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代表的な実験動物

rasH2マウス｜その他の実験動物

rash2 mouse
正式名 CByB6F1-Tg(HARS)2Jic
一般名 rasH2-Tg(tg/wt)
簡略名 rasH2マウス
毛色 野生色（アグーチ）［Aa, Bb, Cc］

医薬品の発がん性試験

医薬品の元となる化学物質が発がん性を有しているか否かを調べることは創薬研究で最も重要なことです。 この発がん性試験には動物実験が不可欠となっています。 しかし、これまでの発がん性の有無を調べる動物実験は2〜3年に及ぶ期間がかかり、しかも明確な結果が得られないこともまれではありませんでした。 この大きな問題のブレークスルーとなったのが、遺伝子改変技術によって開発されたrasH2マウスです。

rasH2マウスの開発と実験動物化

rasH2マウスは、ヒト由来のHRAS（c-Ha-ras）遺伝子が導入された遺伝子改変マウスで、実中研と東海大学医学部、 国立がんセンター研究所（当時）との共同研究により開発されました（Saitoh A. et al., Oncogene. 1990）。 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、 それぞれの活性型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（Sekiya T. et al., Jpn J Cancer Res. 1985）。 それを前核期の受精卵に注入して得られた遺伝子導入マウスが起源で、実中研でC57BL/6J系に20回以上戻し交配して実験動物化しました。 導入遺伝子は15番染色体に3コピーがタンデム（直列）に挿入されているため（Suemizu H. et al., Mol. Carcinog. 2002）、安定的な状態を保っています。 発がん性試験用のマウスは、様々な化学物質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、 近交系よりも幅広い感受性を示す、近交系同士の一代雑種（C57BL/6J系とBALB/cByJ系とのF1ハイブリッド）としました（Tamaoki H. Toxicol Pathol. Suppl. 2001）。

発がん性試験用マウスとして実用化

実中研では、1993年にrasH2マウスを発がん性試験用としての実用化研究を開始しました。 最初にrasH2マウスの計画生産システムを構築して量産体制を確立し、つぎに発がん性試験に使うことができるかを、従来法と優劣を比較検討しました。 その結果、従来法では2年間かかる試験期間がrasH2マウスでは約6カ月と、当初の予想を大幅に短縮できることが判りました（Yamamoto S. et al., Carcinogenesis. 1996；Yamamoto S. et al., Lab Anim Sci. 1997）。 さらにこの結果を踏まえて、1997年から2001年の5年間に国際生命科学研究所（International Life Science Institute）と健康環境科学研究所（Health and Environmental Science Institute）の主導のもとに、 日・米・EUの産官学50以上の施設が連携しながら実施した検証試験に参加し（Usui T. et al., Toxicol Pathol. Suppl. 2001）、 rasH2マウスによる短期発がん性試験の評価結果が従来法よりも精度の高いことを確認しました（MacDonald J. et al., Toxicol Sci. 2004）。 現在このrasH2マウスは、米国食品医薬品局（Food and Drug Administration）主導の米国においても発がん性試験用の標準動物として主流となりつつあります（Jacobs AC. and Brown PC. Toxicol and Pathol. 2015）。

実験動物として厳格な品質管理と品質保証

動物実験の際には、再現性と安定性のある結果を得るために、実験動物の品質管理が極めて重要です。 遺伝的および微生物的な品質管理だけでなく、その動物が保有する形質や特性の品質管理も欠かすことができません。 現在rasH2マウスは、日本だけでなく米国でも生産・供給されていますが、定期的に両施設の種動物を同時期に更新して施設間の亜系化を防ぐとともに、 毎年、実中研で標準化合物による発がん感受性モニタリングを行い、動物の形質と特性を確認しています（Inoue K. et al., Vet Pathol. 2012）。 このようにrasH2マウスは、品質管理だけでなく、品質保証も定期的に行っています。

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文献集

2018年
  1. A Comparison of Spontaneous Tumors in Tg.rasH2 Mice in 26-week Carcinogenicity Studies Conducted at a Single Test Facility during 2004 to 2012 and 2013 to 2018.
    Paranjpe MG, Belich JL, Mann PC, McKeon ME, Elbekai RH, Brown CM, Patrick DJ.
    Toxicol Pathol. 2018 Nov 8:192623318810202.
  2. High Background Incidence of Spontaneous Subcapsular Adrenal Gland Hyperplasia of Tg.rasH2 Mice Used in 26-week Carcinogenicity Studies.
    Boyle MH, Paranjpe MG, Creasy DM.
    Toxicol Pathol. 2018 Jun;46(4):444-448.
  3. Progression process and safety assessment adaptation of endometrial lesions in ENU-induced 2-stage uterine carcinogenicity in a Tg-rasH2 mouse model.
    Kuroda H, Kinomoto T, Ogawa S, Kawabe M, Suguro M, Naraoka H, Takamatsu K, Oishi Y.
    J Toxicol Pathol. 2018 Jan;31(1):35-41.
2017年
  1. Tg.rasH2 Mice and not CByB6 F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies.
    Paranjpe MG, Belich J, Vidmar TJ, Elbekai RH, McKeon M, Brown C.
    Int J Toxicol. 2017 Jul/Aug;36(4):287-292.
  2. Lung Tumor Induction by 26-week Dermal Application of 1,2-Dichloroethane in CB6F1-Tg rasH2 Mice.
    Suguro M, Numano T, Kawabe M, Doi Y, Imai N, Mera Y, Tamano S.
    Toxicol Pathol. 2017 Apr;45(3):427-434.
2016年
  1. Progression of Serosal Vascular Proliferative Lesions to Hemangiosarcomas in the Uterus of the 26-Week Tg.rasH2 Mice Carcinogenicity Studies.
    Paranjpe MG, Belich JL, Richardson DR, Vidmar T, Mann PC, McKeon ME, Elbekai RH.
    Int J Toxicol. 2016 Jul 20.
  2. Renal Tumors in 26-Week Tg.Rash2 Mice Carcinogenicity Studies.
    Paranjpe MG, Belich JL, McKeon ME, Elbekai RH, Mann PC, Hard GC, Seely JC.
    Toxicol Pathol. 2016 Jul;44(5):633-5.
  3. Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints.
    Paranjpe MG, Denton MD, Vidmar TJ, Elbekai RH.
    Toxicol Pathol. 2016 Jan;44(1):5-8.
2015年
  1. Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide.
    Tsuji S, Kuwahara Y, Takagi H, Sugiura M, Nakanishi Y, Wakamatsu M, Tsuritani K, Sato Y.
    J Toxicol Sci. 2015 Dec;40(6):685-700.
  2. Regulatory Forum Commentary* Counterpoint: Dose Selection for Tg.rasH2 Mouse Carcinogenicity Studies.
    Darbes J, Sistare FD, DeGeorge JJ.
    Toxicol Pathol. 2015 Jul;43(5):621-7.
  3. Regulatory Forum Commentary* Counterpoint: Dose Selection for rasH2 Mouse Carcinogenicity Studies.
    Nambiar PR, Morton D.
    Toxicol Pathol. 2015 Jul;43(5):628-32.
  4. Carcinogenicity assessment of the pan-caspase inhibitor, emricasan, in Tg.rasH2 mice.
    Elbekai RH, Paranjpe MG, Contreras PC, Spada A.
    Regul Toxicol Pharmacol. 2015 Jul;72(2):169-78.
  5. Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.
    Paranjpe MG, Denton MD, Vidmar TJ, Elbekai RH.
    Toxicol Pathol. 2015 Jul;43(5):611-20.
2014年
  1. Trend analysis of body weight parameters, mortality, and incidence of spontaneous tumors in Tg.rasH2 mice.
    Paranjpe MG, Denton MD, Vidmar T, Elbekai RH.
    Int J Toxicol. 2014 Nov-Dec;33(6):475-81.
  2. An FDA overview of rodent carcinogenicity studies of angiotensin II AT-1 receptor blockers: pulmonary adenomas and carcinomas.
    Link WT, De Felice A.
    Regul Toxicol Pharmacol. 2014 Nov;70(2):555-63.
  3. Regulatory Forum commentary: alternative mouse models for future cancer risk assessment.
    Morton D, Sistare FD, Nambiar PR, Turner OC, Radi Z, Bower N.
    Toxicol Pathol. 2014 Jul;42(5):799-806.
  4. The 26-week Tg.rasH2 mice carcinogenicity studies: microscopic examination of only select tissues in low- and mid-dose groups.
    Paranjpe MG, Denton MD, Elbekai RH.
    Toxicol Pathol. 2014 Oct;42(7):1153-7.
2013年
  1. The use of genetically modified mice in cancer risk assessment: challenges and limitations.
    Eastmond DA, Vulimiri SV, French JE, Sonawane B.
    Crit Rev Toxicol. 2013 Sep;43(8):611-31.
  2. Incidence of spontaneous non-neoplastic lesions in transgenic CByB6 F1-Tg(HRAS)2Jic mice.
    Paranjpe MG, Shah SA, Denton MD, Elbekai RH.
    Toxicol Pathol. 2013;41(8):1137-45.
  3. The rasH2 mouse model for assessing carcinogenic potential of pharmaceuticals.
    Nambiar PR, Morton D.
    Toxicol Pathol. 2013;41(8):1058-67.
  4. Historical control data of spontaneous tumors in transgenic CByB6 F1-Tg(HRAS)2Jic (Tg.rasH2) mice.
    Paranjpe MG, Elbekaei RH, Shah SA, Hickman M, Wenk ML, Zahalka EA.
    Int J Toxicol. 2013 Jan-Feb;32(1):48-57.
2012年
  1. Reduction in the number of animals and the evaluation period for the positive control group in Tg.rasH2 short-term carcinogenicity studies.
    Shah SA, Paranjpe MG, Atkins PI, Zahalka EA.
    Int J Toxicol. 2012 Sep-Oct;31(5):423-9.
  2. Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 mice.
    Takanashi S, Hara K, Aoki K, Usui Y, Shimizu M, Haniu H, Ogihara N, Ishigaki N, Nakamura K, Okamoto M, Kobayashi S, Kato H, Sano K, Nishimura N, Tsutsumi H, Machida K, Saito N.
    Sci Rep. 2012;2:498.
  3. Spontaneous tumor incidence in rasH2 mice: review of internal data and published literature.
    Nambiar PR, Turnquist SE, Morton D.
    Toxicol Pathol. 2012 Jun;40(4):614-23.
  4. Establishing a laboratory animal model from a transgenic animal: RasH2 mice as a model for carcinogenicity studies in regulatory science.
    Urano K, Tamaoki N, Nomura T.
    Vet Pathol. 2012 Jan;49(1):16-23.
2011年
  1. Detection of the onset of ischemia and carcinogenesis by hypoxia-inducible transcription factor-based in vivo bioluminescence imaging.
    Kadonosono T, Kuchimaru T, Yamada S, Takahashi Y, Murakami A, Tani T, Watanabe H, Tanaka T, Hirota K, Inoue M, Tsukamoto T, Toyoda T, Urano K, Machida K, Eto T, Ogura T, Tsutsumi H, Ito M, Hiraoka M, Kondoh G, Kizaka-Kondoh S.
    PLoS One. 2011;6(11):e26640.
2010年
  1. 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.
  2. 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.
  3. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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
  1. 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.
  2. 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.
  3. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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
  1. 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.
  2. Transgene stability and features of rasH2 mice as an animal model for short-term carcinogenicity testing.
    Suemizu H, Muguruma K, Maruyama C, Tomisawa M, Kimura M, Hioki K, Shimozawa N, Ohnishi Y, Tamaoki N, Nomura T.
    Mol Carcinog. 34(1): 1-9. 2002.
  3. 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
  1. 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.
  2. The rasH2 transgenic mouse: nature of the model and mechanistic studies on tumorigenesis.
    Tamaoki N.
    Toxicol Pathol. 29 Suppl:81-9. 2001.
  3. 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.
  4. 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.
  5. 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
  6. 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
  7. 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
  8. Criteria for the evaluation of studies in transgenic models.
    Popp JA.
    Toxicol Pathol. 29(Suppl.)20-23. 2001.
1999年
  1. 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
  1. 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.
  2. 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.
  3. 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.
  4. 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
  1. 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.
  2. 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.
1997年
  1. 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
  1. 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
  1. 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
  1. 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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