c-Ha-rasトランスジェニックラットの発がん感受性の解析

• Project/Area Number: 09253253
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Research Institution: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• Principal Investigator: 鳥山 弘靖 国立がんセンター, 研究所・化学療法部, 研究員 (70156537)
• Co-Investigator(Kenkyū-buntansha): 津田 洋幸 国立がんセンター, 研究所・化学療法部, 部長 (10163809) ; 朝元 誠人 国立がんセンター, 研究所・化学療法部, 室長 (50212494)
• Project Period (FY): 1997
• Project Status: Completed (Fiscal Year 1997)
• Budget Amount: ¥2,000,000 (Direct Cost: ¥2,000,000); Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: c-Ha-ras / トランスジェニックラット / 発がん感受性 / 乳腺発がん / 膀胱発がん / MNU / DMBA / BBN

Research Abstract

ヒトのがん組織から高頻度に活性型が検出されるc-Ha-rasがん遺伝子がほぼ全臓器で発現しているプロト型c-Ha-ras遺伝子導入ラットを作成し,以下の臓器における発がん感受性の亢進について確認した。
1.乳腺の発がん感受性
50日齢のc-Ha-ras雌トランスジェニックラットにN-methyl-N-nitrosourea(MNU)50mg/kgを1回静脈内投与したところ,8週間という短期間内に100%の動物に乳腺がんが多発した。対照群のnon-Tgラットでは29.2%であり、有意に乳腺の高発がん感受性を示すことを明らかにした。MNU投与により誘発されたTgラットの乳腺がんにおいて,導入したc-Ha-ras遺伝子ならびに内在性のc-Ha-rasの変異は全く認められなかったが,対照群に発生した乳腺がんでは,内在性のc-Ha-ras遺伝子の変異を比較的高率(28.6%)に認めた。さらに,乳腺に対する発がん物質である7,12-dimethylbenz[a]anthracene(DMBA)40mg/kgの投与によっても,このTgラットは、がんの発生期間,発生頻度ならびに発生個数いずれの項目においても,対照群と比較して高発がん感受性を示すことを明らかにした。
2.膀胱発がん感受性
生後6週齢のc-Ha-rasTg雄ラットにN-buthyl-N-(4-hydroxy-bytyl)nitrosoamine(BBN)を0.05%の用量で10週間飲水投与し、全期間20週で屠殺し、膀胱を病理組織学的に検索したところ,ヒトに類似した表在性膀胱がんが発生し、個数において発がん感受性の亢進が認められた。膀胱がんの発生頻度には non-Tgラットと比較して有意な差は認められなかった。TgラットにおけるBBN誘発膀胱がんではごく低頻度に内在性のc-Ha-ras遺伝子にのみ変異が認められた。

Research Products

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• [Publications] Tsuda H.et al.: "Inhibitory effects of oleic and docosahexaenoic acids on lung metastasis by colon-carcinoma-26 cells are associated with reduced matrix metalloproteinase-2 and-9 activities." Int.J.Cancer. 73. 607-612 (1997)
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• [Publications] Toriyama-Baba,H.et al.: "Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1.2-dimethylhydrazine initiation." Carcinogenesis. 19(1). 81-85 (1998)