2000 Fiscal Year Annual Research Report

抗体療法及びがんの前臨床試験研究

Research Project

Project/Area Number	12217127
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	Nagoya City University
Principal Investigator	上田龍三名古屋市立大学, 医学部, 教授 (20142169)
Co-Investigator(Kenkyū-buntansha)	直江知樹名古屋大学, 医学部, 助教授 (50217634) 佐藤滋樹名古屋市立大学, 医学部, 助教授 (80254283)
Keywords	分子標的療法 / 抗体療法 / 抗c-kit / CEA / CD25抗体 / ガングリオシドGD2 / ヒストンデアセチラーゼ(HDAC) / FK228
Research Abstract	難治性がんや高齢者のがんなどに対するQOLを踏まえた科学的な治療法としての分子標的療法を実現性の高い抗体療法の再開発の立場として、ヒトがんに特異性が高く多くの固形癌に共通して過剰発現を認めるCEA,造血器腫瘍に発現を認め免疫調節作用を有するCD25,肺癌の自己増殖に関与するc-kitを対象とした抗c-kit,CEA,CD25抗体の生理活性を有する単鎖抗体を作製中である。また、肺癌治療を目的として小細胞肺癌で高発現が認められるガングリオシドGD2を標的とした抗体療法の可能性に関して基礎的検討を行った。GD2の発現を認めない小細胞肺癌株にα.2,8シアル酸転移酵素遺伝子を導入し糖鎖リモデリングを行いその生物学的特性に関して検討した結果、遺伝子導入株において有意な増殖促進を認めると共に有意な癌細胞浸潤能の亢進が認められた。このGD2高発現小細胞肺癌株における増殖効果は、抗GD2抗体(クローン220-51)投与により有意に抑制されその腫瘍活性機構の解析では、抗体処理によりDNAラダー形成の誘導,annexin V陽性細胞の検出,caspase-3の活性化を認め、アポトーシスが関与することを見いだした。加えて抗癌剤との併用により増強効果が得られた。更に、新しい概念である転写制御療法の可能性を分子標的としてヒストンデアセチラーゼ(HDAC)を対象として成立するか検討し結果、本邦で開発された阻害剤FK228は、PLZF-RARaならびにPML-RARa転座白血病に分化を誘導した。マウスモデルにおいてもこの併用は有効で、ヒストンアセチル化のみならず、分化、増殖抑制、アポトーシスを誘導した。次に、リセプターチロシンリン酸化酵素FLT3を標的とした研究では、変異型FLT3遺伝子はマウスIL3依存性骨髄性細胞株をIL3非依存的に増殖させ、マウスに接種すると白血病死が誘導された。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] Tsuboi,K.: "MUM1/IRF4 expression as a frequent event in mature lymphoid Malignancies "Leukemia. 14. 449-456 (2000)
[Publications] Takeyama,K.: "Therapy-related leukemia and myelodysplastic syndrome : a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors"Int.J.Hematol.,. 71. 144-152 (2000)
[Publications] Zhao,M.: "In vivo treatment of mutant FLT3-transformed munne leukemia with a tyrosine kinase inhibitor."Leukemia. 14. 374-378 (2000)
[Publications] Naoe,T.: "Analysis of genetic polymoriphism in NQO1,GST-M1,GST-T1,and CYP3A4 in 469 Japanese patients with therapy-related leukemia/myelodysplasic syndrome and de novo acute myeloid leukemia."Clin.Cancer Res.. 6. 4091-4095 (2000)
[Publications] Murata,M.: "Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228,on malignant lymphoid cells"Jpn.J.Cancer Res.. 91. 1154-1160 (2000)
[Publications] Kitamura,K.: "Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis"Leukemia. 14・10. 1743-1750 (2000)
[Publications] Kitamura,K.: "Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid"Br J Haematol.. 108・4. 696-702 (2000)
[Publications] Hayakawa,F.: "Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lin"Oncogene. 19・5. 624-631 (2000)
[Publications] Kitagawa,N.: "Epstein-Barr virus-encoded poly(A)(-) RNA supports lymphoma growth through interleukin-10 induction. "EMBO J.. 19・24. 6742-6750 (2000)
[Publications] Shimizu,S.: "High frequency of clonally related tumors in cases of multiple synchronous lung canceres as revealed by molecular diagnosis"Clin.Cancer Res.. 6. 3994-3999 (2000)
[Publications] Hayashi,K.: "Usefulness of uracil loading test for detecting 5-flurorouracil metabolic enzyme deficiencies in humans"Int.J.Clin.Oncol.. 5. 171-173 (2000)
[Publications] Niimi,T.: "Vitamin D receptor gene polymorphism and calcium metabolism in sarcoidosis patients."Basic Science Res.. 17. 266-269 (2000)
[Publications] Maeda,H.: "Human herpesvirus 8 is not associated with sarcoidosis in Japanese Patients"Chest. 118. 923-927 (2000)
[Publications] Takeshita,A.: "Quantitative expression of erythropoietin receptor (EPO-R) on acute leukemia cells : relationships between the amount of EPO-R and CD phenotypes, in vitro proliferative response,the amount of other cytokine receptors and clinical prognosis"Brit.J.Hematology. 108. 55-63 (2000)
[Publications] Tanaka,H: "Lack of integrated TT virus (TTV) genomes into cellular DNA in infected human hematopoietic cells"Leukemia and Lymphoma. 38. 411-417 (2000)
[Publications] Iida,S.: "Anobel human multiple myeloma-derived cell line, NCU-MM-1,carrying(2;11)(Pll;q23) and (8;22)(q24;qll)chromosomal translocations with overexpression of c-myc protein"Int.J.Hematol.. 72. 85-97 (2000)

2000 Fiscal Year Annual Research Report

抗体療法及びがんの前臨床試験研究

Principal Investigator

上田 龍三 名古屋市立大学, 医学部, 教授 (20142169)

Research Products

[Publications] Tsuboi,K.: "MUM1/IRF4 expression as a frequent event in mature lymphoid Malignancies "Leukemia. 14. 449-456 (2000)

[Publications] Takeyama,K.: "Therapy-related leukemia and myelodysplastic syndrome : a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors"Int.J.Hematol.,. 71. 144-152 (2000)

[Publications] Zhao,M.: "In vivo treatment of mutant FLT3-transformed munne leukemia with a tyrosine kinase inhibitor."Leukemia. 14. 374-378 (2000)

[Publications] Naoe,T.: "Analysis of genetic polymoriphism in NQO1,GST-M1,GST-T1,and CYP3A4 in 469 Japanese patients with therapy-related leukemia/myelodysplasic syndrome and de novo acute myeloid leukemia."Clin.Cancer Res.. 6. 4091-4095 (2000)

[Publications] Murata,M.: "Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228,on malignant lymphoid cells"Jpn.J.Cancer Res.. 91. 1154-1160 (2000)

[Publications] Kitamura,K.: "Involvement of CD95-independent caspase 8 activation in arsenic trioxide-induced apoptosis"Leukemia. 14・10. 1743-1750 (2000)

[Publications] Kitamura,K.: "Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid"Br J Haematol.. 108・4. 696-702 (2000)

[Publications] Hayakawa,F.: "Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lin"Oncogene. 19・5. 624-631 (2000)

[Publications] Kitagawa,N.: "Epstein-Barr virus-encoded poly(A)(-) RNA supports lymphoma growth through interleukin-10 induction. "EMBO J.. 19・24. 6742-6750 (2000)

[Publications] Shimizu,S.: "High frequency of clonally related tumors in cases of multiple synchronous lung canceres as revealed by molecular diagnosis"Clin.Cancer Res.. 6. 3994-3999 (2000)

[Publications] Hayashi,K.: "Usefulness of uracil loading test for detecting 5-flurorouracil metabolic enzyme deficiencies in humans"Int.J.Clin.Oncol.. 5. 171-173 (2000)

[Publications] Niimi,T.: "Vitamin D receptor gene polymorphism and calcium metabolism in sarcoidosis patients."Basic Science Res.. 17. 266-269 (2000)

[Publications] Maeda,H.: "Human herpesvirus 8 is not associated with sarcoidosis in Japanese Patients"Chest. 118. 923-927 (2000)

[Publications] Tanaka,H: "Lack of integrated TT virus (TTV) genomes into cellular DNA in infected human hematopoietic cells"Leukemia and Lymphoma. 38. 411-417 (2000)

[Publications] Iida,S.: "Anobel human multiple myeloma-derived cell line, NCU-MM-1,carrying(2;11)(Pll;q23) and (8;22)(q24;qll)chromosomal translocations with overexpression of c-myc protein"Int.J.Hematol.. 72. 85-97 (2000)

上田龍三名古屋市立大学, 医学部, 教授 (20142169)