1993 Fiscal Year Annual Research Report

ドラッグテ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	05151057
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)	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) 戸口始武田製薬, DDS研究所, 所長
Keywords	ドラッグデリバリーシステム / 血管新生阻害剤 / アンチセンス遺伝子 / 高分子化制癌剤
Research Abstract	1.ヒト型のキメラ抗体を開発し、その特性の解析とキメラ抗体と制癌剤(ネオカルチノスタチン、NCS)の複合体(chA7-NCS)の開発に成功した。本剤形の腫瘍集積性や大腸癌、胃癌、膵癌などで検討し、NCSの水溶液より優れた効果を持つことを明らかにした。 2.家兎移植腫瘍VX2に血管新生阻害剤TNP-470を含む3種の油性溶液を投与して、その抗腫瘍効果を検討したところ、ミグリオールに溶解したものが最も強い抗腫瘍効果を示した。 3.固形腫瘍に於ける高分子薬剤のEPR効果(enhanced permeability and retention effect)を利用するために、アンギオテンシン-II昇圧による高分子制癌剤スマンクスの腫瘍集積性向上について検討した。その結果、昇圧した場合スマンクスは非昇圧に比較して投与後6時間で3.4-5.7倍Walker256腫瘍に集積した。一方、骨髄や小腸などの正常組織ではむしろ昇圧によりスマンクス濃度が低下する傾向が認められた。 4.in vivoで癌遺伝子や癌抑制遺伝子、腫瘍血管新生因子に対するターゲティング療法を用いるために各種腫瘍細胞、特に大腸癌に於ける遺伝子変化を検索した。大腸癌培養細胞株5種に於けるK-ras,p53,c-myc,VEGFの4つの遺伝子の変異及び増幅を決定した。その結果3種のK-ras遺伝子の点突然変異と3種のp53遺伝子変異を認めた。又、2種にc-myc遺伝子の異常増幅を確認した。VEGFは大腸癌細胞株で高い発現が認められ、臨床材料でも正常組織より癌組織での増幅の多いことが確認された。 5.ラットWalker256癌肉腫の単離腫瘍還流実験系を用いて、マイトマイシンCの高分子化プロドラッグMMC-デキストランの腫瘍内投与後の薬剤動態を検討した。その結果、マイトマイシンC水溶液の場合には、マイトマイシンCは速やかに静脈系より流出し、MMC-デキストランの方が滞留性が良いことが分った。

Research Products

(25 results)

All Other

All Publications (25 results)

[Publications] Takahashi,T.: "Follow up study of patients treated with monoclonal antibody-drug conjugate:Report of 77 cases with colorectal cancer." Jpn.J.Cancer Res.84. 976-981 (1993)
[Publications] Kitamura,K.: "The role of monoclonal antibody A7 as a drug modifier in cancer therapy." Cancer Immunol Immunother. 36. 177-184 (1993)
[Publications] Kitamura,K.: "Enhanced lymphatic delivery of monoclonal antibody following OK432 pretreatment." Tohoku J.Exp.Med.169. 319-323 (1993)
[Publications] Kitamura,K.: "Inhibitory effect of monosialoganglioside on epidermal growth factor receptor dimerization." J.Kyoto Pref.Univ.Med.102. 973-977 (1993)
[Publications] Yamaguchi,T.: "Production,binding and cytotoxicity of human/mouse chimeric monoclonal antibody-neo-carzinostation conjugate." Jpn.J.Cancer Res.84. 1190-1194 (1993)
[Publications] Otsuji,E.: "Intratumoral administration of neocarzinostation conjugated to monoclonal antibody A7 in a model of pancreatic cancer." J.Surg.Oncl.53. 215-219 (1993)
[Publications] Otsuji,E.: "Increased Tumor localization by monoclonal antibody A7 after F9(ab')2 fragmentation in athymic nude mice bearing human" J.Surg.Oncl.53. 168-174 (1993)
[Publications] Otsuji,E.: "Enhanced tumor localization of radiolaveled Fabfragments of monoclonal antibody A7 in nude mice bearing human pancreatic" Jpn.J.Cancer.Res.84. 914-920 (1993)
[Publications] Otsuji,E.: "Increased antitumor effect of neocarzinostation conjugated to monoclonal antibody A7 on human pancreatic carcinoma grafted in nude mice." Antibody Immunoconjugate,and Radiophrmaceuticals.6. 177-183 (1993)
[Publications] Kamei,S.: "Antitumor effects of antigogenesisi inhibitor TNP-470 in rabbits bearing VX-2 carcinoma by arterial administration of microsphere and oil solution." J.Pharm.Exp.Therap.264. 469-474 (1993)
[Publications] Li,C.J.: "Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure." Br.J.Cancer. 67. 975-980 (1993)
[Publications] Kimura,M.: "Intracavitary treatment of malignant ascitic carcinomatosis with oily anticancer agents in rats." Anticancer Res.13. 1287-1292 (1993)
[Publications] Suzuki,T.: "Genetic alterations of human colorectal cancer" Jpn.J.Cancer Chemother.21. 3 (1994)
[Publications] Kanamaru,R.: "Mutation of the p53 gene and other genes involving in human colorectal carcinogenesis." Tohoku J.Exp.Med.168. 159-166 (1993)
[Publications] Kikuchi,H.: "Monolayer cultures from human tumor xenografts." The Cancer Journal. 6. 72-76 (1993)
[Publications] Tokuda,H.: "Specific uptake of succiniylated proteins via a scavengter receptor-mediated mechanism in cultured brain microvessel" Bichem.Biophys.Res.Commun.196. 18-24 (1993)
[Publications] Nishikawa,M.: "Synthesis and phrmacolinetics of a new liverspecific carrier,Glycosylated caboxymethyl-dextran and its application to drug" Pharm.Res.10. 1253-1264 (1993)
[Publications] Mihara,K.: "Disposition characteristics of proterin drugs in the perfused rat kidney.Pharm.Res." 10. 1993. (823-827)
[Publications] Takino,T.: "Controlled biodistribution of highly Lipophilic drugs with various parenteral formulations." J.Drug Targeting. 1. 117-124 (1993)
[Publications] Mihara,K.: "Disposition characteristics of model macromolecules in the perfused rata kidney." Biol.Pharm.Bull.16. 158-162 (1993)
[Publications] Furithu,H.: "Inhibitory effect of super oxide dismutase derivatives on ischemia/reperfusion injury" Drug Delivery System. 8. 49-52 (1993)
[Publications] Takahashi,T.: "Recent Adbances in Management of Digestive Cancers" Targeting chemotherapy for digestive cancer using monoclonal antibody drug conjugate., 115-120 (1993)
[Publications] Kitamura,K.: "Recent Advances in Management of Digestive Cancers." A new chemotherapy to reduce the local recurrence of rectal cancers., 582-584 (1993)
[Publications] Yamaguchi,T.: "Recent Advances in Management of Digestive Cancers." Radioimmunoimaging of local recurrenceof rectal cancer by rediolabeled mouse monoclonal antibody A7., 567-569 (1993)
[Publications] Otsuji,E.: "Recent Advances in Management of Digestive Cancers." Enhanced antitumor effect of neocarzinostatin conjugated to monoclonal antibody A7 on human pancreatic carcinoma grafted in nude mice, 771-773 (1993)

1993 Fiscal Year Annual Research Report

ドラッグテ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] Takahashi,T.: "Follow up study of patients treated with monoclonal antibody-drug conjugate:Report of 77 cases with colorectal cancer." Jpn.J.Cancer Res.84. 976-981 (1993)

[Publications] Kitamura,K.: "The role of monoclonal antibody A7 as a drug modifier in cancer therapy." Cancer Immunol Immunother. 36. 177-184 (1993)

[Publications] Kitamura,K.: "Enhanced lymphatic delivery of monoclonal antibody following OK432 pretreatment." Tohoku J.Exp.Med.169. 319-323 (1993)

[Publications] Kitamura,K.: "Inhibitory effect of monosialoganglioside on epidermal growth factor receptor dimerization." J.Kyoto Pref.Univ.Med.102. 973-977 (1993)

[Publications] Yamaguchi,T.: "Production,binding and cytotoxicity of human/mouse chimeric monoclonal antibody-neo-carzinostation conjugate." Jpn.J.Cancer Res.84. 1190-1194 (1993)

[Publications] Otsuji,E.: "Intratumoral administration of neocarzinostation conjugated to monoclonal antibody A7 in a model of pancreatic cancer." J.Surg.Oncl.53. 215-219 (1993)

[Publications] Otsuji,E.: "Increased Tumor localization by monoclonal antibody A7 after F9(ab')2 fragmentation in athymic nude mice bearing human" J.Surg.Oncl.53. 168-174 (1993)

[Publications] Otsuji,E.: "Enhanced tumor localization of radiolaveled Fabfragments of monoclonal antibody A7 in nude mice bearing human pancreatic" Jpn.J.Cancer.Res.84. 914-920 (1993)

[Publications] Otsuji,E.: "Increased antitumor effect of neocarzinostation conjugated to monoclonal antibody A7 on human pancreatic carcinoma grafted in nude mice." Antibody Immunoconjugate,and Radiophrmaceuticals.6. 177-183 (1993)

[Publications] Kamei,S.: "Antitumor effects of antigogenesisi inhibitor TNP-470 in rabbits bearing VX-2 carcinoma by arterial administration of microsphere and oil solution." J.Pharm.Exp.Therap.264. 469-474 (1993)

[Publications] Li,C.J.: "Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure." Br.J.Cancer. 67. 975-980 (1993)

[Publications] Kimura,M.: "Intracavitary treatment of malignant ascitic carcinomatosis with oily anticancer agents in rats." Anticancer Res.13. 1287-1292 (1993)

[Publications] Suzuki,T.: "Genetic alterations of human colorectal cancer" Jpn.J.Cancer Chemother.21. 3 (1994)

[Publications] Kanamaru,R.: "Mutation of the p53 gene and other genes involving in human colorectal carcinogenesis." Tohoku J.Exp.Med.168. 159-166 (1993)

[Publications] Kikuchi,H.: "Monolayer cultures from human tumor xenografts." The Cancer Journal. 6. 72-76 (1993)

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

[Publications] Nishikawa,M.: "Synthesis and phrmacolinetics of a new liverspecific carrier,Glycosylated caboxymethyl-dextran and its application to drug" Pharm.Res.10. 1253-1264 (1993)

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

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

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

[Publications] Furithu,H.: "Inhibitory effect of super oxide dismutase derivatives on ischemia/reperfusion injury" Drug Delivery System. 8. 49-52 (1993)

[Publications] Takahashi,T.: "Recent Adbances in Management of Digestive Cancers" Targeting chemotherapy for digestive cancer using monoclonal antibody drug conjugate., 115-120 (1993)

[Publications] Kitamura,K.: "Recent Advances in Management of Digestive Cancers." A new chemotherapy to reduce the local recurrence of rectal cancers., 582-584 (1993)

[Publications] Yamaguchi,T.: "Recent Advances in Management of Digestive Cancers." Radioimmunoimaging of local recurrenceof rectal cancer by rediolabeled mouse monoclonal antibody A7., 567-569 (1993)

[Publications] Otsuji,E.: "Recent Advances in Management of Digestive Cancers." Enhanced antitumor effect of neocarzinostatin conjugated to monoclonal antibody A7 on human pancreatic carcinoma grafted in nude mice, 771-773 (1993)

高橋俊雄京都府立医科大学, 医学部, 教授 (50079828)