2001 Fiscal Year Annual Research Report

血管新生抑制および転移・浸潤抑制を目的とした卵巣癌遺伝子治療に関する基礎的研究

Research Project

Project/Area Number	11671645
Research Institution	Jichi Medical School
Principal Investigator	大和田倫孝自治医科大学, 医学部, 助教授 (40203955)
Co-Investigator(Kenkyū-buntansha)	小澤敬也自治医科大学, 医学部, 教授 (30137707) 小林浩浜松医科大学, 医学部, 講師 (40178330) 鈴木光明自治医科大学, 医学部, 教授 (50110870)
Keywords	卵巣癌 / IL-10 / NK4 / PTEN / bikunin
Research Abstract	本年度は卵巣癌遺伝子治療の臨床応用を目指し、卵巣癌細胞に対して、IL-10,NK4およびbikuninを用いてin vivo, exo vivo, in vitroの感染実験を行い、治療効果の検討を行った。また癌抑制遺伝子PTENを用いた遺伝子治療の可能性およびthymidylate synthase(TS)強発現細胞株の生物学的悪性度についても検討した。まずIL-10については、卵巣癌細胞SHIN-3をマウス腹腔内に接種し、AVV-IL-10を筋肉内に投与した結果、血管新生、腹膜播種、腹水産生が抑制された。さらにマウスの生存期間が延長した。次にNK4については、卵巣癌細胞HRAにNK4遺伝子を導入、強発現させ、マウス腹腔内に接種した結果、コントロールに比べて腹水産生の抑制および延命効果のあることが確認された。作用機序の解明を目的に、cDNA microarray法を用いて遺伝子解析を行った結果、NK4遺伝子導入HRA株はコントロールに比べてアポトーシス抑制遺伝子、血管新生、migration関連遺伝子の減弱が示された。 bikuninについては、bikuninのキメラ遺伝子ATF-HI 8をHRAに遺伝子導入した結果、細胞の遊走、浸潤が抑制された。 PTENについては、SHIN-3に遺伝子導入、強発現させた結果、抗癌剤イリノテカンに対する感受性が増強した。機序としては、アポトーシスの誘導とトポイソメラーゼIの活性抑制が示された。またHRAへの導入、強発現では細胞遊走が抑制された。最後にTSについての検討では、子宮頚癌細胞SKG-IIにTSを遺伝子導入、強発現させた結果、抗癌剤5-FUに対する感受性が低下した。

Research Products
(14 results)

All Other

All Publications (14 results)

[Publications] Suzuki, M.: "Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers ?"Cancer Genet Cytogenet. 124. 152-158 (2001)
[Publications] Suzuki, M.: "Micrometastatic p53-positive cells in the lymph nodes of early stage epithelial ovarian cancer : Prognostic significance"Oncology. 60. 170-175 (2001)
[Publications] Suzuki, M.: "Localization of a novel susceptibity gene for familial ovarian cancer to chromosome 3p22-p25"Hum Mol Genet. 10. 1421-1429 (2001)
[Publications] Ohwada, M.: "Involvement of microsatellite instability in lymph node metastasis of endometrial carcinoma"Cancer Genet Cytogenet. 132. 152-155 (2002)
[Publications] Saga, Y.: "Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival"Gene Ther. 8. 1450-1455 (2001)
[Publications] Saga, Y.: "Enhanced expression of thymidylate synthase mediates desensitization of uterine cervical cancer cells to radiation"Oncology. (in press). (2002)
[Publications] Kobayashi, H.: "Suppression of urokinase expression and tumor metastasis by bikunin overexpression"Hum Cell. 14. 233-236 (2001)
[Publications] Suzuki, M.: "Structure and function analysis of urinary trypsin inhibitor(UTI): identification of binding domains and signaling property of UTI by analysis of truncated proteins"Biochim Biophys Acta. 1547. 26-36 (2001)
[Publications] Ohmine, K.: "Characterization of stage progression in chronic myeloid leukemia by DNA microarray with purified hematopoietic stem cells"Oncogene. 20. 8249-8257 (2001)
[Publications] Okada, T.: "Development and characterization of an antisense-mediated prepackaging cell line for adeno-associated virus vector production"Biochem Biophys Res Commun. 288. 62-68 (2001)
[Publications] Kogure, K.: "Targeted integration of foreign DNA into a defined locus on chromosome 19 in K562 cells using AAV-derived components"Int J Hematol. 73. 469-475 (2001)
[Publications] Yamashita, Y.: "Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase"J Biol Chem. 276. 39012-39020 (2001)
[Publications] Miyazato, A.: "Indentification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction"Blood. 98. 422-427 (2001)
[Publications] Kanazawa, T.: "Gamma-rays enhance rAAV-mediated transgene expression and cytocidal effect of AAV-HSVtk/ganciclovir on cancer cells"Cancer Gene Ther. 8. 99-106 (2001)

2001 Fiscal Year Annual Research Report

血管新生抑制および転移・浸潤抑制を目的とした卵巣癌遺伝子治療に関する基礎的研究

Principal Investigator

大和田 倫孝 自治医科大学, 医学部, 助教授 (40203955)

Research Products

[Publications] Suzuki, M.: "Are DNA mismatch repair deficiencies responsible for accumulation of genetic alterations in epithelial ovarian cancers ?"Cancer Genet Cytogenet. 124. 152-158 (2001)

[Publications] Suzuki, M.: "Micrometastatic p53-positive cells in the lymph nodes of early stage epithelial ovarian cancer : Prognostic significance"Oncology. 60. 170-175 (2001)

[Publications] Suzuki, M.: "Localization of a novel susceptibity gene for familial ovarian cancer to chromosome 3p22-p25"Hum Mol Genet. 10. 1421-1429 (2001)

[Publications] Ohwada, M.: "Involvement of microsatellite instability in lymph node metastasis of endometrial carcinoma"Cancer Genet Cytogenet. 132. 152-155 (2002)

[Publications] Saga, Y.: "Expression of HGF/NK4 in ovarian cancer cells suppresses intraperitoneal dissemination and extends host survival"Gene Ther. 8. 1450-1455 (2001)

[Publications] Saga, Y.: "Enhanced expression of thymidylate synthase mediates desensitization of uterine cervical cancer cells to radiation"Oncology. (in press). (2002)

[Publications] Kobayashi, H.: "Suppression of urokinase expression and tumor metastasis by bikunin overexpression"Hum Cell. 14. 233-236 (2001)

[Publications] Suzuki, M.: "Structure and function analysis of urinary trypsin inhibitor(UTI): identification of binding domains and signaling property of UTI by analysis of truncated proteins"Biochim Biophys Acta. 1547. 26-36 (2001)

[Publications] Ohmine, K.: "Characterization of stage progression in chronic myeloid leukemia by DNA microarray with purified hematopoietic stem cells"Oncogene. 20. 8249-8257 (2001)

[Publications] Okada, T.: "Development and characterization of an antisense-mediated prepackaging cell line for adeno-associated virus vector production"Biochem Biophys Res Commun. 288. 62-68 (2001)

[Publications] Kogure, K.: "Targeted integration of foreign DNA into a defined locus on chromosome 19 in K562 cells using AAV-derived components"Int J Hematol. 73. 469-475 (2001)

[Publications] Yamashita, Y.: "Sak serine-threonine kinase acts as an effector of Tec tyrosine kinase"J Biol Chem. 276. 39012-39020 (2001)

[Publications] Miyazato, A.: "Indentification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction"Blood. 98. 422-427 (2001)

[Publications] Kanazawa, T.: "Gamma-rays enhance rAAV-mediated transgene expression and cytocidal effect of AAV-HSVtk/ganciclovir on cancer cells"Cancer Gene Ther. 8. 99-106 (2001)

大和田倫孝自治医科大学, 医学部, 助教授 (40203955)