Gene therapy for intractable gastrointestinal tumors with tumor promoter-mediated oncolyitc adenoviruses

• Project/Area Number: 15590706
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Chiba Cancer Center Research Institute
• Principal Investigator: KAWAMURA Kiyoko Chiba Cancer Center Res.Inst., Division of Pathology, Senior Researcher, 病理研究部, 主席研究員 (80260248)
• Co-Investigator(Kenkyū-buntansha): TAGAWA Masatoshi Chiba Cancer Center Res.Inst., Division of Pathology, Head, 病理研究部, 部長 (20171572) ; SAISHO Hiromitsu Graduate School of Medicine, Chiba University, Department of Medicine & Clinical Oncology, Professor, 大学院・医学研究院・腫瘍内科学, 教授 (10092058)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: Gene Therapy / Tumor promoter / Transcription regulatory region / Oncolytic virus / Midkine / Survivin / E1A / SCID mouse

Research Abstract

We have constructed adenoviruses in which the E1A transcript was regulated with a 604 bp-regulatory region of the midkine gene (Ad/MK) ; the transcription of the gene is upregulated in a number of human gastrointestinal tumors but is restricted in normal adult tissues. Ad/MK induced greater E1A expression than wild-type Ad (Ad/WT) in human fibroblasts immortalized by the expression of dominant-negative p53 gene, but not in the parent normal fibroblasts. Ad/MK were cytotoxic to the immortalized fibroblasts compared with Ad/WT accordingly. Human hepatocellular carcinoma(HCC) cells were 500 times more susceptible to Ad/MK than normal fibroblasts, and replication of Ad/MK was 1000 times greater than that of Ad/WT in the HCC cells. Intratumoral injection of Ad/MK but not replication-defective Ad suppressed subsequent growth of solid HCC tumors developed in SCID mice. Histological examinations revealed massive necrosis of the tumors injected with Ad/MK. These data suggested that Ad/MK are oncolytic Ad that preferentially destroy tumors. We also examined the feasibility of oncolytic Ad with different a tumor promoter. Expression of the survivin gene is regulated with the cell cycle and is upregulated in tumors ; thereby the regulatory region is a candidate to control E1A expression. We identified a 500-bp region that mediated the preferential expression in tumors and is currently preparing oncolytic Ad with the promoter.

Research Products

• [Journal Article] Insertion of an exogenous promoter in the E1A regulatory region of adenovirus does not disturb viral replication despite reduced E1A transcription. (2004)
  • Author(s): Ling Yu
  • Journal Title: Cancer Lett. 230 Pages: 51-57
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA polymerase θ is preferentially expressed in lymphoid tissues and upregulated in human cancers. (2004)
  • Author(s): Kiyoko Kawamura
  • Journal Title: Int.J.Cancer 109 Pages: 9-16
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Midkine promoter-driven suicide gene expression and -mediated adenovirus replication produced cytotoxic effects to immortalized and tumour cells. (2004)
  • Author(s): Ling Yu
  • Journal Title: Eur.J.Cancer 40 Pages: 1787-1794
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Elevated expression of DNA polymerase κ expression in human lung cancer is associated with p53 inactivation : Negative regulation of POLK promoter activity by p53. (2004)
  • Author(s): YanQing Wang
  • Journal Title: Int.J.Oncol. 25 Pages: 161-165
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of CD40 ligand in CD40-positive murine tumors activates transcription of the interleukin-23 subunit genes and produces antitumor responses. (2004)
  • Author(s): Akihoko Wada
  • Journal Title: Anticancer Res. 24 Pages: 2713-2716
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Midkine promoter can mediate transcriptional activation of a fused suicide gene in abroader range of human breast cancer compared with c-erbB-2 promoter. (2004)
  • Author(s): Ling Yu
  • Journal Title: Oncology 66 Pages: 143-146
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Insertion of an exogenous promoter in the E1A regulatory region of adenovirus does not disturb viral replication despite reduced E1 A transcription. (2004)
  • Author(s): Yu, L., Hamada, K., Namba, M., Kadomatsu, K., Muramatsu, T., Matsubara, S., Tagawa, M.
  • Journal Title: Cancer Lett. 203 Pages: 51-57
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] DNA polymerase θ is preferentially expressed in lymphoid tissues and upregulated in human cancers. (2004)
  • Author(s): Kawamura, K., Bahar, R., Seimiya, M., Chiyo, M., Wada, A., Okada, S., Hatano, M., Tokuhisa, T., Kimura, H., Watanabe, S., Honda, I., Sakiyama, S., Tagawa, M., O-Wang, J.
  • Journal Title: Int.J.Cancer 109 Pages: 9-16
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Midkine promoter-driven suicide gene expression and-mediated adenovirus replication produced cytotoxic effects to immortalized and tumour cells. (2004)
  • Author(s): Yu, L., Hamada, K., Namba, M., Kadomatsu, K., Muramatsu, T., Matsubara, S., Tagawa, M.
  • Journal Title: Eur.J.Cancer 40 Pages: 1787-1794
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Elevated expression of DNA polymerase κ expression in human lung cancer is associated with p53 inactivation : Negative regulation of POLK promoter activity by p53. (2004)
  • Author(s): Wang, Y.Q., Seimiya, M., Kawamura, K., Yu, L., Ogi, T., Takenaga, K., Shishikura, T., Nakagawara, A., Sakiyama, S., Tagawa, M., O-Wang, J.
  • Journal Title: Int.J.Oncol. 25 Pages: 161-165
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of CD40 ligand in CD40-positive murine tumors activates transcription of the interleukin-23 subunit genes and produces antitumor responses. (2004)
  • Author(s): Wada, A., Tada, Y., Shimozato, O., Takiguchi, Y., Tatsumi, K., Kuriyama, T., Tagawa, M.
  • Journal Title: Anticancer Res. 24 Pages: 2713-2716
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Midkine promoter can mediate transcriptional activation of a fused suicide gene in a broader range of human breast cancer compared with c-erbB-2 promoter. (2004)
  • Author(s): Yu, L., Yamamoto, N., Kadomatsu, K., Muramatsu, T., Matsubara, S., Sakiyama S., Tagawa, M.
  • Journal Title: Oncology 66 Pages: 143-146
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Insertion of an exogenous promoter in the E1A regulatory region of adenovirus does not disturb viral replication despite reduced E1A transcription. (2004)
  • Author(s): Yu Ling
  • Journal Title: Cancer Lett. 230 Pages: 51-57
• [Journal Article] DNA polymerase θ is preferentially expressed in lymphoid tissues and upregulated in human cancers. (2004)
  • Author(s): Kawamura Kiyoko
  • Journal Title: Int.J.Cancer 109 Pages: 9-16
• [Journal Article] Midkine promoter-driven suicide gene expression and -mediated adenovirus replication produced cytotoxic effects to immortalized and tumour cells. (2004)
  • Author(s): Yu Ling
  • Journal Title: Eur.J.Cancer 40 Pages: 1787-1794
• [Journal Article] Elevated expression of DNA polymerase κ expression in human lung cancer is associated with p53 inactivation : Negative regulation of POLK promoter activity by p53. (2004)
  • Author(s): Wang YanQing
  • Journal Title: Int.J.Oncol. 25 Pages: 161-165
• [Journal Article] Expression of CD40 ligand in CD40-positive murine tumors activates transcription of the interleukin-23 subunit genes and produces antitumor responses. (2004)
  • Author(s): Wada Akihoko
  • Journal Title: Anticancer Res. 24 Pages: 2713-2716
• [Journal Article] Midkine promoter can mediate transcriptional activation of a fused suicide gene in a broader range of human breast cancer compared with c-erbB-2 promoter. (2004)
  • Author(s): Yu Ling
  • Journal Title: Oncology 66 Pages: 143-146
• [Journal Article] Stage-specific expression of Clast6/E3/LAPTM5 during B cell differentiation : elevated expression in human B lymphomas. (2003)
  • Author(s): Mika Seimiya
  • Journal Title: Int.J.Oncol. 22 Pages: 301-304
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity (2003)
  • Author(s): Yuji Tada
  • Journal Title: Cancer Gene Ther. 10 Pages: 134-140
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. (2003)
  • Author(s): Shin-ich Ugai
  • Journal Title: Cancer Gene Ther. 10 Pages: 187-192
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Down-regulated expression of CCAAT/enhancer binding protein α and β genes in human hepatocellular carcinoma : a possible plognostic marker. (2003)
  • Author(s): Minoru Tomizawa
  • Journal Title: Anticancer Res. 23 Pages: 351-354
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulatory regions of growth-related genes can activate an exogenous gene of the α-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells. (2003)
  • Author(s): Minoru Tomizawa
  • Journal Title: Anticancer Res. 23 Pages: 3273-3278
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cell growth- and P53-dependent transcriptional activity of the midkine promoter confers suicide gene expression in tumor cells. (2003)
  • Author(s): Ling Yu
  • Journal Title: Oncol.Rep. 10 Pages: 1301-1305
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Stage-specific expression of Clast6/E3/LAPTM5 during B cell differentiation : elevated expression in human B lymphomas. (2003)
  • Author(s): Seimiya, M., O-Wang, J., Bahar, R., Kawamura, K., Wang, Y., Saisho, H., Tagawa, M.
  • Journal Title: Int.J.Oncol. 22 Pages: 301-304
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fas ligand-expressing tumors induce tumor-specific protective mmunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity. (2003)
  • Author(s): Tada, Y., O-Wang, J., Wada, A., Takiguchi, Y., Tatsumi, K., Kuriyama, T., Sakiyama, S., Tagawa, M.
  • Journal Title: Cancer Gene Ther. 10 Pages: 134-140
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. (2003)
  • Author(s): Ugai, S., Shimozato, O., Kawamura, K., Wang, Y-Q., Yamaguchi, T., Saisho, H., Sakiyama, S, Tagawa, M.
  • Journal Title: Cancer Gene Ther. 10 Pages: 187-192
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down-regulated expression of CCAAT/enhancer binding protein α and β genes in human hepatocellular carcinoma : a possible prognostic marker. (2003)
  • Author(s): Tomizawa, M., Watanabe, K., Saisho, H., Nakagawara, A., Tagawa, M.
  • Journal Title: Anticancer Res. 23 Pages: 351-354
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulatory regions of growth-related genes can activate an exogenous gene of the α-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells. (2003)
  • Author(s): Tomizawa, M., Saisho, H., Tagawa, M.
  • Journal Title: Anticancer Res. 23 Pages: 3273-3277
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cell growth- and P53-dependent transcriptional activity of the midkine promoter confers suicide gene expression in tumor cells. (2003)
  • Author(s): Yu, L., Ugai, S., O-Wang, J., Namba, M., Kadomatsu, K., Muramatsu, T., Matsubara, S., Sakiyama, S., Tagawa, M.
  • Journal Title: Oncol.Rep. 10 Pages: 1301-1305
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kawamura K, Tagawa M, et al.: "Stage-specific expression of Clast6/E3/LAPTM5 during B cell differentiation : elevated expression in human B lymphomas."Int.J.Oncol. 22. 301-304 (2003)
• [Publications] Kawamura K, Tagawa M, et al.: "Fas ligand-expressing tumors induce tumor-specific protective immunity in the inoculated hosts but vaccination with the apoptotic tumors suppresses antitumor immunity."Cancer Gene Ther. 10. 134-140 (2003)
• [Publications] Kawamura K, Saisho H, Tagawa M, et al.: "Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts."Cancer Gene Ther. 10. 187-192 (2003)
• [Publications] Saisho H, Tagawa M, et al.: "Down-regulated expression of CCAAT/enhancer binding protein α and β genes in human hepatocellular carcinoma : a possible prognostic marker."Anticancer Res.. 23. 351-354 (2003)
• [Publications] Saisho H, Tagawa M, et al.: "Regulatory regions of growth-related genes can activate an exogenous gene of the α-fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells."Anticancer Res.. 23. 3273-3278 (2003)
• [Publications] Tagawa M, et al.: "Cell growth-and P53-dependent transcriptional activity of the midkine promoter confers suicide gene expression in tumor cells."Oncol.Rep. 10. 1301-1305 (2003)