瘍細胞の生化学的、生物学的感受性、腫瘍が発生あるいは転移した部位の血行動態などの環境、全身レベルでの物質代謝動態などを取り上げ、それぞれに関する基礎研究を通じて個々の段階における治療効果の増強を図ると共に、併せて癌を俯瞰的に眺める立場より癌化学療法の最適化設計指針を確立することを目的として研究を行なった。以前からの研究の継続として、耐性克服、転移防止、進行癌の治療、副作用の制御など癌化学療法の隘路となっている諸問題について各領域毎に問題点を取り上げ、それを克服する具体的なアプローチを模索した結果、全体に共通する生物学的要因に対して理解と整理が進み、薬物送達システム(DDS)に代表される治療技術の開発が進展した。具体的には、例えば、シスプラチンやカンプトテシンに代表される抗癌剤の体内動態に関するファーマコキネティクス解析により、至適投与法が確立され奏功率の予測が可能となった。また、モノクローナル抗体、リポソームを利用したターゲティング療法や化学塞栓療法に関する基礎的・臨床的検討が進められ、こうした療法の効果と適用範囲を明確にすることができた。一方、抗癌剤に対する耐性獲得現象に関しても、P糖蛋白が関与する耐性機構や、未だ機構の不明なシスプラチン耐性腫瘍細胞株の耐性について検討が行われ、それぞれの耐性細胞に対してこれを克服する方法が提案されるに至った。さらに、抗癌剤の副作用を抑制する試みに関しても、メタロチオネイン誘導作用の強いビスマス化合物およビその投与法が見いだされ、臨床試験が計画されている。また、アンチセンスオリゴヌクレオチドを用いた遺伝子治療に対する基礎研究に対する取り組みもスタートした。

Research Products

(28 results)

All Other

All Publications (28 results)

[Publications] Mesegi,M.: "Permeability of macromolecules in cultured endothelial and tumor cell layers on microporous membranes" Int.J.Pharm.78. 103-113 (1992)
[Publications] Nishikawa,M.: "Demonstration of the receptor-mediated hepatic uptake of dextran in mice" J.Pharm.Pharmacol.44. 396-401 (1992)
[Publications] Imoto,H.: "Disposition characteristics of macromolecules in the perfused tissue-isolated tumor preparation" Cancer Res.52. 4396-4401 (1992)
[Publications] Fujita,T.: "Targeted delivery of human recombinant superoxide dismutase by chemical modification with mono- and polysaccharide derivatives" J.Pharmacol.Exp.Therap.263. 971-978 (1992)
[Publications] Mihara,K.: "Disposition characteristics of model macromolecules in the perfused rat kidney" Biol.Pharm.Bull.16. 158-162 (1993)
[Publications] Takino,T.: "Controlled biodistribution of highly lipophilic drugs with various parenteral formulations" J.Drug Targeting. 1. (1993)
[Publications] Sato,K.: "Immunohistological evaluation of c- erbB- 2 gene Product in transitional cell carcinoma of human urinary tract" Cancer. (1993)
[Publications] Kasahara,K.: "Determinants of response to the DNA topoisomerase II inhibitors doxorubicin and etoposide in human lung cancer cell lines" J.Natl.Cancer Inst.84. 113-118 (1992)
[Publications] Niimi,S.: "Mechanism of cross resistance to a captothecin analogue (cpt-11)in a human ovarian cancer cell line selected by cisplatin" Cancer Res.52. 328-333 (1992)
[Publications] Ohe,Y.: "Phase I study and pharmacokinetics of CPT-11 with 5-day continuous infusion" J.Natl.Cancer Inst.84. 972-974 (1992)
[Publications] Kubota,N.: "Detection of topoisomerase I gene point mutation in CPT-11 resistant lung cancer cell line" Biochem.Biophys.Res.Commun.188. 571-577 (1992)
[Publications] Tanigawa,N.: "In vitro growth ability and chemosensitivity of gastric and colorectal cancer cells assessed with the human tumour clonogenic assay and the thymidine incorporation assay" Eur.J.Cancer. 28. 31-34 (1992)
[Publications] Miya,T.: "Pharmacokinetic study of mitomycin C with emphasis on the influence of aging" Jpn.J.Cancer Res.83. 1382-1385 (1992)
[Publications] Saito,H.: "Chemosensitivity of hear and neck cancer with the rapid thymidine incorporation assay and its clinical applicatin" Eur.Arch.Oto-Rhino-Laryngol.249. 400-403 (1992)
[Publications] Tashiro,T.: "Characterization of resistance to cis-diammine-dichloroplatinum(II)in mouse leukemia cell lines" Jpn.J.Cancer Res.83. 219-225 (1992)
[Publications] Naito,M.: "Functionally active homodimer of P-glycoprotein in multidrugreistant tumor cells" Biochem.Biophys.Res.Commun.185. 284-290 (1992)
[Publications] Tatsuta,T.: "Functional involvement of P-glycoprotein in blood-brain barrier" J.Biol.Chem.267. 20383-20391 (1992)
[Publications] Naito,M.: "Reversal of multidrug resistance by an immunosuppressive agent FK-506" Cancer Chemother.Pharmacol.29. 195-200 (1992)
[Publications] Ishii,S.: "Expression of 85-kDa protein of adriamycin resistant tumor cells during hematopoietic differentiation of THP-1 and HEL cells" Jpn.J.Cancer Res.83. 107-112 (1992)
[Publications] Ariyoshi,K.: "Mouse-human chimeric antibody MH171 against the multidrug transporter P-glycoprotein" Jpn.J.Cancer Res.83. 515-521 (1992)
[Publications] Satoh,M.: "Effect of administration of selenite on toxicity and antitumor activity of cis-diamminedichloplatinum(II)administered repeatedly in mice" Cancer Chemother.Pharmacol.30. 439-443 (1992)
[Publications] Satoh,M.: "Effect of preinduction of metallothionein on paraquat toxicity in mice" Arch.Toxicol.66. 145-148 (1992)
[Publications] Satoh,M.: "Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis" Cancer Res.(1993)
[Publications] Satoh,M.: "Protection against lethal toxicity of various antitumor drug by preinduction of metallothionein synthesis in mice" J.Trace Elem.Exp.Med.(1993)
[Publications] Harashima,H.: "Kinetic analysis of tissue distribution of doxorubich incorporated in liposomes in rats:I" Biopharm.Drug Disp.13. 155-170 (1992)
[Publications] Noguchi,A.: "Preparation and properties of the immunoconjugate composed of anti-human colon cancer monclonal antibody and mitomycin C-dextran conjugate" Bioconjugate Chem.3. 132-137 (1992)
[Publications] Hashida,M.: "Drug targeting with macromolecular carrier systems.in“Perspectives in Medicinal Chemistry"(Eds.Testa,B.et al.)pp.545-558" Verlag Helvestica Chimica Acta,Besel, 644 (1993)
[Publications] Kato,T.: "Embolization of the kidney.in“Urological Oncology"(eds.Waxman,J.,Williams,G.)pp.216-230," Edward Arnold,London, (1992)

1992 Fiscal Year Annual Research Report

腫瘍・宿主条件の系統的解析に基づく癌化学療法の最適化設計

Principal Investigator

橋田 充 京都大学, 薬学部, 教授 (20135594)

Research Products

[Publications] Mesegi,M.: "Permeability of macromolecules in cultured endothelial and tumor cell layers on microporous membranes" Int.J.Pharm.78. 103-113 (1992)

[Publications] Nishikawa,M.: "Demonstration of the receptor-mediated hepatic uptake of dextran in mice" J.Pharm.Pharmacol.44. 396-401 (1992)

[Publications] Imoto,H.: "Disposition characteristics of macromolecules in the perfused tissue-isolated tumor preparation" Cancer Res.52. 4396-4401 (1992)

[Publications] Fujita,T.: "Targeted delivery of human recombinant superoxide dismutase by chemical modification with mono- and polysaccharide derivatives" J.Pharmacol.Exp.Therap.263. 971-978 (1992)

[Publications] Mihara,K.: "Disposition characteristics of model macromolecules in the perfused rat kidney" Biol.Pharm.Bull.16. 158-162 (1993)

[Publications] Takino,T.: "Controlled biodistribution of highly lipophilic drugs with various parenteral formulations" J.Drug Targeting. 1. (1993)

[Publications] Sato,K.: "Immunohistological evaluation of c- erbB- 2 gene Product in transitional cell carcinoma of human urinary tract" Cancer. (1993)

[Publications] Kasahara,K.: "Determinants of response to the DNA topoisomerase II inhibitors doxorubicin and etoposide in human lung cancer cell lines" J.Natl.Cancer Inst.84. 113-118 (1992)

[Publications] Niimi,S.: "Mechanism of cross resistance to a captothecin analogue (cpt-11)in a human ovarian cancer cell line selected by cisplatin" Cancer Res.52. 328-333 (1992)

[Publications] Ohe,Y.: "Phase I study and pharmacokinetics of CPT-11 with 5-day continuous infusion" J.Natl.Cancer Inst.84. 972-974 (1992)

[Publications] Kubota,N.: "Detection of topoisomerase I gene point mutation in CPT-11 resistant lung cancer cell line" Biochem.Biophys.Res.Commun.188. 571-577 (1992)

[Publications] Tanigawa,N.: "In vitro growth ability and chemosensitivity of gastric and colorectal cancer cells assessed with the human tumour clonogenic assay and the thymidine incorporation assay" Eur.J.Cancer. 28. 31-34 (1992)

[Publications] Miya,T.: "Pharmacokinetic study of mitomycin C with emphasis on the influence of aging" Jpn.J.Cancer Res.83. 1382-1385 (1992)

[Publications] Saito,H.: "Chemosensitivity of hear and neck cancer with the rapid thymidine incorporation assay and its clinical applicatin" Eur.Arch.Oto-Rhino-Laryngol.249. 400-403 (1992)

[Publications] Tashiro,T.: "Characterization of resistance to cis-diammine-dichloroplatinum(II)in mouse leukemia cell lines" Jpn.J.Cancer Res.83. 219-225 (1992)

[Publications] Naito,M.: "Functionally active homodimer of P-glycoprotein in multidrugreistant tumor cells" Biochem.Biophys.Res.Commun.185. 284-290 (1992)

[Publications] Tatsuta,T.: "Functional involvement of P-glycoprotein in blood-brain barrier" J.Biol.Chem.267. 20383-20391 (1992)

[Publications] Naito,M.: "Reversal of multidrug resistance by an immunosuppressive agent FK-506" Cancer Chemother.Pharmacol.29. 195-200 (1992)

[Publications] Ishii,S.: "Expression of 85-kDa protein of adriamycin resistant tumor cells during hematopoietic differentiation of THP-1 and HEL cells" Jpn.J.Cancer Res.83. 107-112 (1992)

[Publications] Ariyoshi,K.: "Mouse-human chimeric antibody MH171 against the multidrug transporter P-glycoprotein" Jpn.J.Cancer Res.83. 515-521 (1992)

[Publications] Satoh,M.: "Effect of administration of selenite on toxicity and antitumor activity of cis-diamminedichloplatinum(II)administered repeatedly in mice" Cancer Chemother.Pharmacol.30. 439-443 (1992)

[Publications] Satoh,M.: "Effect of preinduction of metallothionein on paraquat toxicity in mice" Arch.Toxicol.66. 145-148 (1992)

[Publications] Satoh,M.: "Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis" Cancer Res.(1993)

[Publications] Satoh,M.: "Protection against lethal toxicity of various antitumor drug by preinduction of metallothionein synthesis in mice" J.Trace Elem.Exp.Med.(1993)

[Publications] Harashima,H.: "Kinetic analysis of tissue distribution of doxorubich incorporated in liposomes in rats:I" Biopharm.Drug Disp.13. 155-170 (1992)

[Publications] Noguchi,A.: "Preparation and properties of the immunoconjugate composed of anti-human colon cancer monclonal antibody and mitomycin C-dextran conjugate" Bioconjugate Chem.3. 132-137 (1992)

[Publications] Hashida,M.: "Drug targeting with macromolecular carrier systems.in“Perspectives in Medicinal Chemistry"(Eds.Testa,B.et al.)pp.545-558" Verlag Helvestica Chimica Acta,Besel, 644 (1993)

[Publications] Kato,T.: "Embolization of the kidney.in“Urological Oncology"(eds.Waxman,J.,Williams,G.)pp.216-230," Edward Arnold,London, (1992)

橋田充京都大学, 薬学部, 教授 (20135594)