1998 年度実績報告書

分子標的治療の臨床応用へのアプローチ

研究課題

研究課題/領域番号	09255104
研究機関	名古屋市立大学
研究代表者	上田龍三名古屋市立大学, 医学部, 教授 (20142169)
研究分担者	大野竜三浜松医科大学, 教授 (70093002) 花井陳雄協和醗酵, 東京研究所, 主任研究員真弓忠範大阪大学, 大学院・薬学研究科, 教授 (00098485) 遠藤啓吾群馬大学, 医学部, 教授 (10115800) 山口俊晴京都府立医科大学, 助教授 (90111327)
キーワード	抗体療法 / ヒト化抗体 / 癌組織血管 / RI標識抗体結合物 / GVHD予防 / 分化誘導療法 / 新規分子標的 / Surrogateマーカー
研究概要	1) 抗体療法の基礎研究から臨床導入に関して発現ベクターを骨髄腫細胞に導入してヒト化抗体の恒常的発現細胞の作製に成功。N末端に標識ペプチドをコードする遺伝子を付加した標識ヒト化抗体の発現にも成功した。(花井) 癌組織血管を標的として癌組織血管内皮細胞に対するモノクローナル抗体(TES-23抗体)を作製し検討した。本抗体は正常組織細胞や正常血管内皮の反応は弱く、ヒト癌組織の血管内皮と癌種を越えて反応した、抗体単独静脈内投与にて、著明な抗腫瘍効果を示した。(真弓) 臨床応用として、RI標識抗体結合物を用いた画像診断、癌治療を目的として大腸癌肝転移を対象に標識CEA抗体及び悪性リンパ種を対象に、抗CD20抗体を検討中。(遠藤)また、造血器腫瘍における抗体療法として、CD34抗体陽性幹細胞移植の有効性,移植後GVHD予防を目的とした抗CD6抗体によるT細胞パージングの第1相,第2相試験を施行中(上田),固形癌に対する応用として、大腸癌を対象として抗CEA抗体にネオカルチンスタチンの複合体が抗癌剤との併用効果を示した。臨床プロトコールの検討中。(山口) 2) 分化誘導療法に関しては、レチノイン酸抵抗性の克服として、新規レチノイドAM-80の有用性が判明(大野),9-cis tretinoin tocoferilがAPに対して有効、数種の新規分化誘導剤の候補を選択(本間)。 3) がん化学療法剤の新規分子標的として、チオレドキシン(TRX)やTRXレダクターゼの発現・活性がシスプラチンやプレオマイシン耐性に関与(淀井),Cytostaticな新規抗癌剤UCN-01のSurrogateマーカーとしてp21の臨床応用への可能性が得られ、新規分子標的治療剤の評価基準として期待された。(西條)

研究成果

(23件)

すべてその他

すべて文献書誌 (23件)

[文献書誌] Sao,H.: "A new marrow T cell depletion method using anti-CD6 monoclonal antibody conjugated magnetic beads,and its clinical application for prevention of acute graft-versus-host disease in allogeneic bone marrow transplatation-the results of phase I-II trial." Int.J.Hematol.(in press)
[文献書誌] Nakayama,M.: "Hypometholation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias." Blood. 92(11). 4296-4307 (1998)
[文献書誌] Ni,H.: "Detection of fusion transcripts by semiquantitative multiplex RT-PCR combined with a colormetric assay in Ph positive leukemia." Cancer Letters. 124. 174-180 (1998)
[文献書誌] Yamaguchi,T.: "Changes in expression of the antigen recognized by monoclonal antibody A7 in human pancreatic carcinoma cells." Cancer Letters. 126. 165-172 (1998)
[文献書誌] Oriuchi,N.: "Antibody-dependent difference in biodistribution of monoclonal antibodies in animal models and humans." Cancer Immunol.Immunother. 46. 311-317 (1998)
[文献書誌] Inoue,T.: "Biodistribution studies on 1-3-[fluorine-18] fluoro-α-methyl tyrosine : A potential tumor-detecting agent." J.Nucl.Med.39. 663-667 (1998)
[文献書誌] Higuchi,T.: "Technetium-99m labeled chimeric human/mouse antigranulocyte antibody bone marrow scintigraphy : Preliminary clinical study." Nucl.Med.Commun.19. 463-474 (1998)
[文献書誌] Ohizumi,I.: "Monoclonal antibodies recognize antigens expressed on rat tumor vasculature." Int.J.Cancer. 77. 561-566 (1998)
[文献書誌] Kaneda,Y.: "Antitumor activity of tumor necrosis factor-α conjugated with diviny ether and maleic anhydride copolymer on solid tumors in mice." Cancer Res.58. 290-295 (1998)
[文献書誌] Catimel,B.: "Direct immobilization of gangliosides onto gold-carboxymethyldextran sensor surfaces by hydrophobic interaction : applications to antibody characterization." Glycobioloby. 8. 927-938 (1998)
[文献書誌] Takeuchi,M.: "Relapsed acute promyelocytic leukemia previously treated with all-trans retionic acid : clinical experience with a new synthetic retinoid,am-80." Leukemia and Lymphoma. (in press).
[文献書誌] Zhang, W.: "The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms." Leukemia. 12. 1383-1391 (1998)
[文献書誌] Makishima,M.: "Induction of differentiation in acute promyelocytic leukemia cells by 9-cis retionic acid α-tocopherol ester (9-cis tretinoine tocopheril)." Blood. 91. 4715-4726 (1998)
[文献書誌] Ohnishi,K.: "Modulation of homeobox B6 and B9 genes expression in human leukemia cell lines during myelomonocytic differentiation" Leuk Lymphoma. 12. 1383-1391 (1998)
[文献書誌] Mizuguchi,H.: "Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes in-to the artery that leads to tumors" Cancer Res.(in press).
[文献書誌] Niitsu,N.: "Human monocytoid leukemia cells are highly sensitive to apoptosis induced by 2'-deoxycoformycin and 2'-deoxyaden osine : Association with dATP-dependent activation of caspase-3." Blood. 92. 3368-3375 (1998)
[文献書誌] Kanatani,Y.: "A novel uracil analog, 6-chloro-5-(2-propenyl)uracil preferentially enhances growth inhibition and differentiation of myeloid leukemia cells induced by 1α,25 dihydroxyvitamin D3." Exp.Hematol.26. 198-206 (1998)
[文献書誌] Yokoyama,A.: "Evaluation by multivariate analysis of the differen-tiation inhibitory factor nm23 as a prognostic factor in acute myelogenous leukemia and application to other hematological malignancies." Blood. 91. 1845-1851 (1998)
[文献書誌] Ueda,S.: "Redox regulation of caspase-3(-like)protease activity : Regulatory roles of thioredoxin and cytochromec." J.Immunol.161. 6689-6695 (1998)
[文献書誌] Yoshida,M.: "Mechanism of antitumor action of PKC activator,gnidimacrin." Int.J.Cancer. 77. 243-250 (1998)
[文献書誌] Hana,S.: "Adenovirus-mediated p16 gene transfer prevents drug-induced cell death through G1 arrest in human glioma cells." Int.J.Cancer. 77. 47-54 (1998)
[文献書誌] Kasai,T.: "Factors that influence the eligibility of cancers for inclusion in clinical trials." Jpn.J.Clin.Oncol.28. 214-221 (1998)
[文献書誌] Chen,Z.S.: "An active efflux system for heavy metals in cisplatin-resistant human KB carcinoma cells." Exp.Cell Res.240. 312-320 (1998)

1998 年度 実績報告書

分子標的治療の臨床応用へのアプローチ

研究代表者

上田 龍三 名古屋市立大学, 医学部, 教授 (20142169)

研究成果

[文献書誌] Nakayama,M.: "Hypometholation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias." Blood. 92(11). 4296-4307 (1998)

[文献書誌] Ni,H.: "Detection of fusion transcripts by semiquantitative multiplex RT-PCR combined with a colormetric assay in Ph positive leukemia." Cancer Letters. 124. 174-180 (1998)

[文献書誌] Yamaguchi,T.: "Changes in expression of the antigen recognized by monoclonal antibody A7 in human pancreatic carcinoma cells." Cancer Letters. 126. 165-172 (1998)

[文献書誌] Oriuchi,N.: "Antibody-dependent difference in biodistribution of monoclonal antibodies in animal models and humans." Cancer Immunol.Immunother. 46. 311-317 (1998)

[文献書誌] Inoue,T.: "Biodistribution studies on 1-3-[fluorine-18] fluoro-α-methyl tyrosine : A potential tumor-detecting agent." J.Nucl.Med.39. 663-667 (1998)

[文献書誌] Higuchi,T.: "Technetium-99m labeled chimeric human/mouse antigranulocyte antibody bone marrow scintigraphy : Preliminary clinical study." Nucl.Med.Commun.19. 463-474 (1998)

[文献書誌] Ohizumi,I.: "Monoclonal antibodies recognize antigens expressed on rat tumor vasculature." Int.J.Cancer. 77. 561-566 (1998)

[文献書誌] Kaneda,Y.: "Antitumor activity of tumor necrosis factor-α conjugated with diviny ether and maleic anhydride copolymer on solid tumors in mice." Cancer Res.58. 290-295 (1998)

[文献書誌] Catimel,B.: "Direct immobilization of gangliosides onto gold-carboxymethyldextran sensor surfaces by hydrophobic interaction : applications to antibody characterization." Glycobioloby. 8. 927-938 (1998)

[文献書誌] Takeuchi,M.: "Relapsed acute promyelocytic leukemia previously treated with all-trans retionic acid : clinical experience with a new synthetic retinoid,am-80." Leukemia and Lymphoma. (in press).

[文献書誌] Zhang, W.: "The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms." Leukemia. 12. 1383-1391 (1998)

[文献書誌] Makishima,M.: "Induction of differentiation in acute promyelocytic leukemia cells by 9-cis retionic acid α-tocopherol ester (9-cis tretinoine tocopheril)." Blood. 91. 4715-4726 (1998)

[文献書誌] Ohnishi,K.: "Modulation of homeobox B6 and B9 genes expression in human leukemia cell lines during myelomonocytic differentiation" Leuk Lymphoma. 12. 1383-1391 (1998)

[文献書誌] Mizuguchi,H.: "Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes in-to the artery that leads to tumors" Cancer Res.(in press).

[文献書誌] Niitsu,N.: "Human monocytoid leukemia cells are highly sensitive to apoptosis induced by 2'-deoxycoformycin and 2'-deoxyaden osine : Association with dATP-dependent activation of caspase-3." Blood. 92. 3368-3375 (1998)

[文献書誌] Kanatani,Y.: "A novel uracil analog, 6-chloro-5-(2-propenyl)uracil preferentially enhances growth inhibition and differentiation of myeloid leukemia cells induced by 1α,25 dihydroxyvitamin D3." Exp.Hematol.26. 198-206 (1998)

[文献書誌] Yokoyama,A.: "Evaluation by multivariate analysis of the differen-tiation inhibitory factor nm23 as a prognostic factor in acute myelogenous leukemia and application to other hematological malignancies." Blood. 91. 1845-1851 (1998)

[文献書誌] Ueda,S.: "Redox regulation of caspase-3(-like)protease activity : Regulatory roles of thioredoxin and cytochromec." J.Immunol.161. 6689-6695 (1998)

[文献書誌] Yoshida,M.: "Mechanism of antitumor action of PKC activator,gnidimacrin." Int.J.Cancer. 77. 243-250 (1998)

[文献書誌] Hana,S.: "Adenovirus-mediated p16 gene transfer prevents drug-induced cell death through G1 arrest in human glioma cells." Int.J.Cancer. 77. 47-54 (1998)

[文献書誌] Kasai,T.: "Factors that influence the eligibility of cancers for inclusion in clinical trials." Jpn.J.Clin.Oncol.28. 214-221 (1998)

[文献書誌] Chen,Z.S.: "An active efflux system for heavy metals in cisplatin-resistant human KB carcinoma cells." Exp.Cell Res.240. 312-320 (1998)

1998 年度実績報告書

上田龍三名古屋市立大学, 医学部, 教授 (20142169)