Towards establishment of gene therapy for human pancreatic and endometrial cancers

1999 Fiscal Year Final Research Report Summary

• Project/Area Number: 10557026
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 展開研究
• Research Field: Experimental pathology
• Research Institution: Tohoku University
• Principal Investigator: HORII Akira Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40249983)
• Co-Investigator(Kenkyū-buntansha): YAJIMA Akira Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (80004993) ; FURUKAWA Toru Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (30282122) ; SAKATA Tsuneaki Shionogi Pharmaceuticals, Chief Scientist, 主任研究員 ; SUNAMURA Makoto Tohoku University, Graduate School of Medicine, Lecturer, 医学部附属病院, 講師 (10201584)
• Project Period (FY): 1998 – 1999
• Keywords: Adenovirus vector / SMAD4 / PTEN / pancreatic cancer / endometrial cancer

Research Abstract

1.Among regions of frequent chromosomal aberrations, loss of three chromosomal regions, 12q, 17p, and 18q, associated with poor prognosis in human pancreatic cancer. Adenoviral mediated delivery of the SMAD4 gene in pancreatic cancer cell lines with homozygous deletion of SMAD4 did not show any suppression of cell growth. We previously reported that, loss of 18q is an early event in pancreatic carcinogenesis. There is a possibility that mutation of the SMAD4 gene is responsible for the initial step of pancreatic carcinogenesis as well as prognosis defining factor. However, there is a possibility of unknown tumor suppressor gene on 18q that is distinct from SMAD4.
2.We and others previously reported frequent somatic mutation of the PTEN gene in endometrial cancer. We attempted a trial of gene therapy by adenovirus mediated introduction of this gene in endometrial cancer cell lines with two-hit mutation of this gene. The trial was successful in vitro, and apoptosis was induced in tumor cells after introduction of normal copy of PTEN. However, the attempt was not successful in vivo. These results suggested that the PTEN gene is a good candidate for gene therapy in human endometrial cancer after appropriate improvement.

Research Products

• [Journal Article] Mutational analysis of the CTNNB1 (β-catenin) gene in human endometrial cancer : Frequent mutations at codon 34 that cause nuclear accumulation. (2000)
  • Author(s): Ikeda, T.
  • Journal Title: Oncol.Rep. 7 Pages: 323-326
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] p24/ING1-ALT1 and p47/ING1-ALT2,distinct alternative transcripts of p33/ING1 (2000)
  • Author(s): Saito, A.
  • Journal Title: J.Hum.Genet. 45 Pages: 177-181
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer. (2000)
  • Author(s): Ikeda, T.
  • Journal Title: Oncol.Rep. 7 Pages: 567-570
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium. (2000)
  • Author(s): Semba, S.
  • Journal Title: Int.J.Oncol. 16 Pages: 731-737
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Asscciation of poor prognosis with loss of 12q,17p, and 18q, and concordant loss of 6q/17p and 12q/18q in human pancreatic ductal adenocarcinoma. (2000)
  • Author(s): Yatsuoka, T.
  • Journal Title: Am.J.Gastroent. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutational analysis of the CTNNB1(β-catenin) gene in human endometrial cancer : Frequent mutations at codon 34 that cause nuclear accumulation. (2000)
  • Author(s): Ikeda, T,.Yoshinaga, K., Semba, S., Kondo, E., Ohmori, H., Horii, A.
  • Journal Title: Oncol.Rep. 7 Pages: 323-326
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1. (2000)
  • Author(s): Saito, A., Furukawa, T., Fukushige, S., Koyama, S., Hoshi, M., Hayashi, Y., Horii, A.
  • Journal Title: J.Hum.Genet. 45 Pages: 177-181
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer. (2000)
  • Author(s): Ikeda, T., Yoshinaga, K., Suzuki, A., Sakurada, A., Ohmori, H., Horii, A.
  • Journal Title: Oncol.Rep. 7 Pages: 567-570
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium. (2000)
  • Author(s): Semba, S., Ouyang, H., Han, S.-Y., Kato, Y., Horii, A.
  • Journal Title: Int.J.Oncol. 16 Pages: 731-737
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of poor prognosis with loss of 12q, 17p, and 18q, and concordant loss of 6q/17p and 12q/18q in human pancreatic ductal adenocarcinoma. (2000)
  • Author(s): Yatsuoka, T., Sunamura, M., Furukawa, T., Fukushige, S., Yokoyama, T., Inoue, H., Shibuya, K., Takeda, K., Matsuno, S., Horii, A.
  • Journal Title: Am.J.Gastroent. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer. (1999)
  • Author(s): Abe, T.
  • Journal Title: Genes Chromosomes Cancer 25 Pages: 60-64
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Infrequent somatic mutations of the p73 gene in various human cancers. (1999)
  • Author(s): Han, S.
  • Journal Title: Eur.J.Surg.Oncol. 25 Pages: 194-198
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomic analysis of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma. (1999)
  • Author(s): Yatsuoka, T.
  • Journal Title: Int.J.Panc. 25 Pages: 97-102
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Controlling tumor angiogenesis and metastasis of C26 murin colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785,in two tumor models. (1999)
  • Author(s): Lozonschi L.
  • Journal Title: Cancer Res. 59 Pages: 1252-1258
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cloning and characterization of the human UDP-N-acetylglucosamine : α-1,3-D-mannoside β-1,4-N-acetylglucosaminyltransferase IV-homologue (hGnT-IV-H) gene (1999)
  • Author(s): Furukawa, T.
  • Journal Title: J.Hum.Genet. 44 Pages: 397-401
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenovirus-mediated transfer or p33^<ING> with p53 drastically augments apoptosis in gliomas. (1999)
  • Author(s): Shinoura, N.
  • Journal Title: Cancer Res. 59 Pages: 5521-5528
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Adenovirus-mediated delivery of the PTEN gene inhibits cell growth by induction of apoptosis in endometrial cancer. (1999)
  • Author(s): Sakurada, A.
  • Journal Title: Int.J.Oncol. 15 Pages: 1069-1074
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer. (1999)
  • Author(s): Abe, T., Makino, N., Furukawa.T., Ouyang, H., Kimura, M., Yatsuoka T., Yokoyama, T., Inoue, H., Fukushige, S., Hoshi, M., Hayashi, Y., Sunamura, M., Kobari, M., Matsuno, S., Horii, A.
  • Journal Title: Genes Chromosomes Cancer 25 Pages: 60-64
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Infrequent somatic mutations of the p73 gene in various human cancers. (1999)
  • Author(s): Han, S., Semba, S., Abe, T., Makino, N., Furukawa, T., Fukushige, S., Takahashi, H., Sakurada, A., Sato, M., Shiiba, K., Matsuno, S., Nimura, Y., Nakagawara, A., Horii, A.
  • Journal Title: Eur.J.Surg.Oncol. 25 Pages: 194-198
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic analysis of the thymine-DNA glycosylase (TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma. (1999)
  • Author(s): Yatsuoka, T., Furukawa, T., Abe, T., Yokoyama, T., Sunamura, M., Kobari, M., Matsuno, S., Horii, A.
  • Journal Title: Int.J.Panc. 25 Pages: 97-102
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Controlling tumor angiogenesis and metastasis of C26 murin colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models. (1999)
  • Author(s): Lozonschi L., Sunamura M., Kobari M., Egawa S., Ding L., Matsuno S.
  • Journal Title: Cancer Res. 59 Pages: 1252-1258
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cloning and characterization of the human UDP-N-acetylglucosamine:a-1,3-D-mannosideb-1,4-N-acetylglucosaminyltransferase IV-homologue (hGnT-IV-H) gene. (1999)
  • Author(s): Furukawa.T., Youssef, E.M., Yatsuoka, T., Yokoyama, T., Makino, N., Inoue, H., Fukushige, S., Hoshi, M., Hayashi, Y., Sunamura, M., Horii, A.
  • Journal Title: J.Hum.Genet. 44 Pages: 397-401
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenovirus-mediated transfer of p33ING with p53 drastically augments apoptosis in gliomas. (1999)
  • Author(s): Shinoura, N., Muramatsu, Y., Nishimura, M., Yoshida, Y., Saito, A., Yokoyama, T., Furukawa, T., Horii, A., Hashimoto, M., Asai, A., Kirino, T., Hamada, H.
  • Journal Title: Cancer Res. 59 Pages: 5521-5528
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Adenovirus-mediated delivery of the PTEN gene inhibits cell growth by induction of apoptosis in endometrial cancer. (1999)
  • Author(s): Sakurada, A., Hamada, H., Fukushige, S., Yokoyama, T., Yoshinaga, K., Furukawa, T., Sato, S., Yajima, A., Sato, M., Fujimura, S., Horii, A.
  • Journal Title: Int.J.Oncol. 15 Pages: 1069-1074
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genomic analysis of DUSP6,a dual specificity MAP kinase phosphatase, in pancreatic cancer. (1998)
  • Author(s): Furukawa, T.
  • Journal Title: Cytogenetics and Cell Genetics 82 Pages: 156-159
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. (1998)
  • Author(s): Fukushige, S.
  • Journal Title: Cancer Research 58 Pages: 4222-4226
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The PTEN, BAX, and 1GF11R genes are mutatead in endometrial atypical hyperplasia. (1998)
  • Author(s): Yoshinaga, K.
  • Journal Title: Japanese Journal of Cancer Research 89 Pages: 985-990
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of a 100-kb region of common allelic loss on chromosome bands 10q25-q26 in human endometrial cancer. (1998)
  • Author(s): Yamakawa, H.
  • Journal Title: Genes, Chromosomes & Cancer 23 Pages: 74-77
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. (1998)
  • Author(s): Ouyang, H.
  • Journal Title: Clinical Cancer Research 4 Pages: 1071-1074
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer. (1998)
  • Author(s): Kimura, M.
  • Journal Title: Cancer Research 58 Pages: 2456-2460
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer. (1998)
  • Author(s): Furukawa, T., Yatsuoka, T., Youssef, E.M., Abe, T., Yokoyama, T., Fukushige, S., Soeda, E., Hoshi, M., Hayashi, Y., Sunamura, M., Kobari, M., Horii, A.
  • Journal Title: Cytogenet.Cell Genet. 82 Pages: 156-159
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. (1998)
  • Author(s): Fukushige, S., Furukawa, T., Satoh, K., Sunamura, M., Kobari.M., Koizumi, M., Horii, A.
  • Journal Title: Cancer Res. 58 Pages: 4222-4226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The PTEN, BAX, and IGFIIR genes are mutated in endometrial atypical hyperplasia. (1998)
  • Author(s): Yoshinaga, K., Sasano, H., Furukawa, T., Yamakawa, H., Yuki, M., Sato, S., Yajima, A., Horii, A.
  • Journal Title: Jpn.J.Cancer Res. 89 Pages: 985-990
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of a 100-kb region of common allelic loss on chromosome bands 10q25-q26 in human endometrial cancer. (1998)
  • Author(s): Yamakawa, H., Nagase, S., Yuki, M., Shiwaku, H.O., Furukawa, T., Yoshinaga, K., Soeda, E., Hoshi, M., Hayashi, Y., Sato, S., Yajima, A., Horii, A.
  • Journal Title: Genes Chromosomes Cancer 23 Pages: 74-77
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. (1998)
  • Author(s): Ouyang, H., Furukawa, T., Abe, T., Kato, Y., Horii, A.
  • Journal Title: Clin.Cancer Res. 4 Pages: 1071-1074
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer. (1998)
  • Author(s): Kimura, M., Furukawa, T., Abe, T., Yatsuoka, T., Youssef, E.M., Yokoyama, T., Ouyang, H., Ohnishi, Y., Sunamura, M., Kobari, M., Matsuno, S., Horii, A.
  • Journal Title: Cancer Res. 58 Pages: 2456-2460
  • Description: 「研究成果報告書概要(欧文)」より