2003 Fiscal Year Annual Research Report

肝癌に対する免疫遺伝子治療―局所遺伝子治療との併用療法の検討―

Research Project

Project/Area Number	14370185
Research Institution	Kagawa University
Principal Investigator	栗山茂樹香川大学, 医学部, 教授 (50244710)
Co-Investigator(Kenkyū-buntansha)	吉治仁志奈良県立医科大学, 医学部, 助手 (40336855) 正木勉香川大学, 医学部, 助手 (30335848) 黒河内和貴香川大学, 医学部, 助手 (10294753)
Keywords	遺伝子治療 / 肝癌 / アデノウィルス / レトロウィルス / 免疫 / 自殺遺伝子 / 癌抑制遺伝子 / 血管新生
Research Abstract	消化器癌に対する遺伝子治療の確立を目的に、消化器癌の発生および発育に重要な役割を演じている分子を同定するために、種々の基礎的あるいは臨床的検討を行い、平成15年度においては以下のごとき成果を得た。ヒト肝癌発生過程における細胞周期関連分子の関与を検討したところ、慢性肝炎および肝硬変に比し、肝癌ではcyclin D1、cyclin E、cyclin Aおよびcyclin-dependent kinase 4(Cdk4)さらにWee1が、量的に増加しているのみならず酵素活性が上昇していることを報告した(Hepatology 37:534-543,2003)。肝癌の発生には、C型肝炎ウイルスによる慢性炎症が大きく関与しているが、C型肝炎ウイルスによる肝細胞障害の機序に関しては不明な点が多く残されていた。本年度の検討において、肝内に浸潤したCD28陰性CD8陽性T細胞が、C型肝炎ウイルスによる肝細胞障害に重要な役割を演じていることを見出した(J Clin Immunol 23:518-527,2003)。我々はすでに、肝癌発育には血管内皮増殖因子(VEGF)の発現が必須であることを報告しているが、本年度の検討において、VEGFの発現は肝線維にも必須の因子であり(Gut 52:1347-1354,2003)、interferon-βとangiotensin変換酵素阻害剤の併用投与や銅のキレート剤であるtrientine投与、さらにtissue inhibitor of metalloproteinases-1の発現を阻害することにより、血管新生を抑制し肝癌の発生を抑制することを動物実験において示した(Clin Cancer Res 9:6038-6045,2003;Oncol Rep 10:1369-1373,2003;Int J Cancer 105:340-346,2003)。また、ヒト大腸癌の発生には、cyclin B1の発現増強ならびにCdk inhibitorであるp57の発現消失が関与しており、p57陰性大腸癌は陽性大腸癌に比し予後不良であることを報告した(Int J Oncol 22:1101-1110.2003;Int J Oncol 23:1537-1543,2003)。本年度の研究成果より、消化器癌の発生ならびに発育を制御しえる可能性のある分子が判明してきており、今後はこれらの分子の発現を遺伝子レベルで制御することにより、消化器癌の発生ならびに発育を阻止しえる治療法の開発を検討する予定である。

Research Products

(27 results)

All Other

All Publications (27 results)

[Publications] Masaki T, Shiratori Y, Rengifo W, 9 Others(last).: "Cyclins and cyclin-dependent kinases : comparative study of hepatocellular carcinoma versus cirrhosis."Hepatology. 37. 534-543 (2003)
[Publications] Morishita A, Murota M, Fujita J, 6 Others(last).: "Autoreactive helper T cells specific for cytokeratin 19 in patients with autoimmune hepatitis."Hepatol Res. 25. 415-422 (2003)
[Publications] Murota M, Watanabe S, Fujita J, 10 Others(last).: "Aberrant cytokeratin expression and high susceptibility to apoptosis in autoimmune hepatitis."Hepatol Res. 25. 271-280 (2003)
[Publications] Kobara H, Uchida N, Tsutsui K, 4 Others(last).: "Abnormal bile flow in patients with achalasia."J Gastroenterol. 38. 327-331 (2003)
[Publications] Kurokohchi K, Masaki T, Arima K, 8 Others(last).: "CD28-negative CD8-positive cytotoxic T lymphocytes mediate Hepatocellular damage in hepatitis C virus infection."J Clin Immunol. 23. 518-527 (2003)
[Publications] Wakabayashi H, Ushiyama T, Ishimura K, 6 Others(8^<th>).: "Significance of reduction surgery in multidisciplinary treatment of advanced hepatocellular carcinoma with multiple intrahepatic lesions."J Surg Oncol. 82. 98-103 (2003)
[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others.: "Angiotensin-II induces the tissue inhibitor of metalloproteinases-1 through the protein kinase-C signaling pathway in rat liver fibrosis development."Hepatol Res. 27. 51-56 (2003)
[Publications] Iihara N, Kurokohchi K, Tsukamoto T, 5 Others(5^<th>).: "Hypoglycaemia in patients with liver diseases administered levothyroxine."J Clin Pharm Ther. 28. 355-361 (2003)
[Publications] Li J-Q, Wu F, Usuki H, 9 Others(9^<th>).: "Loss of p57^<KIP2> is associated with colorectal carcinogenesis."Int J Oncol. 23. 1537-1543 (2003)
[Publications] Uchida N, Tsutsui K, Ezaki T, 10 Others(last).: "Combination of assay of human telomerase reverse transcriptase mRNA and cytology using bile obtained by endoscopic transpapillary catheterization into the gallbladder for diagnosis of gallbladder carcinoma."Am J Gastroenterol. 98. 2415-2419 (2003)
[Publications] Noguchi R, Yoshiji H, Kuriyama S, 11 Others.: "Combination of interferon-β and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis."Clin Cancer Res. 9. 6038-6045 (2003)
[Publications] Uchida N, Tsutsui K, Kobara H, 8 Others(last).: "A case of gallbladder carcinoma diagnosed preoperatively by the detection of human telomerase reverse transcriptase mRNA in endoscopically obtained gallbladder bile."Endoscopy. 35. 185-188 (2003)
[Publications] Yoshiji H, Kuriyama S, Yoshii J, 11 Others.: "Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis."Gut. 52. 1347-1354 (2003)
[Publications] Li J-Q, Kubo A, Wu F, 11 Others(last).: "Cyclin B1,unlike cyclin G1,increases significantly during colorectal carcinogenesis and during later metastasis to lymph nodes."Int J Oncol. 22. 1101-1110 (2003)
[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others.: "Extracellular matrix remodeling may predominate over hepatocyte injury in hepatocellular carcinoma development."Oncol Rep. 10. 957-962 (2003)
[Publications] Ikenaka Y, Yoshiji H, Kuriyama S, 8 Others.: "Tissue inhibitor of metalloproteinases-1(TIMP-1) inhibits tumor growth and angiogenesis in the timp-1 transgenic mouse model."Int J Cancer. 105. 340-346 (2003)
[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others.: "The copper-chelating agent, trientine, attenuates liver enzymealtered preneoplastic lesions in rats by angiogenesis suppression."Oncol Rep. 10. 1369-1373 (2003)
[Publications] Masaki T, Igarashi K, Tokuda M, 11 Others(last).: "pp60c-src activation in lung adenocarcinoma."Eur J Cancer. 39. 1447-1455 (2003)
[Publications] Watanabe S, Uchida N, Masaki T, 7 Others(6^<th>).: "Measurement of left portal vein blood flow velocity by doppler sonography in a patient with acute fatty liver of pregnancy."J Med Ultrasound. 30. 57-61 (2003)
[Publications] Uchida N, Tsutsui K, Ezaki T, 5 others(last).: "Conversion from external nasobiliary drainage to internal drainage using endoscopically available scissor forceps."Hepato Gastroenterol. 50. 1891-1893 (2003)
[Publications] Tsujimoto T, Kuriyama S, Yoshiji H, 4 Others.: "Ultrasonographic findings of amebic colitis."J Gastroenterol. 38. 82-86 (2003)
[Publications] Akahane T, Kuriyama S, Matsumoto M, 5 Others.: "Pancreatic pleural effusion with a pancreaticopleural fistula diagnosed by magnetic resonance cholangiopancreatography and cured by somatostatin analogue treatment."Abdom Imaging. 28. 92-95 (2003)
[Publications] Uchida N, Ezaki T, Fukuma H, 10 Others(last).: "Concomitant colitis associated with primary sclerosing cholangitis."J Gastroenterol. 38. 482-487 (2003)
[Publications] Kuriyama S, Tsujinoue H, Yoshiji H: "Immune response to suicide gene therapy. In : Methods in Molecular Medicine vol. 90 (Springer CJ ed.)"Humana Press, Totowa, New Jersey, USA. 353-369 (2003)
[Publications] 栗山茂樹, 吉治仁志, 正木勉ほか12名: "AFP遺伝子の制御領域を含むキメラ制御因子を用いた肝癌細胞選択的遺伝子発現の誘導 IN:臨床応用を目指した消化器分子生物学(小俣政男編)"アークメディア、東京. 93-99 (2003)
[Publications] Yoshiji H, Kuriyama S, Fukui H: "Renin-angiotensin system and hepatocellular carcinoma : Role of angiogenesis. In : Recent Reserarch Development in Cancer Vol 5 (Mukhtar H, Labrie F, eds.)"Transworld Research Network, Kerela, India. 39-51 (2003)
[Publications] 栗山茂樹: "消化器癌に対する遺伝子治療の現状In:肝・胆・膵疾患の最新医療(戸田剛太郎、沖田極、松野正紀:編集主幹.井廻道夫、河田純男、熊田博光、小菅智男、幕内雅敏、門田守人:編集委員.)"先端医療技術研究所、東京. 13-19 (2003)

2003 Fiscal Year Annual Research Report

肝癌に対する免疫遺伝子治療―局所遺伝子治療との併用療法の検討―

Principal Investigator

栗山 茂樹 香川大学, 医学部, 教授 (50244710)

Research Products

[Publications] Masaki T, Shiratori Y, Rengifo W, 9 Others(last).: "Cyclins and cyclin-dependent kinases : comparative study of hepatocellular carcinoma versus cirrhosis."Hepatology. 37. 534-543 (2003)

[Publications] Morishita A, Murota M, Fujita J, 6 Others(last).: "Autoreactive helper T cells specific for cytokeratin 19 in patients with autoimmune hepatitis."Hepatol Res. 25. 415-422 (2003)

[Publications] Murota M, Watanabe S, Fujita J, 10 Others(last).: "Aberrant cytokeratin expression and high susceptibility to apoptosis in autoimmune hepatitis."Hepatol Res. 25. 271-280 (2003)

[Publications] Kobara H, Uchida N, Tsutsui K, 4 Others(last).: "Abnormal bile flow in patients with achalasia."J Gastroenterol. 38. 327-331 (2003)

[Publications] Kurokohchi K, Masaki T, Arima K, 8 Others(last).: "CD28-negative CD8-positive cytotoxic T lymphocytes mediate Hepatocellular damage in hepatitis C virus infection."J Clin Immunol. 23. 518-527 (2003)

[Publications] Wakabayashi H, Ushiyama T, Ishimura K, 6 Others(8^<th>).: "Significance of reduction surgery in multidisciplinary treatment of advanced hepatocellular carcinoma with multiple intrahepatic lesions."J Surg Oncol. 82. 98-103 (2003)

[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others.: "Angiotensin-II induces the tissue inhibitor of metalloproteinases-1 through the protein kinase-C signaling pathway in rat liver fibrosis development."Hepatol Res. 27. 51-56 (2003)

[Publications] Iihara N, Kurokohchi K, Tsukamoto T, 5 Others(5^<th>).: "Hypoglycaemia in patients with liver diseases administered levothyroxine."J Clin Pharm Ther. 28. 355-361 (2003)

[Publications] Li J-Q, Wu F, Usuki H, 9 Others(9^<th>).: "Loss of p57^<KIP2> is associated with colorectal carcinogenesis."Int J Oncol. 23. 1537-1543 (2003)

[Publications] Noguchi R, Yoshiji H, Kuriyama S, 11 Others.: "Combination of interferon-β and the angiotensin-converting enzyme inhibitor, perindopril, attenuates murine hepatocellular carcinoma development and angiogenesis."Clin Cancer Res. 9. 6038-6045 (2003)

[Publications] Uchida N, Tsutsui K, Kobara H, 8 Others(last).: "A case of gallbladder carcinoma diagnosed preoperatively by the detection of human telomerase reverse transcriptase mRNA in endoscopically obtained gallbladder bile."Endoscopy. 35. 185-188 (2003)

[Publications] Yoshiji H, Kuriyama S, Yoshii J, 11 Others.: "Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis."Gut. 52. 1347-1354 (2003)

[Publications] Li J-Q, Kubo A, Wu F, 11 Others(last).: "Cyclin B1,unlike cyclin G1,increases significantly during colorectal carcinogenesis and during later metastasis to lymph nodes."Int J Oncol. 22. 1101-1110 (2003)

[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others.: "Extracellular matrix remodeling may predominate over hepatocyte injury in hepatocellular carcinoma development."Oncol Rep. 10. 957-962 (2003)

[Publications] Ikenaka Y, Yoshiji H, Kuriyama S, 8 Others.: "Tissue inhibitor of metalloproteinases-1(TIMP-1) inhibits tumor growth and angiogenesis in the timp-1 transgenic mouse model."Int J Cancer. 105. 340-346 (2003)

[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others.: "The copper-chelating agent, trientine, attenuates liver enzymealtered preneoplastic lesions in rats by angiogenesis suppression."Oncol Rep. 10. 1369-1373 (2003)

[Publications] Masaki T, Igarashi K, Tokuda M, 11 Others(last).: "pp60c-src activation in lung adenocarcinoma."Eur J Cancer. 39. 1447-1455 (2003)

[Publications] Watanabe S, Uchida N, Masaki T, 7 Others(6^<th>).: "Measurement of left portal vein blood flow velocity by doppler sonography in a patient with acute fatty liver of pregnancy."J Med Ultrasound. 30. 57-61 (2003)

[Publications] Uchida N, Tsutsui K, Ezaki T, 5 others(last).: "Conversion from external nasobiliary drainage to internal drainage using endoscopically available scissor forceps."Hepato Gastroenterol. 50. 1891-1893 (2003)

[Publications] Tsujimoto T, Kuriyama S, Yoshiji H, 4 Others.: "Ultrasonographic findings of amebic colitis."J Gastroenterol. 38. 82-86 (2003)

[Publications] Akahane T, Kuriyama S, Matsumoto M, 5 Others.: "Pancreatic pleural effusion with a pancreaticopleural fistula diagnosed by magnetic resonance cholangiopancreatography and cured by somatostatin analogue treatment."Abdom Imaging. 28. 92-95 (2003)

[Publications] Uchida N, Ezaki T, Fukuma H, 10 Others(last).: "Concomitant colitis associated with primary sclerosing cholangitis."J Gastroenterol. 38. 482-487 (2003)

[Publications] Kuriyama S, Tsujinoue H, Yoshiji H: "Immune response to suicide gene therapy. In : Methods in Molecular Medicine vol. 90 (Springer CJ ed.)"Humana Press, Totowa, New Jersey, USA. 353-369 (2003)

[Publications] 栗山茂樹, 吉治仁志, 正木 勉ほか12名: "AFP遺伝子の制御領域を含むキメラ制御因子を用いた肝癌細胞選択的遺伝子発現の誘導 IN:臨床応用を目指した消化器分子生物学(小俣政男 編)"アークメディア、東京. 93-99 (2003)

[Publications] Yoshiji H, Kuriyama S, Fukui H: "Renin-angiotensin system and hepatocellular carcinoma : Role of angiogenesis. In : Recent Reserarch Development in Cancer Vol 5 (Mukhtar H, Labrie F, eds.)"Transworld Research Network, Kerela, India. 39-51 (2003)

栗山茂樹香川大学, 医学部, 教授 (50244710)

[Publications] 栗山茂樹, 吉治仁志, 正木勉ほか12名: "AFP遺伝子の制御領域を含むキメラ制御因子を用いた肝癌細胞選択的遺伝子発現の誘導 IN:臨床応用を目指した消化器分子生物学(小俣政男編)"アークメディア、東京. 93-99 (2003)