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RasH2 mouse

RasH2 mouse

rash2 mouse
Formal name CByB6 F1-Tg(HRAS)2Jic
Coat color Wild color (Agouti)

１．Origin

The rasH2 mouse is a genetically engineered mouse with the HRAS (c-Ha-ras) gene, developed by CIEM, inserted. The inserted gene is a prototype prepared by removal of the point mutation sites from two HRAS (c-Ha-ras) genes obtained from human malignant sarcoma and human urinary bladder, followed by their recombination. Animals obtained by injection of the prototype gene into the pronucleus oocyte and by backcrossing these animas more than 20 times with the C57BL/6J strain formed the original breed. Stable conditions are maintained by tandem array integration of three copies of the gene, which is located in chromosome number 15E3. Since mice used in carcinogenicity studies must detect the carcinogenicity of many unspecified compounds in each organ, an F1 hybrid (F1 hybrid with the BALB/cByJ strain) with a wider range of susceptibility than the inbred line was prepared.

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２．Data obtained with this mouse model has been accepted by regulatory authorities.

  1. At ICH4 (S1B), it was decided to use this mouse in tests to replace long-term carcinogenicity studies (1997).
  2. The high reproducibility and stability of data obtained with the rasH2 mouse were verified in ILSI/HESI international confirmatory studies (1997-2000).
  3. At an ILSI/HESI workshop in 2003, regulatory authorities in Japan, the United States and EU submitted their policies for acceptance of data from carcinogenicity studies on both genotoxic and non-genotoxic substances using the rasH2 mouse as application data.
  4. At the Congress of the American Society of Toxicologic Pathology in 2009, the results of a questionnaire survey on the alternate mouse carcinogenicity test method were published and the usefulness of the rasH2 mouse was confirmed.
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３．Strict quality control of the animals.

  1. High uniformity of genetic background
    Backcrossing of the original breeding colony has reached more than 20 generations and very high genetic uniformity is maintained. To prevent the appearance of substrains in the international production bases of the rasH2 mouse at CLEA Japan (Shizuoka, Japan) and Taconic-Artemis in the United States, the breeding colonies are renewed every 5 years (or 10 generations) by recovery of breeding stock from cryopreserved embryos at CIEM. All of the candidate breeding stock animals are tested for the integrated gene by Southern blotting to confirm that there are no mutations. All animals supplied are identified as Tg/non-Tg by double PCR.
  2. High reproducibility and stability of carcinogenicity
    Carcinogenicity monitoring is performed using a standard positive control substance (MNU: N-methyl-N-nitrosourea) in carcinogenicity studies using this mouse and periodic tests are performed to ensure that no changes in sensitivity have occurred. In the most recent monitoring (2010), no differences in carcinogenic sensitivity were found between animals produced by CLEA Japan and Taconic-Artemis, and the reproducibility of previous data was confirmed.
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４．Basic protocol for short-term carcinogenicity studies

In the same way as with long-term carcinogenicity studies, short-term studies consist of a preliminary study and the 26-week actual study. The protocol is based on that prepared immediately after the ILSI/HESI international confirmatory studies, but some revisions were gradually made in the United States.

  1. Preliminary study
    The study period is 4 weeks (28 days) with administration on consecutive days. With non-Tg mice, it is necessary to use groups of 10 animals of each gender and also animals for a toxicokinetics (TK) study. The objective of the study is to determine the maximum tolerated dose (MTD) and maximum feasible dose (MFD) values.
  2. 26-week actual study
    The study period is 26 weeks with administration on consecutive days. It is necessary to establish five groups: a negative control group, three dose groups and a positive control group. The animals used are 25 Tg animals of each gender in each group. In addition, it is also necessary to have animals for TK (non-Tg animals) in the negative control and three dose groups. The standard positive control substance is N-methyl-N-nitrosourea (MNU) at 75 mg/kg (vehicle is citrate buffer pH 4.5, prepared at time of use) administered once intraperitoneally.
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５．Result of carcinogenic sensitivity monitoring

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References

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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