| Co-Investigator(Kenkyū-buntansha) |
AOKI Daisuke Keio University, Department of Medicine, Assistant Professor, 医学部, 専任講師 (30167788)
BANNO Kouji Keio University, Department of Medicine, Instructor, 医学部, 助手 (70265875)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Research Abstract |
In advanced endometrial cancers, adjuvant chemotherapy is often needed for preventing from recurrence, however, no evidence has been established about which adjuvant therapy is better, chemotherapy or radiotherapy. We, therefore, examined whether microsatellite instability(MSI) is useful maker or not for individualized treatment for patients with endometrial cancers.
1 MSI : (1)We analyzed MSI state of clinically obtained specimens of endometrial cancers and several cell lines derived from endometrial cancers by methylation-specific PCR in several MSI markers, and found that 35% cases of endometrial cancers showed MSI and this rate was higher than that of colorectal cancers. (2)In immunohistochemical studies using antibodies against DNA mismatch repair(MMR) proteins of hMLH1, hMSH2, hMSH6, MSI cases showed the reduction of either MMR protein in significantly high rate. However, non-sense mutation of hMLH1 was found only 1 case (6% of MSI cases) and methylation of hMLH1 promoter region w
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as recognized in a significantly higher rate than in microsatellite stability (MSS) cases. Therefore, we considered that the cause of high MSI rate in endometrial cancers is derived from methylation of hMLH1 promoter region.
2 Anti-cancer drugs sensitivity test by Histoculture Drug Response Assay(HDRA)
By calculating the IC_<50> value in use of MMT assay for cytotoxic effects of cisplatin against tumor tissues obtained from endometrial cancer tissues, we divides those cases into two categories, high-sensitivity group and low-sensitivity group. In 15 MSI cases, 14 cases(93%) were judged as less sensitive. This rate was significantly higher than that of MSS cases. In addition, we confirmed that the low-sensitivities of endometrial cancer cell lines for cisplatin were recovered by adding unmethylation procedures by using Collagen gel droplet enbedded drug sensitivity test (CDDST).
Thus, we demonstrated the fact that MSI cases is less sensitive for the first time. Furthermore, we showed that the methylation state of hMLH1 promoter region is an important information in choosing the adjuvant therapy(chemotherapy or radiation therapy). Less
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