| Project/Area Number |
10557055
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Gastroenterology
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| Research Institution | GIFU UNIVERSITY |
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Principal Investigator |
MORIWAKI Hisataka GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 医学部, 教授 (50174470)
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| Co-Investigator(Kenkyū-buntansha) |
OKUNO Masataka GIFU UNIVERSITY,SCHOOL OF MEDICINE, 医学部・附属病院, 講師 (10204140)
OMORI Masahide TOKAI WOMEN'S COLLAGE, FACULTY OF HUMANITIES, PROFESSOR, バイオサイエンスセンター, 教授 (30278212)
SHIDOJI Yoshihiro SIEBOLD UNIVERSITY, CELLULAR BIOCHEMISTRY SECTION, PROFESSOR, 看護栄養学部, 教授 (00111518)
SHIRATORI Yoshimune GIFU UNIVERSITY, SCHOOL OF MEDICINE, 医学部, 助手 (20313877)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | CANCER CHEMOPREVENTION / HEPATOCELLULAR CARCINOMA / RETINOID / RETINOID X RECEPTOR / DIFFERENTIATION INDUCTION / APOPTOSIS / CASPASE / レチノイドX受容体 / 遺伝子変異 |
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| Research Abstract |
Retinoid inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retionoids and confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis (New Engl J Med, 1996). Moreover, we reveled significant difference in the survival rate between the retinoid and the placebo groups with a median follow-up of 62 months (P=0.04). Among selected patients variables at the time of randomization, proportional hazards analysis revealed that the administration of acyclic retinoid was the only independent factor that significantly improved survival of the patients. The estimated relative risk of death was 0.3 (95 percent confidence interval, 0.1 to 0.8) in the acyclic retinoid group as compared with the placebo group (New Engl J Med, 340 : 1046-1047 ; 1999).
Acyclic retinoid prevents hepatocarcinogenesis by eradicating premalignant and latent malignant clones of transformed cells from the liver. We demonstrate the mechanism of this clonal deletion at the cellular level. Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to acyclic retinoid for 2 days. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. Acyclic retinoid first induces differentiation and reduces telomerase activity. Subsequent late apoptosis completes the clonal deletion of the cells.
We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.
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