1996 年度実績報告書

がん遺伝子c-kit及びMLLを標的としたがん化学療法の基礎的研究

研究課題

研究課題/領域番号	06282272
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	長田啓隆愛知県がんセンター, 超微形態学部, 主任研究員 (30204176)
キーワード	c-kit / MLL遺伝子 / MLLキメラ蛋白 / Radiation Leukemia / トランスジェニックマウス / 肺小細胞癌 / 白血病 / VP-16耐性
研究概要	がん遺伝子及びその産物は新しいがん治療法の標的分子として、今後の化学療法にとって極めて重要であり、臨床応用を目指した基礎的研究が必要である。本研究ではc-kit遺伝子及びMLL遺伝子をがん化学療法の標的分子モデルとして、将来的には遺伝子レベルから蛋白レベルまでの種々の段階で腫瘍の増殖抑制・分化誘導に効果を示す薬剤等の検索を目指し、昨年に引き続き解析した結果、本年度は以下の成果が得られた。 1. MLL(mixed lineage leukemia)遺伝子の造腫瘍性に関しては、MLL遺伝子の特定領域(Zinc finger領域のN端側)での分断が重要であり、MLLキメラ蛋白が化学療法の標的分子となることが考えられた。 2. MLL-キメラ産物の細胞内局在は核に局在することが普遍的現象であることをMLL-AF6の系にて実証した。 3. Radiation leukemiaの系でもMLLキメラ遺伝子トランスジェニックマウスは、対照群と胸腺腫発生時期、死亡日数に有意な差がなかった。 4. c-kit陽性肺小細胞癌株を指標としチロシンキナーゼ阻害剤の有効性の検討の結果、解析したチロシンキナーゼ阻害剤の中にはc-kit特異的に運動能を抑制する薬剤は得られなかった。 5.緑膿菌外毒素結合ドメンをc-kitのリガンドであるSCF (stem cell factor)に置換した融合物(SCF-PE40)はc-kit受容体を介して、c-kit陽性細胞に特異的な殺効果(障害)を示した。c-kit陽性細胞にrSCF添加により43kDaのSCFにより誘導されたリン酸化チロシンのバンドが得られた。 6. c-kit陽性の肺小細胞癌患者の化学療法前後及びそのVP-16耐性株を樹立した。各細胞のc-kitの発現を検討したところ、発現量は不変であったが、VP-16に対する耐性度は母株のtopoisomerase IIαの発現低下に相関した。

研究成果
(20件)

すべてその他

すべて文献書誌 (20件)

[文献書誌] Miyara, H.: "Modification of chemo-radiosensitivity of a human lung cancer cell line by introduction of the glutathione s-transferase π gene." Jpn. J. Clin. Oncol.26. 1-5 (1996)
[文献書誌] Takeda, S.: "Allelic-expression imbalance of the insulin-like growth factor 2 gene in hepatocellular carcinomas and underlying disease." Oncogene. 12. 1589-1592 (1996)
[文献書誌] Nishio, M.: "Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers." J. Clin. Oncol.14 (2). 497-502 (1996)
[文献書誌] Kobashi, Y.: "Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occuring in sites other than the upper and lower respiratory tract." Histopathology. 28. 111-120 (1996)
[文献書誌] Kobayashi, T.: "Randomized trials btween behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia." J. Clin. Oncol.14. 204-213 (1996)
[文献書誌] Ueda, R.: "Chromosome 16 inversion in acute myelogenous leukemias with bone marrow eosinophilia." Inter. Medicine. 35 (4). 241-242 (1996)
[文献書誌] Hangaishi, A.: "Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies." Blood. 87 (12). 4949-4958 (1996)
[文献書誌] Takahashi, N.: "Translocation (9 ; 11 ; 22) (p22 ; q23 ; q11) ; A new type of complex variant translocation of t (9 ; 11) (p22 ;q23) with MLL rearrangement." Cancer Genet Cytogenet. 88. 26-29 (1996)
[文献書誌] Hirano, N: "Expression of costimulatory molecules in human leukemias." Leukemia. 10. 1168-1176 (1996)
[文献書誌] Yatabe, Y.: "Clinicopahologic study of PRAD1/cyclin D1 overexpressing lymphoma with special reference to mantle cell lymphoma, a distinct molecular pathologic entity." Amer. J. Surg. Pathol.20. 1110-1122 (1996)
[文献書誌] Andoh, T.: "Reduced expression of DNA topoisomerase II confers resistance to VP-16 in small cell lung cancer cell lines established from a refractory tumors of a patient and in vitro selection." Oncology Res.8 (6). 229-238 (1996)
[文献書誌] Taki, T.: "Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia." Leukemia. 10. 1303-1307 (1996)
[文献書誌] Nishida, K.: "Introduction of the c-kit gene leads to growth suppression of a breast cancer cell line MCF-7" Anticancer, Res.16. 3397-3402 (1996)
[文献書誌] Kakuda, H.: "A novel human leukaemic cell line, CTS, has at (6 ; 11) chromosomal translocation and characteristics of pluripotent stem cells." Brit. J. Haematol.95. 306-318 (1996)
[文献書誌] Joh, T.: "Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation." Oncogene. 13. 1945-1953 (1996)
[文献書誌] Hayashi, K.: "Possible prediction of adverse reactions to pyrimidine chemotherapy from urinary pyrimidine levels and a case of asymptomatic adult dihydropyrimidinurial." Clini. Cancer Res.2. 1937-1941 (1996)
[文献書誌] Taki, T.: "Fusion of the MLL gene with two different genes, AF-6 and AF-5α by a complex translocation involving chromosomes 5. 6. 8 and 11 in infant leukemia." Oncogene. 13. 2121-2130 (1996)
[文献書誌] Ohshima, A.: "11q23 aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposode and mitoxantrone." Amer. J. Hematol.53. 264-266 (1996)
[文献書誌] Osada, H.: "Subcellular localization and protein interaction of the human LIMK2 gene expressing alternative transcripts with tissue-specific regulation." Biochem. Biophys. Com.229. 582-589 (1996)
[文献書誌] Orito, E.: "GB virus C/hepatitis G virus infection among Japanese patients with chronic liver diseases and blood donors." Virus Res.46. 89-93 (1996)

1996 年度 実績報告書

がん遺伝子c-kit及びMLLを標的としたがん化学療法の基礎的研究

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] Miyara, H.: "Modification of chemo-radiosensitivity of a human lung cancer cell line by introduction of the glutathione s-transferase π gene." Jpn. J. Clin. Oncol.26. 1-5 (1996)

[文献書誌] Takeda, S.: "Allelic-expression imbalance of the insulin-like growth factor 2 gene in hepatocellular carcinomas and underlying disease." Oncogene. 12. 1589-1592 (1996)

[文献書誌] Nishio, M.: "Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers." J. Clin. Oncol.14 (2). 497-502 (1996)

[文献書誌] Kobashi, Y.: "Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occuring in sites other than the upper and lower respiratory tract." Histopathology. 28. 111-120 (1996)

[文献書誌] Kobayashi, T.: "Randomized trials btween behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia." J. Clin. Oncol.14. 204-213 (1996)

[文献書誌] Ueda, R.: "Chromosome 16 inversion in acute myelogenous leukemias with bone marrow eosinophilia." Inter. Medicine. 35 (4). 241-242 (1996)

[文献書誌] Hangaishi, A.: "Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies." Blood. 87 (12). 4949-4958 (1996)

[文献書誌] Takahashi, N.: "Translocation (9 ; 11 ; 22) (p22 ; q23 ; q11) ; A new type of complex variant translocation of t (9 ; 11) (p22 ;q23) with MLL rearrangement." Cancer Genet Cytogenet. 88. 26-29 (1996)

[文献書誌] Hirano, N: "Expression of costimulatory molecules in human leukemias." Leukemia. 10. 1168-1176 (1996)

[文献書誌] Yatabe, Y.: "Clinicopahologic study of PRAD1/cyclin D1 overexpressing lymphoma with special reference to mantle cell lymphoma, a distinct molecular pathologic entity." Amer. J. Surg. Pathol.20. 1110-1122 (1996)

[文献書誌] Andoh, T.: "Reduced expression of DNA topoisomerase II confers resistance to VP-16 in small cell lung cancer cell lines established from a refractory tumors of a patient and in vitro selection." Oncology Res.8 (6). 229-238 (1996)

[文献書誌] Taki, T.: "Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia." Leukemia. 10. 1303-1307 (1996)

[文献書誌] Nishida, K.: "Introduction of the c-kit gene leads to growth suppression of a breast cancer cell line MCF-7" Anticancer, Res.16. 3397-3402 (1996)

[文献書誌] Kakuda, H.: "A novel human leukaemic cell line, CTS, has at (6 ; 11) chromosomal translocation and characteristics of pluripotent stem cells." Brit. J. Haematol.95. 306-318 (1996)

[文献書誌] Joh, T.: "Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation." Oncogene. 13. 1945-1953 (1996)

[文献書誌] Hayashi, K.: "Possible prediction of adverse reactions to pyrimidine chemotherapy from urinary pyrimidine levels and a case of asymptomatic adult dihydropyrimidinurial." Clini. Cancer Res.2. 1937-1941 (1996)

[文献書誌] Taki, T.: "Fusion of the MLL gene with two different genes, AF-6 and AF-5α by a complex translocation involving chromosomes 5. 6. 8 and 11 in infant leukemia." Oncogene. 13. 2121-2130 (1996)

[文献書誌] Ohshima, A.: "11q23 aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposode and mitoxantrone." Amer. J. Hematol.53. 264-266 (1996)

[文献書誌] Osada, H.: "Subcellular localization and protein interaction of the human LIMK2 gene expressing alternative transcripts with tissue-specific regulation." Biochem. Biophys. Com.229. 582-589 (1996)

[文献書誌] Orito, E.: "GB virus C/hepatitis G virus infection among Japanese patients with chronic liver diseases and blood donors." Virus Res.46. 89-93 (1996)

1996 年度実績報告書

上田龍三名古屋市立大学, 医学部, 教授 (20142169)