Grant-in-Aid for Scientific Research (A)
|Allocation Type||Single-year Grants|
|Research Institution||Nara Medical University|
KONISHI Yoichi Nara Medical Univeresity Oncological Pathology, Professor, 医学部, 教授 (00075061)
TSUTSUMI Masahiro Nara Medical University Oncological Pathology, Assistant Prof., 医学部, 講師 (00207416)
DENDA Ayumi Nara Medical University Oncological Pathology, Assistant Prof., 医学部, 講師 (90110858)
NAKAE Dai Nara Medical University Oncological Pathology, Associate Prof., 医学部, 助教授 (90207712)
TSUJIUCHI Toshifume Nara Medical University Oncological Pathology, Assistant Prof., 医学部, 助手 (10254492)
|Project Period (FY)
1996 – 1999
Completed(Fiscal Year 1999)
|Budget Amount *help
¥32,600,000 (Direct Cost : ¥32,600,000)
Fiscal Year 1999 : ¥2,500,000 (Direct Cost : ¥2,500,000)
Fiscal Year 1998 : ¥3,700,000 (Direct Cost : ¥3,700,000)
Fiscal Year 1997 : ¥6,300,000 (Direct Cost : ¥6,300,000)
Fiscal Year 1996 : ¥20,100,000 (Direct Cost : ¥20,100,000)
|Keywords||pancreatic carcinoma / hamster / heterocyclicamine / carcinogen / chemoprevention / 化学発癌 / 遺伝子異常 / テロメラーゼ|
The importance of basic research related to pancreatic cancer should be focused on ductal adenocarcinoma since the incidence of * cancer is the highest, showing poor prognosis among various histological types of human pancreatic malignant neoplasms. However, experimental pancreatic duct adenocarcinoma (PDA) resembled histologically, biologically and genetically to human PDA can be induced by nitrosamines only in hamsters and dogs but not in other animal spieces. In this projects, we performed the research related to control the development and progression of PDA using a rapid production model of PDC in hamsters which was developed by us (Mizumoto, K. et al.,J.Natl.Cancer Inst.1998 ; 80 : 1564-1567) and PDA cell lines which were also established by us (Mori, T.et al.Int.J.Pancreao.1994 ; 16 : 171-177).
Genetic alterations related to the development and progression of PDA
1. The shortened telomeas and increased telomerase activities were detected in hamster PDA and also increased telomeras
e activities were detected in 32 out of 38 cases (84%) of human PDA tissues. Among those cases, Ki-ras mutations were also detected in 20 cases (53%).
2. Midkine, one of growth factors, was overexpressed at mRNA level and also expressed at protein level in PDAs.
3. MMP-2, one of MMP families, was importantly involved in the development and progression of PDAs.
4. Bax, one of apoptosis related genes, was overexpressed in PDAs.
5.β-catenine was not involved in the development and progression of PDAs.
Possible control of PDA
1. Possible involvement of heterocyclic amines of Trp-p-1 and DiMeIQx in the development of PDA was suggested.
2. OPB-3206, a inhibition of MMPs, inhibited pancreatic duct carcinogenesis.
3.β-carotin at a dose of 0.0025%, palm carotin at 0.004%, greentea polyphynol at 0.05 and 0.5%, 4-hydoxyphenyl retinamide (4-HPR) at 0.0015% and tranexamic acid at 0.1% in the diets inhibited pancreatic duct carcinogenesis.
4. 4-HPR at the concentration of 10μ M and auraptene at 50μ M introduced apoptosis in culture PDA cells. Less