1993 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	05151037
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) 田代田鶴子 (財)癌研究会, 癌化学療法センター, 研究員 (50085635) 谷川允彦福井医科大学, 助教授 (00111956) 加藤哲郎秋田大学, 医学部, 助教授 (40004642) 西條長宏国立がんセンター研究所, 部長 (00215526)
Keywords	癌化学療法 / ドラッグデリバリーシステム / ターゲティング / 多剤耐性 / 転移 / 遺伝子治療 / 腫瘍ワクチン / 抗癌剤感受性
Research Abstract	本研究班では、癌化学療法の効果を決定する腫瘍・宿主側因子を総合的に抽出し、それぞれに関する基礎研究を通じて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に研究を行っている。今年度は、臨床、基礎等のそれぞれの分野で最適癌化学療法を実現する上で隘路となっている各種問題点の克服法について具体的に検討し研究の完成を図った。具体的な成果として、抗体等を用いる抗癌剤ターゲティングDDSの開発に関し、分子特性と体内動態の関係が速度論的に解析され、DDSの分子設計の指針が得られた。また、ファーマコダイナミクスの立場に基づく抗癌剤の投与設計に関しても進展がみられた。また、癌の増殖や転移に伴う抗癌剤感受性の変化、あるいは血管新生等と関連した組織構築の変化について情報が集積され、これらを踏まえた癌化学療法のあり方について検討が行われた。他剤耐性現象の克服法の関発についても研究が進展し、さらに新しい課題として、細胞内抗酸化因子の活性と抗癌剤感受性との関係についても解析が行われた。遺伝子治療に対する基礎研究も重要課題として取り上げたが、その中で腫瘍ワクチンの開発を目的に、癌細胞に各種サイトカインや接着因子などの遺伝子を発現させるためのベクターの開発を進めると共に、ワクチンと免疫修飾薬との併用効果についても検討を行いその有用性を報告した。また、プラスミドDNAの一般的な生体内安定性や体内分布挙動についても、有用な知見を得た。

Research Products
(23 results)

All Other

All Publications (23 results)

[Publications] Nishikawa,M.: "Synthesis and pharmacokinetics of a new liver-specific carrier,glycosy-lated carboxymethyl-dextran,and its application to drug targeting" Pharm.Res.10. 1253-1264 (1993)
[Publications] Tokuda,H.: "Specific uptake of succinylated proteins via a scavenger receptor-mediated mechanism in cultured brain microvessel endothelial cells" Biochem.Biophys.Res.Commun.196. 18-24 (1993)
[Publications] Takino,T.: "Controlled biodistribution of highly lipophilic drugs with various parenteral" J.Drug Targeting. 1. 117-124 (1993)
[Publications] Mihara,K.: "Disposition characteristics of protein drugs in the perfused rat kidney" Pharm.Res.10. 823-827 (1993)
[Publications] Hashida,M.: "Targeting Delivery of protein drugs by chemical modification" Drug Dev.Ind.Pharm.20. 581-590 (1994)
[Publications] Takino,T.: "Long circulating emulsion carrier systems for highly lipophilic drugs" Biol.Pharm.Bull.17. 121-125 (1993)
[Publications] Ohe,Y.: "Combination effect of vaccination with IL2 and IL4 cDNA transfected cells on the induction of a therapeutic immune response against lewis lung carcinoma cells" Int.J.Cancer. 53. 432-437 (1993)
[Publications] Nishio,M.: "Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer" Jpn.J.Clin,.Oncol.23. 284-290 (1993)
[Publications] Karato,A.: "Phase I study of CPT-11 and etoposide in patients with refractory solid tumors" J.Clin.Oncol.11. 2030-2035 (1993)
[Publications] Sato,K.: "Granulocyte colony-stimulating factor produced by bladder carcinoma of a patient with leukemoid reaction did not affect proliferation of the tumor cells" J.Urol.(in press).
[Publications] Tanigawa,N.: "Thymidine uptake in vitro as a prognostic indicator for primary gastric cancer" Cancer. 72. 2883-2888 (1993)
[Publications] Tanigawa,N.: "Detection of P-glycoprotein in solid tumors by flow cytometry" Anticancer Res.13. 2171-2176 (1993)
[Publications] Tashiro,T.: "Mechanisms for reduced drug accumulation in cisplatin-resistant sublines of human small cell lung cancer cell lines" KURRI Prog.Rep.1992. 270-271 (1993)
[Publications] Naito,M.: "Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance" J.Natl.Cancer Inst.85. 311-316 (1993)
[Publications] Naito,M.: "Enhancement of reversing effect of cyclosporin A on vincristine resistance by anti-P-glycoprotein monoclonal antibody MRK-16" Jpn.J.Cancer Res.84. 489-492 (1993)
[Publications] Noguchi,K.: "cDNA expression cloning of the 85-kDa protein overexpressed in adriamycin-resistant cells" Biochem.Biophys.Res.Commun.192. 88-95 (1993)
[Publications] Satoh,M.: "Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis" Cancer.Res.53. 1829-1832 (1993)
[Publications] Kondo,Y.: "Tissue-specific induction of metallothionein by bismuth as a promising protocol for chemotherapy with repeated administration of cis-diamminedichloroplatinum(II)against bladder tumor" Anticancer Res.12. 2303-2308 (1993)
[Publications] Satoh,M.: "Prevention of carcinogenicity of anticancer drugs by metallothionein induction" Cancer Res.53. 4767-4768 (1993)
[Publications] Sugimoto,Y.: "Molecular cloning and characterization of the complementary DNA for the Mr 85,000 Protein overexpressed in Adriamycin-resistant human tumor cells" Cancer Res.53. 2538-2543 (1993)
[Publications] Dranoff,G.: "Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent,specific,and long-lasting anti-tumor immunity" Proc.Natl.Acad.Sci.USA. 90. 3539-3543 (1993)
[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,Basel, 644 (1993)
[Publications] Hanada,H.: "Strategies for immunogene therapy against cancer.in"Excerpta Medical International Congress Series"" Excerpta Medica,Tokyo(in press), (1994)

1993 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] Nishikawa,M.: "Synthesis and pharmacokinetics of a new liver-specific carrier,glycosy-lated carboxymethyl-dextran,and its application to drug targeting" Pharm.Res.10. 1253-1264 (1993)

[Publications] Tokuda,H.: "Specific uptake of succinylated proteins via a scavenger receptor-mediated mechanism in cultured brain microvessel endothelial cells" Biochem.Biophys.Res.Commun.196. 18-24 (1993)

[Publications] Takino,T.: "Controlled biodistribution of highly lipophilic drugs with various parenteral" J.Drug Targeting. 1. 117-124 (1993)

[Publications] Mihara,K.: "Disposition characteristics of protein drugs in the perfused rat kidney" Pharm.Res.10. 823-827 (1993)

[Publications] Hashida,M.: "Targeting Delivery of protein drugs by chemical modification" Drug Dev.Ind.Pharm.20. 581-590 (1994)

[Publications] Takino,T.: "Long circulating emulsion carrier systems for highly lipophilic drugs" Biol.Pharm.Bull.17. 121-125 (1993)

[Publications] Ohe,Y.: "Combination effect of vaccination with IL2 and IL4 cDNA transfected cells on the induction of a therapeutic immune response against lewis lung carcinoma cells" Int.J.Cancer. 53. 432-437 (1993)

[Publications] Nishio,M.: "Pharmacokinetic re-evaluation and phase I study of high dose epirubicin in advanced non-small cell lung cancer" Jpn.J.Clin,.Oncol.23. 284-290 (1993)

[Publications] Karato,A.: "Phase I study of CPT-11 and etoposide in patients with refractory solid tumors" J.Clin.Oncol.11. 2030-2035 (1993)

[Publications] Sato,K.: "Granulocyte colony-stimulating factor produced by bladder carcinoma of a patient with leukemoid reaction did not affect proliferation of the tumor cells" J.Urol.(in press).

[Publications] Tanigawa,N.: "Thymidine uptake in vitro as a prognostic indicator for primary gastric cancer" Cancer. 72. 2883-2888 (1993)

[Publications] Tanigawa,N.: "Detection of P-glycoprotein in solid tumors by flow cytometry" Anticancer Res.13. 2171-2176 (1993)

[Publications] Tashiro,T.: "Mechanisms for reduced drug accumulation in cisplatin-resistant sublines of human small cell lung cancer cell lines" KURRI Prog.Rep.1992. 270-271 (1993)

[Publications] Naito,M.: "Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance" J.Natl.Cancer Inst.85. 311-316 (1993)

[Publications] Naito,M.: "Enhancement of reversing effect of cyclosporin A on vincristine resistance by anti-P-glycoprotein monoclonal antibody MRK-16" Jpn.J.Cancer Res.84. 489-492 (1993)

[Publications] Noguchi,K.: "cDNA expression cloning of the 85-kDa protein overexpressed in adriamycin-resistant cells" Biochem.Biophys.Res.Commun.192. 88-95 (1993)

[Publications] Satoh,M.: "Modulation of both cisplatin nephrotoxicity and drug resistance in murine bladder tumor by controlling metallothionein synthesis" Cancer.Res.53. 1829-1832 (1993)

[Publications] Kondo,Y.: "Tissue-specific induction of metallothionein by bismuth as a promising protocol for chemotherapy with repeated administration of cis-diamminedichloroplatinum(II)against bladder tumor" Anticancer Res.12. 2303-2308 (1993)

[Publications] Satoh,M.: "Prevention of carcinogenicity of anticancer drugs by metallothionein induction" Cancer Res.53. 4767-4768 (1993)

[Publications] Sugimoto,Y.: "Molecular cloning and characterization of the complementary DNA for the Mr 85,000 Protein overexpressed in Adriamycin-resistant human tumor cells" Cancer Res.53. 2538-2543 (1993)

[Publications] Dranoff,G.: "Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent,specific,and long-lasting anti-tumor immunity" Proc.Natl.Acad.Sci.USA. 90. 3539-3543 (1993)

[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,Basel, 644 (1993)

[Publications] Hanada,H.: "Strategies for immunogene therapy against cancer.in"Excerpta Medical International Congress Series"" Excerpta Medica,Tokyo(in press), (1994)

橋田充京都大学, 薬学部, 教授 (20135594)