2002 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 Medical School
Principal Investigator	栗山茂樹香川医科大学, 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) 正木勉香川医科大学, 医学部, 助手 (30335848) 黒河内和貴香川医科大学, 医学部, 助手 (10294753)
Keywords	遺伝子治療 / 肝癌 / アデノウイルス / レトロウイルス / 免疫 / 自殺遺伝子 / 癌抑制遺伝子 / 血管新生
Research Abstract	肝癌に対する遺伝子治療の確立を目標とし、肝癌発生あるいは肝癌発育に重要な役割を演じている分子を同定するために、種々の基礎的検討を行い、以下のごとき成果を得た。まず、ヒトにおける種々の肝疾患組織を用いて、肝癌発生における細胞周期関連分子の関与を検討したところ、慢性肝炎および肝癌周囲の肝硬変組織に比較し、肝癌ではサイクリンD1、サイクリンE、サイクリンAおよびサイクリン依存性キナーゼ(Cdk)4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, in press)。さらに,ヒト肝癌においては、p33^<ING1>やp57^<KIP2>などのCdk inhibitorの発現量ならびに活性が低下していることも確認した(Int J Oncol 20:769-775, 2002; Scand J Gastroenterol 37:1440-1448,2002)。また、我々はすでに、肝癌発育には血管内皮増殖因子(VEGF)の発現が必須の因子であることを報告しているが(Hepatology 28:1489-1496,1998; Hepatology 30:1179-1186,1999; CancerRes59:4413-4418,1999; Hepatology 33:841-847,2001)、本年度の検討において、basic fibroblast growth factor(bFGF)の発現が、VEGFの発現によって誘導される肝癌発育を相乗的に促進することを報告した(Hepatology 35:834-842,2002)。以上の結果より、肝癌発生および肝癌発育に重要な役割を担っているサイクリン、Cdkなどの細胞周期関連分子、あるいはVEGFやbFGFなどの腫瘍発育促進分子の発現を制御できれば、肝癌の発育のみならず発生を抑制し得る可能性が示された。事実、遺伝子レベルにおける制御ではなく、蛋白質レベルにおける検討ではあるが、肝発癌モデルラットにアンギオテンシン変換酵素の阻害剤を投与すれば、アンギオテンシンIIの活性を抑制することによってVEGF活性が抑制され、肝線維化の抑制のみならず肝癌発生を阻止し得ることを確認している(Clin Cancer Res 7:1073-1078,2001; J Hepatol 37:22-30,2002)。本年度の研究成果より、肝癌の発生ならびに発育を制御し得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って、肝癌の発生および発育を阻止し得る遺伝子治療の可能性を検討していく予定である。

Research Products
(23 results)

All Other

All Publications (23 results)

[Publications] Yoshida S, Kurokohchi K, Arima K, 7 Others (last): "Clinical significance of lens culinaris agglutinin-reactive fraction of serum α-fetoprotein in patients with hepatocellular carcinoma"Int J Oncol. 20. 305-309 (2002)
[Publications] Wu F, Nishioka M, Fujita J, 4 Others (last): "Expression of cytokeratin 19 in human hepatocellular carcinoma cell lines"Int J Oncol. 20. 31-37 (2002)
[Publications] Uchida N, Ezaki T, Fukuma H, 12 Others (last): "Conversion of endoscopic nasobiliary drainage to internal drainage by means of endoscopic scissor forceps"Endoscopy. 34. 180 (2002)
[Publications] Nakai S, Masaki T, Shiratori Y, 5 Others (last): "Expression of p57^<KIP2> in hepatocellular carcinoma : relationship between tumor differentiation and patient survival"Int J Oncol. 20. 769-775 (2002)
[Publications] Yoshiji H, Kuriyama S, Yoshii J, 9 Others: "Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma"Hepatology. 35. 834-842 (2002)
[Publications] Deguchi A, Arima K, Masaki T, 7 Others (last): "Enhanced expression of bcl-2 in lymphocytes infiltrating into the liver of patients with primary biliary cirrhosis"Int J Mol Med. 9. 571-577 (2002)
[Publications] Akahane M, Kuriyama S, Ohgushi H, 7 Others: "Enhancing and suppressing effects of dexamethasone on transgene expression in vitro."Int J Mol Med. 10. 107-112 (2002)
[Publications] Watanabe S, Sasahara K, Kinekawa F, 8 Others (last): "Aldehyde dehydrogenase-2 genotypes and HLA haplotypes in Japanese patients with esophageal cancer"Oncol Rep. 9. 1063-1068 (2002)
[Publications] Kurokohchi K, Watanabe S, Masaki T, 8 Others (last): "Combination therapy of percutaneous ethanol injection and radiofrequency ablation against hepatocellular carcinomas difficult to treat"Int J Oncol. 21. 611-615 (2002)
[Publications] Wu F, Fujita J, Murota M, 5 Others (last): "CYFRA 21-1 is released in TNF-α-induced apoptosis in the hepatocellular carcinoma cell line HuH-7"Int J Oncol. 21. 441-445 (2002)
[Publications] Kurokouchi K, Watanabe S, Masaki T, 6 Others (last): "Combined use of percutaneous ethanol injection and radiofrequency ablation for the effective treatment of hepatocellular carcinoma"Int J Oncol. 21. 841-846 (2002)
[Publications] Yoshiji H, Yoshii J, Ikenaka Y, 7 Others (9th): "Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats"J Hepatol. 37. 22-30 (2002)
[Publications] Deguchi K, Sasaki I, Tsukaguchi M, 4 Others (last): "Abnormalities of rate-corrected QT intervals in Parkinson's disease-a comparison with multiple system atrophy and progressive supranuclear palsy"J Neurol Sci. 199. 31-37 (2002)
[Publications] Ishizaka S, Shiroi A, Kanda S, 6 Others (6th): "Development of hepatocytes from ES cells after transfection with the HNF-3β gene"FASEB J. 16. 1444-1446 (2002)
[Publications] Ohgi T, Masaki T, Nakai S, 8 Others (last): "Expression of p33^<ING1> in hepatocellular carcinoma : relationships to tumor differentiation and cyclin E kinase activity"Scand J Gastroenterol. 37. 1440-1448 (2002)
[Publications] Wu F.Li J, Miki H, 5 Others (last): "p107 Expression in colorectal tumours rises during carcinogenesis and falls during invasion"Eur J Cancer. 38. 1838-1848 (2002)
[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others: "Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse"Hepatology. 36. 850-860 (2002)
[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. (in press). (2002)
[Publications] Murota M, Watanabe S, Fujita J, 10 Others(last): "Aberrant cytokeratin expression and high susceptibility to apoptosis in autoimmune hepatitis"Hepatol Res. (in press). (2002)
[Publications] Kobara H, Uchida N, Tsutsui K, 4 Others(last): "Abnormal bile flow in patients with achalasia"J Gastroenterol. (in press). (2002)
[Publications] Uchida N, Ezaki T, Fukuma H, 10 Others(last): "Concomitant colitis associated with primary sclerosing cholangitis"J Gastroenterol. (in press). (2002)
[Publications] Akahane M, Ohgushi H, Kuriyama S, 3 Others: "Lacz gene transfer to cultured bone marrow cells with hydroxyapatite.In : BIOCERAMICS Volume 14(Brown S, Clarke I, Williams P, eds.)"Trans Tech Publications Ltd, Zurich, Switzerland. 223-226 (2002)
[Publications] Kuriyama S, Tsujinoue H, Nakatani T, 2 Others: "Gene therapy for hepatocellular carcinoma : recent advancements and problems to overcome. In : Molecular Biology and Immunology in Hepatology(Tsuji T, Higashi T, Zeniya M, Mayer zum Buschenfelde K-H, eds.)"Elsevier Science, Amsterdam. 147-168 (2002)

2002 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 香川医科大学, 医学部, 教授 (50244710)

Research Products

[Publications] Yoshida S, Kurokohchi K, Arima K, 7 Others (last): "Clinical significance of lens culinaris agglutinin-reactive fraction of serum α-fetoprotein in patients with hepatocellular carcinoma"Int J Oncol. 20. 305-309 (2002)

[Publications] Wu F, Nishioka M, Fujita J, 4 Others (last): "Expression of cytokeratin 19 in human hepatocellular carcinoma cell lines"Int J Oncol. 20. 31-37 (2002)

[Publications] Uchida N, Ezaki T, Fukuma H, 12 Others (last): "Conversion of endoscopic nasobiliary drainage to internal drainage by means of endoscopic scissor forceps"Endoscopy. 34. 180 (2002)

[Publications] Nakai S, Masaki T, Shiratori Y, 5 Others (last): "Expression of p57^<KIP2> in hepatocellular carcinoma : relationship between tumor differentiation and patient survival"Int J Oncol. 20. 769-775 (2002)

[Publications] Yoshiji H, Kuriyama S, Yoshii J, 9 Others: "Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma"Hepatology. 35. 834-842 (2002)

[Publications] Deguchi A, Arima K, Masaki T, 7 Others (last): "Enhanced expression of bcl-2 in lymphocytes infiltrating into the liver of patients with primary biliary cirrhosis"Int J Mol Med. 9. 571-577 (2002)

[Publications] Akahane M, Kuriyama S, Ohgushi H, 7 Others: "Enhancing and suppressing effects of dexamethasone on transgene expression in vitro."Int J Mol Med. 10. 107-112 (2002)

[Publications] Watanabe S, Sasahara K, Kinekawa F, 8 Others (last): "Aldehyde dehydrogenase-2 genotypes and HLA haplotypes in Japanese patients with esophageal cancer"Oncol Rep. 9. 1063-1068 (2002)

[Publications] Kurokohchi K, Watanabe S, Masaki T, 8 Others (last): "Combination therapy of percutaneous ethanol injection and radiofrequency ablation against hepatocellular carcinomas difficult to treat"Int J Oncol. 21. 611-615 (2002)

[Publications] Wu F, Fujita J, Murota M, 5 Others (last): "CYFRA 21-1 is released in TNF-α-induced apoptosis in the hepatocellular carcinoma cell line HuH-7"Int J Oncol. 21. 441-445 (2002)

[Publications] Kurokouchi K, Watanabe S, Masaki T, 6 Others (last): "Combined use of percutaneous ethanol injection and radiofrequency ablation for the effective treatment of hepatocellular carcinoma"Int J Oncol. 21. 841-846 (2002)

[Publications] Yoshiji H, Yoshii J, Ikenaka Y, 7 Others (9th): "Inhibition of renin-angiotensin system attenuates liver enzyme-altered preneoplastic lesions and fibrosis development in rats"J Hepatol. 37. 22-30 (2002)

[Publications] Deguchi K, Sasaki I, Tsukaguchi M, 4 Others (last): "Abnormalities of rate-corrected QT intervals in Parkinson's disease-a comparison with multiple system atrophy and progressive supranuclear palsy"J Neurol Sci. 199. 31-37 (2002)

[Publications] Ishizaka S, Shiroi A, Kanda S, 6 Others (6th): "Development of hepatocytes from ES cells after transfection with the HNF-3β gene"FASEB J. 16. 1444-1446 (2002)

[Publications] Ohgi T, Masaki T, Nakai S, 8 Others (last): "Expression of p33^<ING1> in hepatocellular carcinoma : relationships to tumor differentiation and cyclin E kinase activity"Scand J Gastroenterol. 37. 1440-1448 (2002)

[Publications] Wu F.Li J, Miki H, 5 Others (last): "p107 Expression in colorectal tumours rises during carcinogenesis and falls during invasion"Eur J Cancer. 38. 1838-1848 (2002)

[Publications] Yoshiji H, Kuriyama S, Yoshii J, 8 Others: "Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse"Hepatology. 36. 850-860 (2002)

[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. (in press). (2002)

[Publications] Murota M, Watanabe S, Fujita J, 10 Others(last): "Aberrant cytokeratin expression and high susceptibility to apoptosis in autoimmune hepatitis"Hepatol Res. (in press). (2002)

[Publications] Kobara H, Uchida N, Tsutsui K, 4 Others(last): "Abnormal bile flow in patients with achalasia"J Gastroenterol. (in press). (2002)

[Publications] Uchida N, Ezaki T, Fukuma H, 10 Others(last): "Concomitant colitis associated with primary sclerosing cholangitis"J Gastroenterol. (in press). (2002)

[Publications] Akahane M, Ohgushi H, Kuriyama S, 3 Others: "Lacz gene transfer to cultured bone marrow cells with hydroxyapatite.In : BIOCERAMICS Volume 14(Brown S, Clarke I, Williams P, eds.)"Trans Tech Publications Ltd, Zurich, Switzerland. 223-226 (2002)

栗山茂樹香川医科大学, 医学部, 教授 (50244710)