1997 Fiscal Year Annual Research Report

悪性グリオーマ特異的遺伝子治療の開発的研究

Research Project

Project/Area Number	09255231
Research Institution	Osaka University
Principal Investigator	清水惠司大阪大学, 医学部, 助教授 (50162699)
Co-Investigator(Kenkyū-buntansha)	池中一裕岡崎国立共同研究機構, 生理学研究所, 教授 (00144527) 宮尾泰慶大阪大学, 医学部・付属病院, 医員
Keywords	Retrovirus / MBP / Promoter / Gene therapy / Bystander effect / HVJ-liposome / Monoclonal antibody / Humanized antibody
Research Abstract	脳特異的に発現するMBPプロモータで制御された殺細胞遺伝子を組み込んだレトロウイルスベクターを用いて、悪性グリオーマに特異的な遺伝子治療法の研究を続けてきた。そして、Polyoma ori発現遺伝子をパッケージング細胞に導入することで、高力価な脳特異的レトロウイルスベクターの開発に成功した(Hum Gene Ther 9:161-172,1998)。そして、現在マウス脳腫瘍モデルを用いて、適切な治療プロトコールを検討中である。また、ウイルス産生細胞を腫瘍内に移植する場合には、それ自体は移動性に大変乏しいが、腫瘍内で産生されたウイルスベクターを取り込んだグリオーマ細胞は腫瘍内をよく移動するので、bystander効果が最も有効に作用する時点にganciclovir等の後療法を行うことが賢明であることも実証されている(Hum Gene Ther 8:381-391,1997:Gene Ther,in submitted)。一方、マウスモノクローナル抗体(ONS-M21)が認識するグリオーマ関連抗原がintegrin α3であると同定され(Br J Cancer,in revised)、この抗原の発現メカニズムを現在解析中である。また、ONS-M21抗体のみならず、そのヒト型化や単鎖抗体が細胞膜表面上の腫瘍関連抗原と結合すると、グリオーマ細胞や髄芽腫細胞によく取り込まれることから(Cancer Lett,in press)、殺細胞遺伝子導入法や、免疫複合体を用いたバイオターゲッティングへの応用が期待されている。さらにレトロウイルスレセプターを有しないグリオーマを対象にして、ONS-M21抗体やそのヒト型化抗体とHVJリポソームとの併用によるグリオーマ特異的イムノリポソーム法の開発にも着手している(Gene Ther 4:768-772,1997)。なお、SAGE(Serial analysis of gene expression)法による、悪性グリオーマ普遍発現遺伝子やそのプロモータの検索は現在も研究途上である。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] Moriuchi S: "Decreased N-myc expression in human medulloblastoma cell lines during differentiation." Anticancer Res. 17. 301-306 (1997)
[Publications] Tamura M: "Targeted killing of migrating glioma cells by injection of HTK-modified glioma cells." Hum Gene Ther. 8. 381-391 (1997)
[Publications] Miyao Y: "Usefulness of a mouse myelin basic protein promoter for gene therapy of malignant glioma : myelin basic protein promoter is strongly active in human malignant glioma cells." Jpn J Cancer Res. 88. 678-686 (1997)
[Publications] Mabuchi E: "Gene delivery by HVJ-liposome in the experimental gene therapy of murine glioma." Gene Ther. 4. 768-772 (1997)
[Publications] Miyao Y: "FT-175,a Synthetic Inhibitor of the Complement pathway,Protects against the Inactivation of Infectious Retrovirus by Human Serum." Hum Gene Ther. 8. 1575-1583 (1997)
[Publications] Kishima H: "Possible common origin of α-fetoprotein- and human chorionic gonadotropin- secreting cells in intracranial germ cell tumor." J Neurosurg. 88. 576-580 (1998)
[Publications] Park KC: "Interferon yield MHC antigen expression of human medulloblastoma cells and its suppression during dibutyryl cyclic AMP-induced differentiation :" Cell Mol Neurobiol. (in press). (1998)
[Publications] Yamada M: "In vitro study on intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for meningeal dissemination of malignant brain tumors." J Neuro-oncol. (in press). (1998)
[Publications] Park KC: "Regulation of interferon responses in medulloblastoma cells by interferon regulatory factor -1 and -2." Br J Cancer. (in press). (1998)
[Publications] Shimizu K: "Internalization with high targeting potential of mouse monoclonal antibody ONS-M21 recognizing human malignant glioma antigen." Cancer lett. (in press). (1998)
[Publications] Kishima H: "Systemic interleukin-12 displays antitumor activity in the mouse central nervous system." Br J Cancer(in press). (1998)
[Publications] Ikeda H: "Retroviral introduction of the p16 gene into murine cell lines to elicit marked antiproliferative effects." Jpn.J Cancer Res. 88. 712-717 (1997)
[Publications] Baba H: "GFAP gene expression during development of astrocyte." Dev Neurosci. 19. 49-57 (1997)
[Publications] Morita N: "Astrocytic lineage analysis by detection of GFAP promoter activity in vitro." Dev Neurosci. 19. 210-218 (1997)
[Publications] Yoshimatsu T.: "Improvement of retroviral packaging cell lines by introducing the polyomavirus early region." Hum Gene Ther. 9. 161-172 (1998)
[Publications] Peyron F: "In situ expression of PLP/DM20,MBP,and CNP during embryonic and postnatal development of the jimpy mutant and of transgenic mice overexpressing PLP." J Neurosci Res. (in press). (1998)

1997 Fiscal Year Annual Research Report

悪性グリオーマ特異的遺伝子治療の開発的研究

Principal Investigator

清水 惠司 大阪大学, 医学部, 助教授 (50162699)

Research Products

[Publications] Moriuchi S: "Decreased N-myc expression in human medulloblastoma cell lines during differentiation." Anticancer Res. 17. 301-306 (1997)

[Publications] Tamura M: "Targeted killing of migrating glioma cells by injection of HTK-modified glioma cells." Hum Gene Ther. 8. 381-391 (1997)

[Publications] Miyao Y: "Usefulness of a mouse myelin basic protein promoter for gene therapy of malignant glioma : myelin basic protein promoter is strongly active in human malignant glioma cells." Jpn J Cancer Res. 88. 678-686 (1997)

[Publications] Mabuchi E: "Gene delivery by HVJ-liposome in the experimental gene therapy of murine glioma." Gene Ther. 4. 768-772 (1997)

[Publications] Miyao Y: "FT-175,a Synthetic Inhibitor of the Complement pathway,Protects against the Inactivation of Infectious Retrovirus by Human Serum." Hum Gene Ther. 8. 1575-1583 (1997)

[Publications] Kishima H: "Possible common origin of α-fetoprotein- and human chorionic gonadotropin- secreting cells in intracranial germ cell tumor." J Neurosurg. 88. 576-580 (1998)

[Publications] Park KC: "Interferon yield MHC antigen expression of human medulloblastoma cells and its suppression during dibutyryl cyclic AMP-induced differentiation :" Cell Mol Neurobiol. (in press). (1998)

[Publications] Yamada M: "In vitro study on intrathecal use of 5-fluoro-2'-deoxyuridine (FdUrd) for meningeal dissemination of malignant brain tumors." J Neuro-oncol. (in press). (1998)

[Publications] Park KC: "Regulation of interferon responses in medulloblastoma cells by interferon regulatory factor -1 and -2." Br J Cancer. (in press). (1998)

[Publications] Shimizu K: "Internalization with high targeting potential of mouse monoclonal antibody ONS-M21 recognizing human malignant glioma antigen." Cancer lett. (in press). (1998)

[Publications] Kishima H: "Systemic interleukin-12 displays antitumor activity in the mouse central nervous system." Br J Cancer(in press). (1998)

[Publications] Ikeda H: "Retroviral introduction of the p16 gene into murine cell lines to elicit marked antiproliferative effects." Jpn.J Cancer Res. 88. 712-717 (1997)

[Publications] Baba H: "GFAP gene expression during development of astrocyte." Dev Neurosci. 19. 49-57 (1997)

[Publications] Morita N: "Astrocytic lineage analysis by detection of GFAP promoter activity in vitro." Dev Neurosci. 19. 210-218 (1997)

[Publications] Yoshimatsu T.: "Improvement of retroviral packaging cell lines by introducing the polyomavirus early region." Hum Gene Ther. 9. 161-172 (1998)

[Publications] Peyron F: "In situ expression of PLP/DM20,MBP,and CNP during embryonic and postnatal development of the jimpy mutant and of transgenic mice overexpressing PLP." J Neurosci Res. (in press). (1998)

清水惠司大阪大学, 医学部, 助教授 (50162699)