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2002 Fiscal Year Final Research Report Summary

Targeted gene therapy for malignant melanoma

Research Project

Project/Area Number 12557071
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Dermatology
Research InstitutionSapporo Medical University

Principal Investigator

HAMADA Hirofumi  Sapporo Medical University, Professor, School of Medicine, 医学部, 教授 (00189614)

Co-Investigator(Kenkyū-buntansha) SAIDA Toshiaki  Professor, Shinshu University School of Medicine, 医学部, 教授 (10010381)
SHIMADA Shinji  Professor, Yamanashi Medical University, 医学部, 教授 (10114505)
JINBO Koichi  Sapporo Medical University, Professor, School of Medicine, 医学部, 教授 (30094238)
Project Period (FY) 2000 – 2002
KeywordsAdenoviral vector / Gene therapy / integrin / malignant melanoma / receptor / peptide ligand / cancer / fiber
Research Abstract

Effective gene transfer to human melanomas via integrin-targeted adenoviral vectors. The utility of recombinant adenoviral vectors (Adv) for gene therapy is limited by their low transduction efficiency and lack of specificity for target cells. The low transduction efficiency is often recognized as due to deficiency of the primary adenoviral receptor, the coxsackievirus-adenovirus receptor (CAR). In this paper, studies of CAR levels on human melanoma cell lines confirmed that low transduction efficiency was closely related to deficiency of the adenoviral receptor. To achieve CAR-independent gene transfer via Adv, we modified viral tropism via genetic alteration of the adenovirus type 5 (Ad5) fiber protein. Insertion of an Arg-Gly-Asp (RGD)-containing peptide in the HI loop of the fiber knob domain allowed the virus to use an alternative receptor, the integrin receptor, during the cell entry process. With this modified vector (Adv-F/RGD) transduction was increased 5- to 96-fold relative to a vector containing wild-type fiber (Adv-F/wt) in five human melanoma cells expressing integrins of the alpha(v)beta(3), alpha(v)beta(5) class, which are recognized by the RGD peptide motif. In contrast, no significant difference in transduction efficiency between Adv-F/RGD and Adv-F/wt was observed in 293 cells, which show high-level expression of CAR. In this study, we attempted to apply Adv-F/RGD for gene therapy for malignant melanoma. At the same multiplicity of infection, melanoma cells infected with Adv-F/RGD carrying human interleukin 2 (AxCAhIL2-F/RGD) produced a higher level of cytokine than cells infected with AxCAhIL2-F/wt. Treatment by intratumoral injection of AxCAhIL2-F/RGD was more effective than intratumoral injection of AxCAhIL2-F/wt in regressing tumors in a melanoma xenograft model. These data suggest that integrin-targeted adenoviral vectors may be a powerful tool in gene therapy for CAR-deficient melanomas.

  • Research Products

    (52 results)

All Other

All Publications (52 results)

  • [Publications] Shinoura N, Yamamoto N, Yoshida Y, Fujita T, Saito N, Asai A, Kirino T, Hamada H.: "Adenovirus-mediated gene transduction of IkappaB or IkappaB plus Bax gene drastically enhances tumor necrosis factor (TNF)-induced apoptosis in human gliomas"Jpn J Cancer Res.. 91(1). 41-51 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, Yoshida, Y., Asai, A., Kirino, T., Hamada H.: "Adenovirus-mediated transfer of p53 and Fas ligand drastically enhances apoptosis in gliomas"Cancer Gene Ther.. 7(5). 732-738 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, Saito, K., Yoshida, Y., Hashimoto, M., Asai, A., Kirino, T., Hamada, H.: "Adenovirus-mediated transfer of Bax with caspase-8 controlled by myelin basic protein promoter induces enhanced apoptosis in gliomas"Cancer Gene Ther.. 7(5). 739-748 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Motoi, F., Sunamura, M., Ding, L., Duda, DG., Yoshida, Y., Zhang, W-P., Matsuno, S., Hamada, H.: "Effective gene therapy for pancreatic cancer by cytokines mediated by restricted replication-competent adenovirus"Human Gene Ther.. 11(2). 223-235 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, N., Satou, R., Yoshida, Y., Asai, A., Kirino, T., Hamada, H.: "Adenovirus-mediated transfer of Bcl-X protects neuronal cells from Bax-induced apoptosis"Exp.Cell Res. 254(2). 221-231 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, N., Muramatsu, Y., Yoshida, Y., Asai, A., Kirino, T., Hamada, H.: "Adenovirus-mediated transfer of caspase-3 with Fas ligand induces drastic apoptosis in U-373MG glioma cells"Exp.Cell Res.. 256(2). 423-433 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, N., Yoshida, Y., asai, A., Kirino, T., Hamada, H.: "Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas : Implication for gene therapy"Hum.Gene Ther. 11(8). 1123-1137 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, S., Yamamoto, N., Yoshida, Y., Asai, A., Kirino, T., Hamada, H.: "Adenovirus-mediated transfer of caspase-8 in combination with super-repressor of NF-kB drastically induced apoptosis in gliomas"Biochem.Biophys.Res.Commun.. 271(2). 544-552 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Furitsu T, Asai A, Kirino T, Hamada H.: "Co-transduction of p27Kip1 strongly augments Fas ligand-and caspase-8-mediated apoptosis in U-373MG glioma cells"Anticancer Res.. 21(5). 3261-3268 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, Hamada H: "Caspase-8 gene transduction augments radiation-induced apoptosis in DLD-1 cells"Biochem Biophys Res Commun.. 292(2). 347-354 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yamamoto S., et al., Hamada H.: "Reduced Transduction Efficiency of Adenoviral Vectors Expressing Human p53 Gene by Repeated Transduction into Glioma Cells in Vitro"Clin Cancer Res.. 8(3). 913-921 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakamura T, Sato K., Hamada H.: "Effective Gene Transfer to Human Melanomas via Integrin-Targeted Adenoviral Vectors"Hum.Gene Ther.. 13(5). 613-626 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Sakurai S, Shibasaki F, Asai A, Kirino T, Hamada H.: "Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas"Br J Cancer. 86(4). 587-595 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kawano Y, Kobune M, Yamaguchi M, Nakamura K, Ito Y, Sasaki K, Takahashi S, Nakamura T, Chiba H, Sato T, Matsunaga T, Azuma H, Ikebuchi K, Ikeda H, Kato J, Niitsu Y, Hamada H.: "Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subnit (hTERT)-transfected human stromal cells"Blood. 101(2). 532-540 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, Hamada H.: "5-Fluorouracil efficiently enhanced apoptosis induced by adenovirus-mediated transfer of caspase-8 in DLD-1 colon cancer cells"J Gene Med.. 5(4). 287-299 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuda H, et al., Hamada H.: "Effeicient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector"Mol.Ther.. 7(2). 1-12 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, N., Sakurai, S., Asai, A., Kirino, T., Hamada, H.: "Transduction of Apaf-1 or caspase-9 induces apoptosis in A-172 cells which are resistant to p53-mediated apoptosis"Biochem.Biophys.Res.Commun.. 272(3). 667-673 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Yamamoto N, Asai A, Kirino T, Hamada H.: "Adenovirus-mediated transfer of Fas ligand gene augments radiation-induced apoptosis in U-373MG glioma cells"Jpn J Cancer Res.. 91(10). 1044-1050 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Sakurai S, Asai A, Kirino T, Hamada H.: "Transduction of a fiber-mutant adenovirus for the HSVtk gene highly augments the cytopathic effect towards gliomas"Jpn J Cancer Res.. 91(10). 1028-1034 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Muramatsu Y, Asai A, Han S, Horii A, Kirino T, Hamada H.: "Degree of apoptosis induced by adenovirus-mediated transduction of p53 or p73alpha depends on the p53 status of glioma cells"Cancer Lett.. 160(1). 67-73 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shimizu, T., Shimada, H., Ochiai T., Hamada, H.: "Enhanced growth suppression in esophageal carcinoma cells using adenovirus-mediated fusion gene transfer (uracl phosphoribosyl-transferase and herpes simplex virus thymidine kinase)"Cancer Gene Therapy. 8(7). 512-521 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura, N., Sakurai, S., Asai, A., Kirino, T., Hamada, H.: "Co-transduction of apaf-1 and caspase-9 augments estoposide-induced apoptosis in U-373MG glioma cells"Jpn J Cancer Res.. 92(4). 467-474 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Sakurai S, Asai A, Kirino T, Hamada H.: "Over-expression of APAF-1 and caspase-9 augments radiation-induced apoptosis in U-373MG glioma cells"Int J Cancer. 93(2). 252-261 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Sakurai S, Asai A, Kirino T, Hamada H.: "Caspase-9 transduction overrides the resistance mechanism against p53-mediated apoptosis in U-87MG glioma cells"Neurosurgery discussion 186-7. 49(1). 177-186 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakamura T, Sato K, Hamada H.: "Reduction of natural adenovirus tropism to the liver by both ablation of fiber-coxsackievirus and adenovirus receptor interaction and use of replaceable short fiber"J Virol.. 77(4). 2512-2521 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Dehari H, Ito Y, Nakamura T, Kobune M, Sasaki K, Yonekura N, Kohama G, Hamada H.: "Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer"Cancer Gene Therapy. 10(1). 75-85 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinoura N, Yamamoto N, Yoshida Y, Fujita T, Saito N, Asai A, Kirino T, Hamada H.: "Adenovirus-mediated gene transduction of IkappaB or IkappaB plus Bax gene drastically enhances tumor necrosis factor (TNF)-induced apoptosis in human gliomas"Jpn J Cancer Res. 91(1). 41-51 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, Yoshida, Y., Asai, A., Kirino, T., and Hamada, H.: "Adenovirus-mediated transfer of p53 and Fas ligand drastically enhances apoptosis in gliomas"Cancer Gene Ther.. 7(5). 732-738 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, Saito, K., Yoshida, Y., Hashimoto, M., Asai, A., Kirino, T., and Hamada, H.: "Adenovirus-mediated transfer of Bax with caspase-8 controlled by myelin basic protein promoter induces enhanced apoptosis in gliomas"Cancer Gene Ther.. 7(5). 739-748 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Motoi, F., Sunamura, M., Ding, L., Duda, DG., Yoshida, Y., Zhang, W-P., Matsuno, S., and Hamada, H.: "Effective gene therapy for pancreatic cancer by cytokines mediated by restricted replication-competent adenovirus"Human Gene Ther.. 11(2). 223-235 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, N., Satou, R., Yoshida, Y., Asai, A., Kirino, T., and Hamada, H.: "Adenovirus-mediated transfer of Bcl-xl protects neuronal cells from Bax-induced apoptosis"Exp.Cell Res.. 254(2). 221-231 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, N., Muramatsu, Y., Yoshida, Y., Asai, A., Kirino, T., and Hamada, H.: "Adenovirus-mediated transfer of caspase-3 with Fas ligand Induces drastic apoptosis In U373MG glioma cells"Exp.Cell Res.. 256(2). 423-433 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, N., Yoshida, Y., Asai, A., Kirino, T., and Hamada, H.: "Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas : Implication for gene therapy"Hum.Gene Ther. 11(8). 1123-1137 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, S., Yamamoto, N., Yoshida, Y., Asai, A., Kirino, T., and Hamada, H.: "Adenovirus-mediated transfer of caspase-8 in combination with super-repressor of NF-kB drastically induced apoptosis in gliomas"Biochem.Biophys.Res.Commun.. 271(2). 544-552 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, N., Sakurai, S., Asai, A., Kirino, T., and Hamada, H.: "Transduction of Apaf-1 or caspase-9 induces apoptosis in A172 cells, which are resistant to p53-mediated apoptosis"Biochem.Biophys.Res.Commun.. 272(3). 667-673 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura N, Yamamoto N, Asai A, Kirino T, and Hamada H.: "Adenovirus-mediated Transfer of Fas Ligand Gene Augments Radiation-induced Apoptosis in U-373MG Glioma Cells"Jpn J Cancer Res. 91(10). 1044-1050 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura N, Sakurai S, Asai A, Kirino T, and Hamada H.: "Transduction of a Fiber-mutant Adenovirus for the HSVtk Gene Highly Augments the Cytopathic Effect towards Gliomas"Jpn J Cancer Res. 91(10). 1028-1034 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura N, Muramatsu Y, Asai A, Han S, Horii A, Kirino T, Hamada H.: "Degree of apoptosis induced by adenovirus-mediated transduction of p53 or p73alpha depends on the p53 status of glioma cells"Cancer Lett.. 160(1). 67-73 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shimizu, T., Shimada, H., Ochiai, T., and Hamada, H.: "Enhanced growth suppression in esophageal carcinoma cells using adenovirus-mediated fusion gene transfer (uracl phosphoribosyl-transferase and herpes simplex virus thymidine kinase)"Cancer Gene Therapy. 8(7). 512-521 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura, N., Sakurai, S., Asai, A., Kirino, T., and Hamada, H.: "Co-transduction of apaf-1 and caspase-9 augments etoposide-induced apoptosis in U-373MG glioma cells"Jpn J Cancer Res. 92(4). 467-474 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sninoura N, Sakurai S, Asai A, Kirino T, and Hamada, H.: "Over-expression of APAF-1 and caspase-9 augments radiation-induced apoptosis in U-373MG glioma cells"Int J Cancer. 15 : 93(2). 252-261 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura N, Sakurai S, Asai A, Kirino T, and Hamada H.: "Caspase-9 transduction overrides the resistance mechanism against p53-mediated apoptosis in U-87MG glioma cells"Neurosurgery. 49(1) (discussion 186-187). 177-186 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura N, Furitsu T, Asai A, Kirino T, and Hamada H.: "Co-transduction of p27Kipl strongly augments Fas ligand- and caspase-8-mediated apoptosis in U-373MG glioma cells"Anticancer Res.. 21(5). 3261-3268 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, and Hamada H.: "Caspase-8 gene transduction augments radiation-induced apoptosis in DLD-1 cells"Biochem Biophys Res Commun. 292(2). 347-354 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamamoto S., et al. and Hamada H.: "Reduced transduction efficiency of adenoviral vectors expressing human p53 gene by repeated transduction into glioma cells in vitro"Clin Cancer Res. 8(3). 913-921 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura T, Sato K. and Hamada H.: "Effective Gene Transfer to Human Melanomas via Integrin-Targeted Adenoviral Vectors"Hum.Gene Ther.. 13(5). 613-626 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinoura N, Sakurai S, Shibasaki F, Asai A, Kirino T, and Hamada H.: "Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas"Br J Cancer. 86(4). 587-595 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawano Y, Kobune M, Yamaguchi M, Nakamura K, Ito Y, Sasaki K, Takahashi S, Nakamura T, Chiba H, Sato T, Matsunaga T, Azuma H, Ikebuchi K, Ikeda H, Kato J, Niitsu Y, Hamada H.: "Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subnit (hTERT)-transfected human stromal cells"Blood. 101(2). 532-540 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Uchida H, Shinoura N, Kitayama J, Watanabe T, Nagawa H, Hamada, H.: "5-Fluorouracil efficiently enhanced apoptosis induced by adenovirus-mediated transfer of caspase-8 in DLD-1 colon cancer cells"J Gene Med. 5(4). 287-299 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuda H, et al and Hamada H.: "Efficient BMP2 gene transfer and bone formation of mesenchymal stem cells by a fiber-mutant adenoviral vector"Mol.Ther.. 7(2). 1-12 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakamura T, Sato K, and Hamada H.: "Reduction of natural adenovirus tropism to the liver by both ablation of fiber-Coxsackievirus and adenovirus receptor interaction and use of replaceable short fiber"J Virol. 77(4). 2512-2521 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Dehari H, Ito Y, Nakamura T, Kobune M, Sasaki K, Yonekura N,Kohama G, Hamada H.: "Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer"Cancer Gene Therapy. 10(1). 75-85 (2003)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2004-04-14  

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