2002 Fiscal Year Final Research Report Summary
Suicide gene therapy for intractable gastrointestinal cancer with tumor specific promoters
| Project/Area Number |
13670580
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Chiba Cancer Center Research Institute |
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Principal Investigator |
KAWAMURA Kiyoko Chiba Cancer Center Research Institute Division of Pathology Research Fellow, 病理研究部, 主席研究員 (80260248)
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| Co-Investigator(Kenkyū-buntansha) |
SAISHO Hiromitsu Chiba University, Graduate School of Medicine Department of Medicine and Clinical Oncology Professor, 大学院・医学研究院腫瘍内科学, 教授 (10092058)
TAGAWA Masatoshi Chiba Cancer Center Research Institute Division of Pathology Head, 病理研究部, 部長 (20171572)
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| Project Period (FY) |
2001 – 2002
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| Keywords | Gene therapy / Tumor promoter / HSV-TK / Reporter assay / c-erbB-2 / Survivin / Midkine |
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| Research Abstract |
We examined the transcriptional regulatory regions of the midkine gene, which is expressed in a variety of tumors but scarcely in normal cells, with luciferase reporter assays. We demonstrated that the most potent transcriptional activity was obtained with the 2335-bp upstream region tested in hepatocellular carcinoma and with the 609-bp region in pancreatic tumors. The 1041- and the 335-bp but not the 70-bp region contained cis-acting elements for transcriptional activation in both types of tumor cells. Transfection of the herpes simplex virus-thymidine kinase (HSV-TK) gene fused with the midkine regulatory region in tumor cells increased their susceptibility to a prodrug ganciclovir. The regulatory regions of the c-erbB-2 gene, which is highly expressed in breast and gastric cancer, were also analyzed with the same reporter assays. We showed that the activity of the 251-bp region was the strongest in tumors among other genomic fragments deleted from 5'-side. Tumor cells transfected with the 251-bp region linked with the HSV-TK gene was more sensitive to ganciclovir in vitro and in vivo than parent cells. We also investigated the transcriptional control regions of the survivin gene, which is highly expressed in the G2/M phase. Deletion of the regulatory regions from the 5'-side showed that the 500-bp region was responsible for the preferential expression in tumor cells but not in normal cells.
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[Publications] Kawamura, K., O-Wang, J., Bahar, R., Koshikawa, N., Shishikura, T. Nakagawara, A., Sakiyama, S., Kajiwara, K., Kimura, M. and Tagawa, M.: "The error-prone DNA polymerase ζ catalytic subunit (Rev3) gene is ubiquitously expressed in normal and malignant human tissues"Int. J. Oncol.. 18. 97-103 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Kawamura, K., Bahar, R., Namba, H., Seimiya, M., Takenaga, K., Hamada, H., Sakiyama, S. and Tagawa, M.: "Bystander effect in uracil phosphoribosyltransferase/5-fluorouracil-mediated suicide gene therapy is correlated with the level of intercellular communication"Int J. Oncol.. 18. 117-120 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] O-Wang, J., Kawamura, K., Tada, Y., Ohmori, H., Kimura, H., Sakiyama, S and Tagawa, M.: "DNA polymerase κ implicated in spontaneous and DNA damage-induced mutagenesis, is overexpressed in lung cancer"Cancer Res.. 61. 5366-5369 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Miyauchi, M., Yoshida, Y., Tada, Y., Narita, M., Maeda, T., Bahar, R., Kadomatsu, K., Muramatsu, T., Matsubara, S., Nakagawara, A., Sakiyama, S. and Tagawa, M.: "Expression of herpes simplex virus-thymidine kinase gene controlled by a promoter region of the midkine gene confers selective cytotoxicity to ganciclovir in human carcinoma cells"Int J. Cancer. 91. 723-727 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Maeda, T., O-Wang, J., Matsubara, H., Asano, T., Ochiai, T., Sakiyama, S. and Tagawa, M.: "A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir"Cancer Gene Ther.. 8. 890-896 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Yoshida, Y., Tomizawa, M., Bahar, R., Miyauchi, M., Yamaguchi, T., Saisho, H., Kadomatsu, K., Muramatsu, T., Matsubara, S., Sakiyama, S. and Tagawa, M.: "A promoter region of midkine gene can activate transcription of an exogenous suicide gene in human pancreatic cancer"Anticancer Res.. 22. 117-120 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] O-Wang, J., Kajiwara, K., Kawamura K., Kimura, M., Miyagishima, H., Kosei, A. and Tagawa, M.: "An essential role for REV3 in mammalian cell survival : absence of REV3 induces p53-independent embryonic cells"Biochem. Biophys. Res. Commun.. 293. 1132-1137 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Ba|har, R., O-Wang, J., Kawamura, K., Seimiya, M., Wang, Y., Hatano, M., Okada, S., Tokuhisa, T., Watanabe, T. and Tagawa, M.: "Growth retardation, polyploidy and multinucleation induced by Clast3, a novel cell cycle-regulated protein"J. Biol. Chem.. 277. 40012-40019 (2002)
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[Publications] Ugai, S., Shimozato, O., Kawamura, K., Wang, Y-Q., Yamaguchi, T., Saisho, H., Sakiyama, S and Tagawa, M.: "Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts"Cancer Gene Ther.. (in press).
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「研究成果報告書概要(欧文)」より
