1994 Fiscal Year Annual Research Report

ドラッグデリバリーシステムを利用した癌のターゲティング療法

Research Project

Project/Area Number	06282119
Research Institution	Kyoto Prefectural University of Medicine
Principal Investigator	高橋俊雄京都府立医科大学, 医学部, 教授 (50079828)
Co-Investigator(Kenkyū-buntansha)	山口俊晴京都府立医科大学, 医学部, 講師 (90111327) 平野隆通産省, 工業技術院, 主任研究官橋田充京都大学, 薬学部, 教授 (20135594) 金丸龍之介東北大学, 加齢医学研究所, 教授 (70152783) 前田浩熊本大学, 医学部, 教授 (90004613)
Keywords	ドラッグデリバリーシステム / ターゲッティング / 癌転移 / 化学療法 / モノクローナル抗体 / 血管新生 / 遺伝子治療 / アンチセンスDNA
Research Abstract	(1)癌転移に対するターゲッティグ:リンパ行性、腹膜播種性転移に対するDDSとして我々が開発した活性炭吸着抗癌剤(MMC-CH)、ポリ乳酸封入抗癌剤(CDDP-MS)、高分子抗癌剤(MMC-D,MMC-DIVEMA)などの、生体内に於ける分布や代謝経路、毒性、について検討した。そしてその結果、これらの剤形はいずれも薬剤の徐放効果や、選択性を向上させるなど、優れた特性を持つことが証明された(高橋、前田、橋田、平野)。癌細胞レベルのターゲッティングとして、マウスモノクローナル抗体A7をヒト型に変換したキメラA7とNCSとの複合体C-A7-NCSを用い、その抗原性、癌特異性、効果等をin vitro,in vivoで検討しその優れた効果が実験的に確認された。一方、臨床応用のためにその毒性と最大耐量を決定するための臨床第1相試験が試みられ、その安全性が確認された。また、同時に検討されたヒトの複合体に対する免疫反応については、予想されたようにマウス抗体に比較して著しく改善されていることが確認された(高橋、山口)。 (2)血管新生抑制剤の腫瘍血管へのターゲッティング:血管新生抑制剤に腫瘍血管特異性を持たせるため、リピオドール、マイクロカプセルなどを用いて安定な剤形を作製した。これらを用いて実験腫瘍で効果を検討したところ、優れた増殖抑制効果が認められ、しかもこの効果が新生血管の抑制によるものであることが、血管の鋳型の検討から証明された。 (3)抗体を利用した癌遺伝子へのターゲッティング療法:遺伝子を選択的にin vivoで標的細胞に導入するために、モノクローナル抗体A7の利用するのが最終目的であるが、その前に基礎的な検討として、癌遺伝子の発現をアンチセンスDNAで阻害することができるか胃癌細胞で検討した。その結果、proliferating cell nuclear antigenのmessengerRNAに対するanti-sense Oligonucleotideが胃癌細胞の増殖を抑制することが証明された

Research Products

(29 results)

All Other

All Publications (29 results)

[Publications] Yamaguchi,T.: "In vivo efficacy of neocarzinostatin coupled with Fab human/mouse chimeric monoclonal antibody A7 against human colorectal cancer." Jpn.J.Cancer Res.85. 167-171 (1994)
[Publications] Shimotsuma,M.: "Ontogeny of milky spots in the fetal lamb omentum." Arch.Histol.Cytol.57. 291-299 (1994)
[Publications] Yamaoka,N.: "In vitro reactivity and in vivo biodistribution of the monoclonal antibody A7 using human gastric carcinoma cell lines.Br.J.Cancer 70:405-408,1994." Brit.J.Cancer. 70. 405-408 (1994)
[Publications] Otsuji,E: "Biodistribution of neocarzinostatin conjugatedto chimeric Fab fragments of the monoclonal antibody A7 in nude mice bearing human pancreatic cancer xenografts." Jpn.J.Cancer Res.85. 530-535 (1994)
[Publications] Takeuchi,K.: "Experimental study on the continuous infusion of 5-fluorouracil against VX2 tumors metastasizing to the liver of rabbits." J.Kyoto Pref.Univ.Med. 103. 913-921 (1994)
[Publications] Takahashi,T.: "Intraperitoneal chemotherapy with mitomycin C bound to activated carbon particlles for patients with advanced gastric cancer." European J,Surg.Oncol.20. 183-184 (1994)
[Publications] Uematsu,Y: "Restriction fragment length polymorphismof the human CYP2E1(cytochrome p450 II E1)geneand susuceptibility to lung cancer:possible relevance to low smoking exposure." Pharmacogenetics. 4. 58-63 (1994)
[Publications] Takino,T.: "Long circulating emulsion carrier systems for highly lipophilic drugs." Biological and Pharmaceutical Bulletin. 17. 121-125 (1994)
[Publications] Hashida,M.: "Targeting delivery of protein drugs by chemical modification." Indust.Pharmacy. 20. 581-591 (1994)
[Publications] Takakura,Y.: "Pharmacokinetics of succinylated proteins and dextran sulfate in mice:Implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors." Int.J.Pharmaceutics.105. 19-29 (1994)
[Publications] Yoshioka,T.: "Accumulation of 2-Deoxy-2(^<18>F)Fluoro-D-Glucose in human cancers hetero-transplanted in nude mice:comparison between histology and glycolytic status." J.Nuclear Med.35. 97-109 (1994)
[Publications] Iato,S.: "The cDNA sequence encoding mouse Mg^<2+>-dependent protein phospatase a." Gene. 145. 311-312 (1994)
[Publications] Hirano,T.: "Synthesis of the conjugate of superoxide dismutase with the copolymer of divinyl ether and maleic anhydride retaining enzymatic activity." J.Control.Release. 28. 203-209 (1994)
[Publications] Sato,K.: "Generation of free radicals neocarzinostatin mediated by NADPH/cytochrome p-450 reductase via activation of enediyne chromophore." Biochem.Biophys.Res.Commun.205. 1716-1723 (1994)
[Publications] Fujita,T.: "Control of invivo fate of albumin derivatives utilizing combined chemical modification." J.Drug Targeting. 2. 157-165 (1994)
[Publications] Hashida,M.: "Pharmacokinetics in design of polymeric drug delivery systems." J.Controlled Release. 31. 163-171 (1994)
[Publications] Mihara,K.: "Improvement of therapeutic effect of human recombinant superoxide dismutase on ischemic acute renal failure in the rat via ca-tionization and conjugation with polyethylene glycol." J.Drug Targeting. 2. 317-321 (1994)
[Publications] Takino,T.: "Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system." Int.J.Pharmaceutics. 114. 43-54 (1994)
[Publications] Takakura,Y: "Macromolecular drug carrier systems in cancer chemotherapy:Macro-molecular prodrugs" Crit.Rev.in Oncol.and Hematology. 18. 207-231 (1994)
[Publications] Kitamura,K.: "Identification by activated carbon injection of cancer lesion during laparoscopic surgery." The Lancet. 789. 789 (1994)
[Publications] Hagiwara,A.: "Selective delivery of a greater amount of methotrexate to regional lymph nodes using a new dosage formulation,methotrexate adsorbed on activated carbon particles,in rats." Anti-Cancer Drugs. 5. 194-198 (1994)
[Publications] Hagiwara,A: "Reduced toxicity of a new formulation-Peplomycin adsorbed on activated carbon particles-in mice." Anti-Cancer Drugs. 5. 31-34 (1994)
[Publications] Sakakura,C.: "Growth inhibition and induction of differentiation of t(8;21)acute myeloid leukemia cells by the DNA-Binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisense oligonucleotide." Proc.Natl.Acad.Sa.U.S.A.91. 11723-11727 (1994)
[Publications] Sakakura,C.: "Inhibition of gastric cancer cell proliferation by antisense oligonucleotides targeting the messenger RNA encoding proliferating cell nuclear antigen." Brit.J.Cancer. 70. 1060-1066 (1994)
[Publications] Maeda,H: "Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both new nitric oxide scavenger and nitric oxide synthase inhibitor." Jpn.J.Cancer Res.85. 331-334 (1994)
[Publications] Maeda,H.: "Drug Absorption Enhancement.(ed.A.G.de Boer)Harwood Academic Publishers GmbH,Netherlands." Oily formulations of protein drugs for arterial injection and for oral administration., 221-247 (1994)
[Publications] Maeda,H.: "Polymeric Site-Specific Pharmacotherapy.(ed.A.J.Domb)John Wiley & Sons Ltd.,New York." Polymer conjugated macromolecular drugs for tumor-specific targeting., 95-116 (1994)
[Publications] Maeda,H.: "Enediyne Antibiotics as Antitumor Agents(eds.D.B.Borders and T.W.Doyle),Marcel Dekker,Inc." The clinical effects of neocarzino-statin and its polymer conjugate,SMANCS., 363-381 (1994)
[Publications] Sugiyama,K.: "Cancer Treatment An Updatae(ed.by P.Pancet,J.F.Holl and,Dkhayat,M.Weil),Springer-Verlag,Paris," Neo-adjuvant chemotherapy for advanced gastricn cancer:a pilot study with angiotensin II induced drug delivery sistem., 393-395 (1994)

1994 Fiscal Year Annual Research Report

ドラッグデリバリーシステムを利用した癌のターゲティング療法

Principal Investigator

高橋 俊雄 京都府立医科大学, 医学部, 教授 (50079828)

Research Products

[Publications] Yamaguchi,T.: "In vivo efficacy of neocarzinostatin coupled with Fab human/mouse chimeric monoclonal antibody A7 against human colorectal cancer." Jpn.J.Cancer Res.85. 167-171 (1994)

[Publications] Shimotsuma,M.: "Ontogeny of milky spots in the fetal lamb omentum." Arch.Histol.Cytol.57. 291-299 (1994)

[Publications] Yamaoka,N.: "In vitro reactivity and in vivo biodistribution of the monoclonal antibody A7 using human gastric carcinoma cell lines.Br.J.Cancer 70:405-408,1994." Brit.J.Cancer. 70. 405-408 (1994)

[Publications] Otsuji,E: "Biodistribution of neocarzinostatin conjugatedto chimeric Fab fragments of the monoclonal antibody A7 in nude mice bearing human pancreatic cancer xenografts." Jpn.J.Cancer Res.85. 530-535 (1994)

[Publications] Takeuchi,K.: "Experimental study on the continuous infusion of 5-fluorouracil against VX2 tumors metastasizing to the liver of rabbits." J.Kyoto Pref.Univ.Med. 103. 913-921 (1994)

[Publications] Takahashi,T.: "Intraperitoneal chemotherapy with mitomycin C bound to activated carbon particlles for patients with advanced gastric cancer." European J,Surg.Oncol.20. 183-184 (1994)

[Publications] Uematsu,Y: "Restriction fragment length polymorphismof the human CYP2E1(cytochrome p450 II E1)geneand susuceptibility to lung cancer:possible relevance to low smoking exposure." Pharmacogenetics. 4. 58-63 (1994)

[Publications] Takino,T.: "Long circulating emulsion carrier systems for highly lipophilic drugs." Biological and Pharmaceutical Bulletin. 17. 121-125 (1994)

[Publications] Hashida,M.: "Targeting delivery of protein drugs by chemical modification." Indust.Pharmacy. 20. 581-591 (1994)

[Publications] Takakura,Y.: "Pharmacokinetics of succinylated proteins and dextran sulfate in mice:Implications for hepatic targeting of protein drugs by direct succinylation via scavenger receptors." Int.J.Pharmaceutics.105. 19-29 (1994)

[Publications] Yoshioka,T.: "Accumulation of 2-Deoxy-2(^<18>F)Fluoro-D-Glucose in human cancers hetero-transplanted in nude mice:comparison between histology and glycolytic status." J.Nuclear Med.35. 97-109 (1994)

[Publications] Iato,S.: "The cDNA sequence encoding mouse Mg^<2+>-dependent protein phospatase a." Gene. 145. 311-312 (1994)

[Publications] Hirano,T.: "Synthesis of the conjugate of superoxide dismutase with the copolymer of divinyl ether and maleic anhydride retaining enzymatic activity." J.Control.Release. 28. 203-209 (1994)

[Publications] Sato,K.: "Generation of free radicals neocarzinostatin mediated by NADPH/cytochrome p-450 reductase via activation of enediyne chromophore." Biochem.Biophys.Res.Commun.205. 1716-1723 (1994)

[Publications] Fujita,T.: "Control of invivo fate of albumin derivatives utilizing combined chemical modification." J.Drug Targeting. 2. 157-165 (1994)

[Publications] Hashida,M.: "Pharmacokinetics in design of polymeric drug delivery systems." J.Controlled Release. 31. 163-171 (1994)

[Publications] Mihara,K.: "Improvement of therapeutic effect of human recombinant superoxide dismutase on ischemic acute renal failure in the rat via ca-tionization and conjugation with polyethylene glycol." J.Drug Targeting. 2. 317-321 (1994)

[Publications] Takino,T.: "Pharmacokinetic disposition analysis of lipophilic drugs injected with various lipid carriers in the single-pass rat liver perfusion system." Int.J.Pharmaceutics. 114. 43-54 (1994)

[Publications] Takakura,Y: "Macromolecular drug carrier systems in cancer chemotherapy:Macro-molecular prodrugs" Crit.Rev.in Oncol.and Hematology. 18. 207-231 (1994)

[Publications] Kitamura,K.: "Identification by activated carbon injection of cancer lesion during laparoscopic surgery." The Lancet. 789. 789 (1994)

[Publications] Hagiwara,A.: "Selective delivery of a greater amount of methotrexate to regional lymph nodes using a new dosage formulation,methotrexate adsorbed on activated carbon particles,in rats." Anti-Cancer Drugs. 5. 194-198 (1994)

[Publications] Hagiwara,A: "Reduced toxicity of a new formulation-Peplomycin adsorbed on activated carbon particles-in mice." Anti-Cancer Drugs. 5. 31-34 (1994)

[Publications] Sakakura,C.: "Growth inhibition and induction of differentiation of t(8;21)acute myeloid leukemia cells by the DNA-Binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisense oligonucleotide." Proc.Natl.Acad.Sa.U.S.A.91. 11723-11727 (1994)

[Publications] Sakakura,C.: "Inhibition of gastric cancer cell proliferation by antisense oligonucleotides targeting the messenger RNA encoding proliferating cell nuclear antigen." Brit.J.Cancer. 70. 1060-1066 (1994)

[Publications] Maeda,H: "Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both new nitric oxide scavenger and nitric oxide synthase inhibitor." Jpn.J.Cancer Res.85. 331-334 (1994)

[Publications] Maeda,H.: "Drug Absorption Enhancement.(ed.A.G.de Boer)Harwood Academic Publishers GmbH,Netherlands." Oily formulations of protein drugs for arterial injection and for oral administration., 221-247 (1994)

[Publications] Maeda,H.: "Polymeric Site-Specific Pharmacotherapy.(ed.A.J.Domb)John Wiley & Sons Ltd.,New York." Polymer conjugated macromolecular drugs for tumor-specific targeting., 95-116 (1994)

[Publications] Maeda,H.: "Enediyne Antibiotics as Antitumor Agents(eds.D.B.Borders and T.W.Doyle),Marcel Dekker,Inc." The clinical effects of neocarzino-statin and its polymer conjugate,SMANCS., 363-381 (1994)

[Publications] Sugiyama,K.: "Cancer Treatment An Updatae(ed.by P.Pancet,J.F.Holl and,Dkhayat,M.Weil),Springer-Verlag,Paris," Neo-adjuvant chemotherapy for advanced gastricn cancer:a pilot study with angiotensin II induced drug delivery sistem., 393-395 (1994)

高橋俊雄京都府立医科大学, 医学部, 教授 (50079828)