1998 Fiscal Year Annual Research Report

遺伝子異常を指標とした膵癌の合理的な診断・治療法の開発〜癌の個性に応じた診療体制の確立〜

Research Project

Project/Area Number	10307032
Research Institution	Tohoku University
Principal Investigator	松野正紀東北大学, 医学部, 教授 (80004737)
Co-Investigator(Kenkyū-buntansha)	古川徹東北大学, 医学部, 助手 (30282122) 福重真一東北大学, 医学部, 助手 (90192723) 砂村真琴東北大学, 医学部・附属病院, 助手 (10201584) 小針雅男東北大学, 医学部, 助教授 (30170369) 堀井明東北大学, 医学部, 教授 (40249983)
Keywords	膵癌 / 診療システム / 早期診断 / 遺伝子異常 / 染色体異常 / LOH / CGH / FISH
Research Abstract	1. 1971年1月から1997年12月までに当教室で経験した膵癌症例は膵頭部癌232例,膵体尾部癌130例の合計362例であるが,最近の3年間に凍結保存した切除標本及びそれ以前に採取したホルマリン固定パラフィンブロック標本を再検鏡の後,約100例を越す膵腫瘍のDNAを抽出して,今回の多数の検体を対象とした研究の足掛かりとした. 2. 上記の腫瘍DNAを対象に,CGH法による全染色体レベルの異常を検索した結果,膵癌では1,3p,6q,12q,17p,l8qなどの複数染色体領域のK欠失と、8pと20pに染色体増幅が存在する事を明らかにした.特に染色体欠失は、各染色体のマイクロサテライトマーカーを用いたPCR法及びFISH法においてもCGHと同様な異常を検出することができた.染色体欠失と臨床病期の間には有意な関連を認めなかったが,これは膵癌では進行例が非常に多いことによるサンプリングのバイアスに起因するものと思われた. 3. 膵腫瘍の良性悪性の鑑別や膵癌の早期診断をルーチンの検査で診断する方法を確立する目的で,ERCPから採取した膵液を用いてFISHによる複数の染色体異常を検索したが,膵腫瘍を有する患者では63%に染色体異常を認めたのに対して,慢性膵炎等の非腫瘍性疾患の患者では全く異常が検出されなかった.特に膵腫瘍を有する患者の染色体異常の92%が18qの欠失であった.さらに,ERCPや膵液細胞診などルーチンの検査で異常を認めないとされた症例において,われわれの膵液FISHによる18qの異常の指摘を契機にして,さらなる詳細な臨床検査を加えた結果,直径10mmという微少serous cystadenomaを発見し得た.以上から,膵液を用いたFISHが膵悪性腫瘍の診断,特に早期診断に有用なことが示唆された. 4. 膵癌治療に関する実験では,背部に透明窓を装着したマウスモデルを用い,生体顕微鏡観察システム下に腫瘍血管新生に関わる因子や薬剤の影響を検討してきた結果,MMP inhibitor投与群では血管密度が有意に低下し腫瘍増殖抑制効果を認めた.さらにIL-12遺伝子導入癌細胞株でも有意な血管新生抑制効果がみられた.本知見を参考にして臨床への応用を検討中である.

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] Kimura,M.: "Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer." Cancer Research. 58. 2456-2460 (1998)
[Publications] Shinoda,M.: "Effective adoptive immunotherapy by T-LAK cells retargeted with bacterial super-antigen-conjugated antibody to MUCI in xenografted severe combinded." Cancer Research. 58. 2838-2843 (1998)
[Publications] Fukushige,S.: "Loss of chromosome 18q is an early event in pancreatic ductal turnorigenesis." Cancer Research. 58. 4220-4226 (1998)
[Publications] Lozonschi,L.: "Controlling tumor angiogenesis and metastasis of C26 murin colon adenocarcinoma by a new matrix metalloproteinase inhibitor,KB-R7785,in two tumor models." Cancer Research. (in press).
[Publications] Kobari,M.: "Staging systems for pancreatic cancer.Differences between the Japanese and UICC systems." J.Hep Bil Pancr Surg. 5. 121-127 (1998)
[Publications] Sunamura,M.: "Intraoperative radiotherapy for patients with advanced pancreatic adenocarcinoma." J.Hep Bil Pancr Surg. 5. 151-156 (1998)
[Publications] Okusaka,T.: "Tumor markers in walnating the response to radiotherapy in unresectable pancreatic cancer." Hepato Gastroenterology. 45. 872-876 (1998)
[Publications] Sunamura,M.: "The anti-angiogenic effect of IL-12 on early growth of human pancreatic cancer in SCID mice." Microcirculation annual. 14. 143-144 (1998)
[Publications] Lozonschi,L.: "The anti-angiogenic and anti-metastatic properties of a new matrix metalloproteinase inhibitor,KB-R7785." Microcirculation annual. 14. 145-146 (1998)
[Publications] Matsumoto,G.: "Adjuvant immunotherapy using genetically engineered interleukin 12 secreting fibroblasts prevents recurrence after surgical resection of established tumors in a murine adenocarcinoma model." Surgery. (in press).
[Publications] Furukawa,T.: "Genomic analysis of DUSP6,a dual specificity MAP kinase phosphatase,in pancreatic cancer." Cytogenet.Cell Genet.82. 156-159 (1998)
[Publications] Ouyang,H.: "The BAX gene,the promoter of apoptosis,is mutated in genetically unstable cancers of the colorectum,stomach,and endometrium." Clinical Cancer Research. 4. 1071-1074 (1998)
[Publications] Abe,T.: "Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer." Genes Chromosomes Cancer. (in press).
[Publications] Han,S.: "Infrequent somatic mutations of the p73 gene in various human cancers." European Journal of Surgical Oncology. (in press).
[Publications] Yatsuoka,T.: "Genomic analysis of the thymine-DNA glycosylase(TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma." International Journal of Pancreatology. (in press).

1998 Fiscal Year Annual Research Report

遺伝子異常を指標とした膵癌の合理的な診断・治療法の開発〜癌の個性に応じた診療体制の確立〜

Principal Investigator

松野 正紀 東北大学, 医学部, 教授 (80004737)

Research Products

[Publications] Kimura,M.: "Identification of two common regions of allelic loss in chromosome arm 12q in human pancreatic cancer." Cancer Research. 58. 2456-2460 (1998)

[Publications] Shinoda,M.: "Effective adoptive immunotherapy by T-LAK cells retargeted with bacterial super-antigen-conjugated antibody to MUCI in xenografted severe combinded." Cancer Research. 58. 2838-2843 (1998)

[Publications] Fukushige,S.: "Loss of chromosome 18q is an early event in pancreatic ductal turnorigenesis." Cancer Research. 58. 4220-4226 (1998)

[Publications] Lozonschi,L.: "Controlling tumor angiogenesis and metastasis of C26 murin colon adenocarcinoma by a new matrix metalloproteinase inhibitor,KB-R7785,in two tumor models." Cancer Research. (in press).

[Publications] Kobari,M.: "Staging systems for pancreatic cancer.Differences between the Japanese and UICC systems." J.Hep Bil Pancr Surg. 5. 121-127 (1998)

[Publications] Sunamura,M.: "Intraoperative radiotherapy for patients with advanced pancreatic adenocarcinoma." J.Hep Bil Pancr Surg. 5. 151-156 (1998)

[Publications] Okusaka,T.: "Tumor markers in walnating the response to radiotherapy in unresectable pancreatic cancer." Hepato Gastroenterology. 45. 872-876 (1998)

[Publications] Sunamura,M.: "The anti-angiogenic effect of IL-12 on early growth of human pancreatic cancer in SCID mice." Microcirculation annual. 14. 143-144 (1998)

[Publications] Lozonschi,L.: "The anti-angiogenic and anti-metastatic properties of a new matrix metalloproteinase inhibitor,KB-R7785." Microcirculation annual. 14. 145-146 (1998)

[Publications] Matsumoto,G.: "Adjuvant immunotherapy using genetically engineered interleukin 12 secreting fibroblasts prevents recurrence after surgical resection of established tumors in a murine adenocarcinoma model." Surgery. (in press).

[Publications] Furukawa,T.: "Genomic analysis of DUSP6,a dual specificity MAP kinase phosphatase,in pancreatic cancer." Cytogenet.Cell Genet.82. 156-159 (1998)

[Publications] Ouyang,H.: "The BAX gene,the promoter of apoptosis,is mutated in genetically unstable cancers of the colorectum,stomach,and endometrium." Clinical Cancer Research. 4. 1071-1074 (1998)

[Publications] Abe,T.: "Identification of three commonly deleted regions on chromosome arm 6q in human pancreatic cancer." Genes Chromosomes Cancer. (in press).

[Publications] Han,S.: "Infrequent somatic mutations of the p73 gene in various human cancers." European Journal of Surgical Oncology. (in press).

[Publications] Yatsuoka,T.: "Genomic analysis of the thymine-DNA glycosylase(TDG) gene on 12q22-q24.1 in human pancreatic ductal adenocarcinoma." International Journal of Pancreatology. (in press).

松野正紀東北大学, 医学部, 教授 (80004737)