世界の医薬・医療技術向上と
人々の健康と福祉向上にむけて

NOG mouse
正式名 CBYB6F1-Tg(HRAS)2Jic
毛色 野生色(Agouti)

rasH2マウスに関するお問い合わせ

1.起源

rasH2 マウスは実験動物中央研究所で開発された遺伝子改変マウスで、HRAS (c-Ha-ras) 遺伝子が導入されています。導入遺伝子は、ヒト悪性黒色腫およびヒト膀胱がんから得られた2つのHRAS (c-Ha-ras) 遺伝子から、それぞれ点変異のある箇所を切り離して再結合されたプロト型が、用いられています。それを前核期卵に注入して得られた動物を、C57BL/6J系に20回以上戻し交配した動物が起源で、導入遺伝子は15番染色体に3コピーがタンデムに挿入されているため、安定的な状態を保っています。なお、発がん性試験用のマウスは、不特定多数の化合物が持つあらゆる臓器に対する発がん性を検出することが望ましいため、近交系よりも広い感受性を示す、1代雑種(BALB/cByJ系とのF1ハイブリッド)としました。

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2.新薬の申請用マウスは発がん性試験データとして認められています

ICH4(S1B)でマウス長期発がん性試験の代替法として決定されました(1997年)。
ILSI/HESI国際共同検証試験(1997-2000年)により、rasH2マウスの高いデータの再現性と安定性が証明されました。 ILSI/HESIワークショップ(2003年)において、日・米・EU行政当局が、rasH2マウスを遺伝毒性物質および非遺伝毒性物質双方の発がん性試験申請データとして受理する旨の指針を出しました。
米国毒性病理学会総会(2009年)において、マウス発がん性試験代替法に関するアンケート調査結果が公表され、rasH2マウスの高い有用性が認められています。

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3.動物の厳格な品質管理が行われています

長期発がん性試験と同様に、予備試験、本試験の順に実施されます。プロトコールはILSI/HESI国際共同検証試験のものが基本となりますが、米国では逐次修正が加えられています。

  1. 予備試験

    投与期間は4週(28日)間であり、連日投与となります。使用動物はnon-Tgマウスで、10匹/性/群の他にTK用の動物の追加が必要です。試験目的はMTD探索あるいはMFD探索です。

  2. 本試験

    投与期間は26週間で、連日投与となります。陰性対照群、3用量群および陽性対照群の設定が必要で、使用動物はTgマウスで25匹/性/群が基本です。この他、陰性対照群および3用量群においては、TK用の動物(基本的にnon-Tgマウス)も必要です。標準陽性対照物質は、N-methyl-N-nitrosourea(MNU)であり、75 mg/kg(溶媒はpH4.5クエン酸緩衝液、用事調製厳守)を単回腹腔内投与します。

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文献集
2010年

Inhibitory effect of yogurt on aberrant crypt foci formation in the rat colon and colorectal tumorigenesis in rasH2 mice.
Narushima S, Sakata T, Hioki K, Itoh T, Nomura T and Itoh K.
Exp Anim. 59(4):487-94. 2010.

Alternative mouse models for carcinogenicity assessment: Industry use and issues with pathology interpretation.
Long GG, Morton D, Peters T, Short B and Skydsgaard M.
Toxicol Pathol. 38(1):43-50. 2010.

26-Week carcinogenicity study of di-isodecyl phthalate by dietary administration to CB6F1-rasH2 transgenic mice.
Cho WS, Jeong J, Choi M, Park SN, Han BS and Son WC.
Arch Toxicol. 85(1):59-66. 2010.

2009年

Panel discussion: Alternative mouse models for carcinogenicity assessment.
French JE, Leblanc B, Long GG, Morton D, Storer R, Leighton J, Swenberg J and Tsuda H.
Toxicol Pathol. 38(1):72-75. 2009.

Hepatocarcinogenic susceptibility of rasH2 mice to troglitazone in a two-stage hepatocarcinogenesis model.
Jin M, Saekusa Y, Dewa Y, Nishimura J, Matsumoto S, Shibutani M, Hasumi K and Mitsumori K.
Arch Toxicol. 83:173-181. 2009.

An industry perspective on the utility of short-term carcinogenicity testing in transgenic mice in pharmaceutical development.
Storer RS, Sistare FD, Reddy MV and DeGeorge JJ.
Toxicol Pathol. 38(1):51-61. 2009.

The transgenic mouse assay as an alternative test method for regulatory carcinogenicity studies―Implications for REACH.
Wells MY and Williams ES.
Regul Toxicol Pharmacol. 53(2):150-155. 2009.

Cancer risk assessment approaches at the FDA/CDER: Is the era of the 2-year bioassay drawing to a close?
Jacobson-Kram D.
Toxicol Pathol. 38(1):169-170. 2009.

2008年

Commentary: Regulatory toxicology and the critical path: Predicting long-term outcomes from short-term studies.
Jacobson-Kram D.
Vet Pathol. 45(5):707-709. 2008.

Extremely weak tumor-promoting effect of troglitazone on splenic hemangiosarcomas in rasH2 mice induced by urethane.
Jin M, Matsumoto S, Dewa Y, Nishimura J, Saekusa Y, Hasumi K and Mitsumori K.
Arch Toxicol. 82:771-777. 2008.

Epithelial proliferative lesions in the nasal cavities of c-Ha-ras transgenic mice.
Katoku K, Oshikata T, Kumabe S, Kuwasaki E, Mithuishi M, Nakahara Y and Hamamura M.
J Toxicol Pathol. 21:193-197. 2008.

Hepatocarcinogenic susceptibility of fenofibrate and its possible mechanism of carcinogenicity in a two-stage hepatocarcinogenesis model of rasH2 mice.
Kawai M, Jin M, Nishimura J, Dewa Y, Saegusa Y, Matsumoto S, Taniai E, Shimutani M and Mitsumori K.
Toxicol Pathol. 36(7):950-957. 2008.

Carcinogenic comparative study on rasH2 mice produced by two breeding facilities.
Machida K, Urano K, Yoshimura M, Tsutsumi H, Nomura T and Usui T.
J Toxicol Sci. 33(4):493-501. 2008.

Partial functional overlap of the three ras genes in mouse embryonic development.
Nakamura K, Ichise H, Nakao K, Hatta T, Otani H, Sakagami H, Kondo H and Katsuki M.
Oncologg. 27:2961-2968. 2008.

Use of rasH2 transgenic mice for carcinogenesis testing of medical implants.
Palazzi X and Kergozien-Framery S.
Exp Toxicol Pathol. 61(5):433-441. 2008.

2007年

The possible mechanism of enhanced carcinogenesis induced by genotoxic carcinogens in rasH2 mice.
Okamura M, Unami A, Moto M, Muguruma M, Ito T, Jin M, Oishi Y, Kashida Y and Mitsumori K.
Cancer Lett. 245(1-2):321-30. 2007.

Carcinogenic susceptibility of rasH2 mice to troglitazone.
Jin M, Takahashi M, Moto M, Muguruma M, Ito K, Watanabe K, Kenmochi Y, Kono T, Hasumi K and Mitsumori K.
Arch Toxicol. 81(12):883-894. 2007.

Decreased c-kit function inhibits enhanced skin carcinogenesis in c-Ha-ras protooncogene transgenic mice.
Muto S, Katsuki M and Horie S.
Cancer Sci. 98(10):1549-1556. 2007.

Examination of percutaneous application in a 26-week carcinogenicity test in CB6F1-TgrasH2 mice.
Urano K, Suzuki S, Machida K, Eguchi N, Sawa N, Kikuchi Y, Hattori Y and Usui T.
J Toxicol Sci. 32(4):367-375. 2007.

2006年

Nine-week detection of six genotoxic lung carcinogens using the rasH2/BHT mouse model.
Umemura T, Kodama Y, Nishikawa A, Hioki K, Nomura T, Kanki K, Kuroiwa Y, Ishii Y, Kurokawa Y and Hirose M.
Cancer Lett. 231(2):314-318. 2006.

Gene expresssion analysis of urethane-induced lung tumors in rasH2 mice.
Okamura M, Unami A, Matsumoto M, Oishi Y, Kashida Y and Mitsumori K.
Toxicol. 217(2-3):129-138. 2006.

Use of IC tags in short-term carcinogenicity study on CB6F1 TGrasH2 mice.
Urano K, Suzuki S, Machida K, Sawa N, Eguchi N, Kikuchi K, Fukasawa K, Taguchi F and Usui T.
J Toxicol Sci. 31(5):407-418. 2006.

Rapid induction of skin tumors in human but not mouse c-Ha-ras proto-oncogene transgenic mice by chemical carcinogenesis.
Muto S, Katsuki M and Horie S.
Cancer Sci. 97(9):842-847. 2006

2005年

Evaluation of the carcinogenic potential of clofibrate in the rasH2 mouse.
Nesfield SR, Clarke CJ, Hoivik DJ, Miller RT, Allen JS, Selinger K and Santostefano MJ.
Int J Toxicol. 24(5):301-11. 2005.

Susceptibility of heterozygous and nullizygous p53 knockount mice to chemical carcinogens: tissue dependence and role of p53 gene mutations.
Tsukamoto T, Hirata A and Tatematsu M.
J Toxicol Pathol. 18(3):121-134. 2005.

Histopathological characterization of the skeletal myopathy in rasH2 mice carrying human prototype c-Ha-ras gene.
Tsuchiya T, Okada M, Sakairi T, Sano F, Sugimoto J and Takagi S.
J Vet Med Sci. 67(5):481-489. 2005.

2004年

The utility of genetically modified mouse assays for identifying human carcinogens: A basic understanding and path forward. The Alternatives to Carcinogenicity Testing Committee ILSI HESI.
MacDonald J, French JE, Gerson RJ, Goodman J, Inoue T, Jacobs A, Kasper P, Keller D, Lavin A, Long G, McCullough B, Sistare FD, Storer R and van der Laan JW.
Toxicol Sci. 77(2):188-94. 2004.

Analysis of gene expression profiles of forestomach tumors in rasH2 mice initiated with N-ethyl-N-nitrosourea.
Okamura M, Sumida K, Muto T, Kashida Y, Machida N, Watanabe T and Mitsumori K.
Arch Toxicol. 78(12):688-696. 2004.

Lung tumorigenicity in A/J and rasH2 transgenic mice following mainstream tobacco smoke inhalation.
Curtin GM, Higuchi MA, Ayres PH, Swauger JE and Mosberg AM.
Toxicol Sci. 81(1):26-34. 2004.

PCR method for genotyping and Zygosity-testing of rasH2 transgenic mice.
Suemizu H, Kito-Maruyama C, Sotomaru Y, Ogura T, Hioki K, Ohnishi Y and Tamaoki N.
Exp Anim. 53(5):463-466. 2004.

2003年

Interlaboratory comparison of short-term carcinogenicity studies using CB6F1-rasH2 transgenic mice.
Takaoka M, Sehata S, Maejima T, Imai T, Torii M, Satoh H, Toyosawa K, Tanakamaru Y, Adachi T, Hisada S, Ueda M, Ogasawara H, Matsumoto M, Kobayashi K, Mutai M and Usui T.
Toxicol Pathol. 31(2):191-9. 2003.

Possible mechanism on enhanced carcinogenesis of genotoxic carcinogens and unsolved mechanisms on lesser carcinogenic susceptibility to some carcinogens in rasH2 mice.
Mitsumori K.
J Toxicol Sci. 28(5):371-83. 2003.

Mutation analysis of vinyl carbamate or urethane induced lung tumors in rasH2 transgenic mice.
Tomisawa M, Suemizu H, Ohnishi Y, Maruyama C, Urano K, Usui T, Yasuhara K, Tamaoki N and Mitsumori K.
Toxicol Lett. 142(1-2):111-7. 2003.

The role of transgenic mouse models in carcinogen identification.
Pritchard JB, French JE, Davis BJ and Haseman JK.
Environ Health Perspect. 111(4):444-54. 2003.

Historical background data in CB6F1-Tg-rasH2 mice and CB6F1-nonTg-rasH2 mice over a 26-week experimental period.
Kanno H, Tanakamaru Z, Ishimura Y, Kandori H, Yamasaki H and Sasaki S.
J Toxicol Pathol. 16:267-274. 2003.

2002年

The mouse rasH2/BHT model as an in vivo rapid assay for lung carcinogens.
Umemura T, Kodama Y, Hioki K, Nomura T, Nishikawa A, Hirose M and Kurokawa Y.
Jpn J Cancer Res. 93(8):861-6. 2002.

The Tg rasH2 mouse in cancer hazard identification.
Morton D, Alden CL, Roth AJ and Usui T.
Toxicol Pathol. 30(1):139-46. 2002.

2001年

Butylhydroxytoluene (BHT) increases susceptibility of transgenic rasH2 mice to lung carcinogenesis.
Umemura T, Kodama Y, Hioki K, Inoue T, Nomura T and Kurokawa Y.
J Cancer Res Clin Oncol. 127(10):583-90. 2001.

The rasH2 transgenic mouse: nature of the model and mechanistic studies on tumorigenesis.
Tamaoki N.
Toxicol Pathol. 29 Suppl:81-9. 2001.

CB6F1-rasH2 mouse: overview of available data.
Usui T, Mutai M, Hisada S, Takoaka M, Soper KA, McCullough B and Alden C.
Toxicol Pathol. 29 Suppl:90-108. 2001.

Overexpression of human H-ras transgene is responsible for tumors induced by chemical carcinogens in mice.
Maruyama C, Tomisawa M, Wakana S, Yamazaki H, Kijima H, Suemizu H, Ohnishi Y, Urano K, Hioki K, Usui T, Nakamura M, Tsuchida T, Mitsumori K, Nomura T, Tamaoki N and Ueyama Y.
Oncol Rep. 8(2):233-7. 2001.

Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice.
Ariyoshi N, Imaoka S, Nakayama K, Takahashi Y, Fujita K, Funae Y and Kamataki T.
Toxicol Pathol. 29(Suppl.):161-172. 2001

Diesel exhaust-induced airway hyperresponsiveness in c-Ha-ras transgenic mice.
Birumachi J, Suzuki KA, Itoh K, Hioki K, Maruyama C and Ohnishi Y.
Toxicol. 163(2-3):145-152. 2001

Induction of drug metabolism-related enzymes by methylcholanthrene and phenobarbital in transgenic mice carrying human prototype c-Ha-ras gene and their wild type littermates.
Ohnishi Y, Arai T, Koshirakawa M, Horii N, Nakajo S, Urano K, Usui T, Tamaoki N and Ueyama Y.
Exp. Anim. 50(1):33-39. 2001

Criteria for the evaluation of studies in transgenic models.
Popp JA.
Toxicol Pathol. 29(Suppl.)20-23. 2001.

1999年

Susceptibility to urethane carcinogenesis of transgenic mice carrying a human prototype c-Ha-ras gene (rasH2 mice) and its modification by butylhydroxytoluene.
Umemura T, Kodama Y, Hioki K, Inoue T, Nomura T and Kurokawa Y. Cancer Lett. 145(1-2):101-6. 1999.

1998年

Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing.
Yamamoto S, Urano K, Koizumi H, Wakana S, Hioki K, Mitsumori K, Kurokawa Y, Hayashi Y and Nomura T.
Environ Health Perspect. 106 Suppl 1:57-69. 1998.

Pulmonary fibrosis caused by N-methyl-N-nitrosourethane inhibits lung tumorigenesis by urethane in transgenic mice carrying the human prototype c-Ha-ras gene.
Mitsumori K, Yasuhara K, Mori I, Hayashi S, Shimo T, Onodera H, Nomura T and Hayashi Y.
Cancer Lett. 129(2):181-190. 1998.

Pathological features of spontaneous and induced tumors in transgenic mice carrying a human prototype c-Ha-ras gene used for six-month carcinogenicity studies.
Mitsumori K, Koizumi H, Nomura T and Yamamoto S.
Toxicol Pathol. 26(4):520-531. 1998.

Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing.
Yamamoto S, Urano K and Nomura T
Toxicol Lett. 102-103:473-478. 1998.

1997年

Rapid carcinogenicity testing system with transgenic mice harboring human prototype c-HRAS gene.
Yamamoto S, Hayashi Y, Mitsumori K and Nomura T.
Lab Anim Sci. 47(2):121-126. 1997.

Susceptibility of transgenic mice carrying human prototype c-Ha-ras gene in a short-term carcinogenicity study of vinyl carbamate and ras gene analyses of the induced tumors.
Mitsumori K, Wakana S, Yamamoto S, Kodama Y, Yasuhara K, Nomura T, Hayashi Y and Maronpot RR.
Mol Carcinog. 20(3):298-307. 1997.

1996年

Rapid induction of more malignant tumors by various genotoxic carcinogens in transgenic mice harboring a human prototype c-Ha-ras gene than in control non-transgenic mice.
Yamamoto S, Mitsumori K, Kodama Y, Matsumura N, Manabe S, Okamiya H, Suzuki H, Fukuda T, Sakamaki Y, Sunaga M, Nomura G, Hioki K, Wakana S, Nomura T and Hayashi Y.
Carcino. 17(11):2455-2461. 1996.

1992年

Chemically induced tumors in transgenic mice carrying prototype human c-Ha-ras genes.
Katsuki M, Ando K, Saitoh A, Doi S, Kimura M, Takahashi R, Hasegawa T, Yokoyama M, Nomura T, Izawa M and Nishimura S.
Multistage carcinogenesis c. c. harris et al. (EDS.)
Japan Sci. Soc. Press Tokyo/CRC press boca raton. pp.249-257. 1992.

1990年

Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes.
Saitoh A, Kimura M, Takahashi R, Yokoyama M, Nomura T, Izawa M, Sekiya T, Nishimura S and Katsuki M.
Onco. 5(8):1195-1200. 1990.

1984年

Molecular cloning and the total nucleotide sewuence of the human c-Ha-ras-1 gene activated in a melanoma from a Japanese patient.
Sekiya T, Fushimi M, Hori H, Hirohashi S, Nishimura S and Sugimura T.
Proc Natl Acad Sci. 81(15):4771-4775. 1984.

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