Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Gulezian, D.
Right arrow Articles by Neumann, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gulezian, D.
Right arrow Articles by Neumann, D. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Reviews

Review Article: Use of Transgenic Animals for Carcinogenicity Testing: Considerations and Implications for Risk Assessment

Donna Gulezian

Taconic Farms, Inc, Madison, Connecticut 06443

David Jacobson-Kram

BioReliance, Rockville, Maryland 20850

C. Bruce Mccullough

Aventis Pharmaceutical Products, Collegeville, Pennsylvania 19426

Harry Olson

Pfizer Central Research, Groton, Connecticut 06340

Leslie Recio

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

Denise Robinson

ILSI Health and Environmental Sciences Institute, Washington, DC 20036

Richard Storer

Merck Research Laboratories, West Point, Pennsylvania 27709

Raymond Tennant

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Jerrold M. Ward

National Cancer Institute, Frederick, Maryland 21702

David A. Neumann

ILSI Risk Science Institute, Washington, DC 20036, dneumann{at}ilsi.org

Advances in genetic engineering have created opportunities for improved understanding of the molecular basis of carcinogenesis. Through selective introduction, activation, and inactivation of specific genes, investigators can produce mice of unique genotypes and phenotypes that afford insights into the events and mechanisms responsible for tumor formation. It has been suggested that such animals might be used for routine testing of chemicals to determine their carcinogenic potential because the animals may be mechanistically relevant for understanding and predicting the human response to exposure to the chemical being tested. Before transgenic and knockout mice can be used as an adjunct or alternative to the conventional 2-year rodent bioassay, information related to the animal line to be used, study design, and data analysis and interpretation must be carefully considered. Here, we identify and review such information relative to Tg.AC and rasH2 transgenic mice and p53+/- and XPA -/- knockout mice, all of which have been proposed for use in chemical carcinogenicity testing. In addition, the implications of findings of tumors in transgenic and knockout animals when exposed to chemicals is discussed in the context of human health risk assessment.

Key Words: Transgenic animals • knockout animals • carcinogenicity testing • risk assessment • carcinogens • bioassay

References

  • Adams JM, Cory S. ( 1991). Transgenic models of tumor development. Science 254: 1161-1167.[Abstract/Free Full Text]
  • Aigner B., Fleischman M., Muller M., Brem G. ( 1999). Stable long term germ-line transmission of transgene integration sites in mice. Transgen Res 8: 1-8.[Medline] [Order article via Infotrieve]
  • Alden CL, Smith PF, Piper CE, Brej L. ( 1996). A critical appraisal of the value of the mouse cancer bioassay in safety assessment. Toxicol Pathol 24: 722-725.[Abstract/Free Full Text]
  • Allen JD, Berns A. (1996). Complementation tagging of cooperating oncogenes in knockout mice. Semin Cancer Biol 7: 299-306.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Amati B., Land H. ( 1994). Myc-Max-Mad: A transcription factor network controlling cell cycle progression, differentiation and death. Curr Opin Genet Dev 4: 102-108.[CrossRef][Medline] [Order article via Infotrieve]
  • Ando K., Saitoh A., Hino O., Takahashi R., Kimura M., Katsuki M. (1992). Chemically induced forestomach papillomas in transgenic mice carry mutant human c-Ha-ras transgenes. Cancer Res 52: 978-982.[Abstract/Free Full Text]
  • Anonymous (1998). BALB/cJ vs. BALB/cByJ. JAX Notes 430.
  • Berg RJ, de Vries A., van Steeg H., de Gruiji FR (1997). Relative susceptibilities of XPA knockout mice and their heterzygous and wild-type littermates to UVB-induced skin cancer. Cancer Res 57: 581-584.[Abstract/Free Full Text]
  • Blanchard KT, Ball DJ, Holden HE, Furst SM, Stoltz JH, Stoll RE (1998). Dermal carcinogenicity in transgenic mice: Relative responsiveness of male and female hemizygous and homozygous Tg.AC mice to 12-o-tetra decanoylphorbol, 13-acetate (TPA), and benzene. Toxicol Pathol 26:541-547.[Abstract/Free Full Text]
  • Bol SA, van Steeg H., Jansen JG, van Oostrom C., de Vries A., de Groot AJ, Tates AD, Brieling H., van Zeeland AA, Mullenders LH (1998). Elevated frequencies of benzo(a)pyrene-induced Hprt mutations in internal tissue of XPA-deficient mice. Cancer Res 58: 2850-2856.[Abstract/Free Full Text]
  • Boorman GA, Maronpot RR, Eustis SL (1994). Rodent carcinogenicity bioassay: Past, present and future. Toxicol Pathol 22: 105-111.[Abstract/Free Full Text]
  • Bos JL (1989). Ras oncogenes in human cancer: A review. Cancer Res 49: 4682-4689.[Abstract/Free Full Text]
  • Bradley A. (1996). Introduction: Mutant mice in cancer research. Semin Cancer Biol 7: 27-228.
  • Brandon RL, Idzerda RL, McKnight GS (1995). Targeting the mouse genome: A compendium of knockouts (part I). Curr Biol 5: 625-634.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Brandon RL, Idzerda RL, McKnight GS (1995). Targeting the mouse genome: A compendium of knockouts (part II). Curr Biol 5: 758-765.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Brandon RL, Idzerda RL, McKnight GS (1995). Targeting the mouse genome: A compendium of knockouts (part III). Curr Biol 5: 873-881.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Camper SA (1987). Research applications of transgenic mice. BioTechniques 5: 638-649.[Web of Science]
  • Cannon RE, Spalding JW, Trempus CS, Szczesniak CJ, Virgil KM, Humble MC, Tennant RW (1997). Kinetics of wound induced v-Ha-ras transgene expression and papilloma development in transgenic Tg.AC mice. Mol Carcinog 20: 108-114.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Cannon RE, Spalding JW, Virgil KM, Faircloth RS, Humble MC, Lacks GD, Tennant RW (1998). Induction of transgene expression in Tg.AC (v-Ha-ras) transgenic mice concomitant with DNA hypomethylation. Mol Carcinog 21: 244-250.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Capecchi MR (1994). Targeted gene replacement. Sci Am 270: 52-59.[Web of Science][Medline] [Order article via Infotrieve]
  • Cardiff RD, Leder A., Kuo A., Pattengate PK, Leder P. (1993). Multiple tumor types appear in a transgenic mouse with the ras oncogene. Am J Pathol 142: 1199-1207.[Abstract]
  • Clark WR (1991). The Experimental Foundations of Modern Immunology, 4th ed. Wiley & Sons, New York.
  • Cleaver JE (1968). Defective DNA repair replication of DNA in xeroderma pigmentosum. Nature 218: 652-656.[CrossRef][Medline] [Order article via Infotrieve]
  • Cleaver JE (1969). Xerdoman pigmentosum: A human disease in which an initial stage of DNA replication repair is defective. Proc Natl Acad Sci USA 63: 428-435.[Abstract/Free Full Text]
  • Cox DR (1972). Regression models and life tables. J R Stat Soc 1334: 187-220.
  • Davies TS, Monro A. (1994). The rodent carcinogenicity bioassay produces a similar frequency of tumor increases and decreases: Implications for risk assessment. Regul Toxicol Pharmacol 20: 281-301.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Delker DA, Yano BL, Gollapudi BB (1999). v-Ha-ras gene epression in liver and kidney of transgenic Tg.AC mice following chemically induced tissue injury. Toxicol Sci 50: 90-97.[Abstract/Free Full Text]
  • Devereux TR, Anderson MW, Belinsky SA (1991). Role of ras protooncogene activation in the formation of spontaneous and nitrosamine-induced lung tumors in the resistant C3H mouse. Carcinogenesis 12: 299-303.[Abstract/Free Full Text]
  • de Vries A., Dolle ME, Broekhof JL, Muller JJ, Kroese ED, van Kreij1 CF, Capel PH, Vijg J., van Steeg H. (1997). Induction of DNA adducts and mutations in spleen, liver and lung of XPAdeficient/lacZ transgenic mice after oral treatment with benzo[a]pyrene: Correlation with tumour development. Carcinogenesis 18: 2327-2332.[Abstract/Free Full Text]
  • de Vries A., van Oostrom CT, Dortant PM, Beems RB, van Kreijl CF, Capel PJ, van Steeg H. (1997). Spontaneous liver tumors and benzo[a]pyrene-induced lymphomas in XPA-deficient mice. Mol Carcinog 19: 46-53.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • de Vries A., van Oostrom Ctm, Hofhius Fma, Dortant PM, Berg Fjw, de Gruijl FR, Wester PW, van Kreijl CF, Capel Pja, van Steeg H., Verbeek SJ (1995). Increased susceptibility to ultraviolet-B and carcinogens of mice lacking the DNA excision repair gene XPA. Nature 377: 169-173.[CrossRef][Medline] [Order article via Infotrieve]
  • de Vries A., van Steeg H. (1996). Xpa knockout mice. Semin Cancer Biol 7: 229-240.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Donehower LA, Harvey M., Vogel H., McArthur MJ, Montgomery CA Jr, Park SH, Thompson T., Ford RJ, Bradley A. (1995). Effects of genetic background on tumorigenesis in p53-deficient mice. Mol Carcinog 14: 16-22.[Web of Science][Medline] [Order article via Infotrieve]
  • Donehower LA (1996). The p53-deficient mouse: A model for basic and applied cancer studies. Semin Cancer Biol 7: 269-278. 35. Donehower LA, Godley LA, Aldaz CM, Pyle R., Shi YP, Pinkel D., Gray J., Bradley A., Medina D., Varmus HE (1996). The role of p53 loss in genomic instability and tumor progression in a murine mammary cancer model. Prog Clin Biol Res 395: 1-11.[Web of Science][Medline] [Order article via Infotrieve]
  • Donehower LA, Harvey M., Slagle BL, McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215-221.[CrossRef][Medline] [Order article via Infotrieve]
  • Drinkwater NR, Ginsler JJ (1986). Genetic control of hepatocarcinogenesis in C57BL/6J and C3H/HeJ inbred mice. Carcinogenesis 7: 1701-1707.[Abstract/Free Full Text]
  • Dunnick JK, Hardisty JF, Herbert RA, Seely JC, Furedi-Machacek EM, Foley JF, Lacks GD, Stasiewicz S., French JE (1997). Phenolphthalein induces thymic lymphomas accompanied by loss of the p53 wild type allele in heterozygous p53-deficient (+/-) mice. Toxicol Pathol 25: 533-540.[Abstract/Free Full Text]
  • Dunson, DB, Haseman JK (1999). Modeling tumor onset and multiplicity using transition models with latent variables. Biometrics 55: 965-970.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Eastin WC, Haseman JK, Mahler JF, Bucher JR (1998). The National Toxicology Program evaluation of genetically altered mice as predictive models for identifying carcinogens. Toxicol Pathol 26: 461-473.[Abstract/Free Full Text]
  • Faustman EM, Omenn GS (1996). Risk assessment. In: Casarett and Doull's Toxicology: The Basic Science of Poisons, 5th ed, Amdur MO, J Doull, Klaassen CD (eds). McGraw-Hill Health Professions Division, New York, pp 75-88.
  • Festing Mfw (1998). Mouse genome informatics. http://www.informatics.jax.org/strains/mouse.
  • Finch GL, March TH, Hahn FF Barr EB, Belinsky SA, Hoover MD, Lechner JF, Nikula KJ, Hobbs CH (1998). Carcinogenic responses of transgenic heterozygous p53 knockout mice to inhaled 239PuO2 or metallic beryllium. Toxicol Pathol 26: 484-491.[Abstract/Free Full Text]
  • Foran JA (ed) (1997). Dose Selection in Chronic Rodent Bioassays. ILSI Press, Washington. DC
  • Fox TR, Schumann AM, Watanabe PG, Yano BL, Maher VM (1990). Mutational analysis of the H-ras oncogene in spontaneous C57BL/6 X C3H/He mouse liver tumors and tumors induced with genotoxic and non-genotoxic hepatocarcinogens. Cancer Res 50: 4014-4019.[Abstract/Free Full Text]
  • French JE, Lacks GD, Trempus C., Dunnick JK, Mahler J., Tice RR, Tennant RW (in press). Mutation and loss of the p53 wild type allele is carcinogen dependent in heterozygous p53(+/-) mice.
  • Frith CH, Ward JM, Chandra M. (1993). The morphology, immunohistochemistry, and incidence of hematopoietic neoplasms in mice and rats. Toxicol Pathol 21: 206-218.[Abstract/Free Full Text]
  • Frith CH, Wiley LD (1981). Morphologic classification and correlation of incidence of hyperplastic and neoplastic hematopoietic lesions in mice with age. J Gerontol 36: 534-545.[Abstract/Free Full Text]
  • Gerlai R. (1996). Gene targeting studies of mammalian behavior: Is it the mutation or the background genotype? Trends Neurosci 19: 177-181.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Glode LM, Rosenstreich DL (1976). Genetic control of B cell activation by bacterial lipoploysaccharide is mediated by multiple distinct genes or allies. J Immunol 117: 2061-2066.[Abstract/Free Full Text]
  • Goodman DF, Boorman GA, Strandberg JD (1994). Selection and use of the B6C3 F1 mouse and F344 rat in long-term bioassays for carcinogenicity. In: Handbook of Carcinogen Testing, 2nd ed, Milman HA, Weisburger EK (eds). Noyes Publications, Park Ridge, New Jersey, pp 347-390.
  • Goodrow TL, Storer RD, Leander KR, Prahalada SR, van Zwieten MJ, Bradley MO (1992). Murine p53 intron sequences 5-8 and their use in polymerase chain reaction/direct sequencing analysis of p53 mutations in CD-1 mouse liver and lung tumors. Mol Carcinog 5: 9-15.[Web of Science][Medline] [Order article via Infotrieve]
  • Graves S., Cannon RE, Spalding JW, Furedi-Machacek EM, Tice RR, Tennant RW (1997). Oral administration of DMVC in TG.AC mice induces v-Ha-ras transgene expression in forestomach. Environ Mol Mutagen 29: 18.
  • Green MC (ed) (1981). Genetic Variants and Strains of the Laboratory Mouse. Gustav Fischer Verlag, Stuttgart.
  • Greenblatt MS, Bennett WP, Hollstein M., Harris CC (1994). Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res 54: 4855-4878.[Free Full Text]
  • Gu H., Marth JD, Orban PC, Mossmann H., Rajewsky K. (1994). Deletion of a DNA polymerase b gene segment in T cells using cell type-specific gene targeting. Science 265: 103-106.[Abstract/Free Full Text]
  • Hamm TE Jr (1994). Design of a long-term animal bioassay for carcinogenicity. In: Handbook of Carcinogen Testing, 2nd ed, Milman HA, Weisburger EK (eds). Noyes Publications, Park Ridge, New Jersey, pp 270-285.
  • Hanahan D. (1989). Transgenic mice as probes into complex systems. Science 246: 1265-1275.[Abstract/Free Full Text]
  • Hansen LA, Trempus CS, Mahler JF, Tennant RW (1996). Association of tumor development with increased cellular proliferation and transgene overexpression, but not c-Ha-ras mutations, in v-Ha-ras transgenic Tg.AC mice. Carcinogenesis 17: 1825-1833. 60. Hart RW, Neumann DA, Robertson RT (1995). Dietary Restriction: Implications for the Design and Interpretation of Toxicity and Carcinogenicity Studies. ILSI Press, Washington, DC.[Web of Science]
  • Harvey M., McArthur MJ, Montgomery CA Jr, Bradley A., Butel JS, Donehower LA (1993). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat Genet 5: 225-229. 62. Harvey M., McArthur MJ, Montgomery CA Jr., Bradley A., Donehower LA (1993). Genetic background alters the spectrum of tumors that develop in p53-deficient mice. FASEB J 7: 938-943. 63. Harvey M., Vogel H., Morris D., Bradley A., Bernstein A., Donehower LA (1995). A mutant p53 transgene accelerates tumour
  • development in heterozygous but not nullizygous p53-deficient mice. Nat Genet 9: 305-311.
  • Haseman JK (1995). Data analysis: Statistical analysis and use of historical control data. Regul Toxicol Pharniacol 21: 52-59.[CrossRef]
  • Hayashi SM, Mori I., Nonoyama T., Mistumori K. (1998). Point mutations of the C-H-ras gene in spontaneous liver tumors of transgenic mice carrying the human C-H-ras gene. Toxicol Pathol 26: 556-561.[Abstract/Free Full Text]
  • Hegi ME, Soderkvist P., Foley JF, Schoonhoven R., Swenberg JA, Kari F., Maranpot R., Anderson MW, Wiseman R. (1993). Characterization of p53 mutations in methylene chloride-induced lung tumors from B6C3F1 mice. Carcinogenesis 14: 803-810.[Abstract/Free Full Text]
  • Hollstein M, Sidransky D, Vogelstein B, Harris Cc (1991). p53 mutations in human cancers. Science 253: 49-53.[Abstract/Free Full Text]
  • Hongyo T., Buzard GS, Calvert RJ, Weghorst CM (1993). Cold SSCP: A simple, rapid and non-radioactive method for optimized single-strand conformation polymorphism analyses. Nucleic Acids Res 21: 3637-3642.[Abstract/Free Full Text]
  • Hursting SD, Perkins, SN, Phang JM (1994). Calorie restriction delays spontaneous tumorigenesis in p53-knockout transgenic mice. Proc Natl Acad Sci USA 91: 7036-7040.[Abstract/Free Full Text]
  • International Conference on Harmonisation (1995). Technical requirements for registration of pharmaceuticals for human use. Fed Regist 60: 11278-11286.
  • International Conference on Harmonisation (1996). Draft guideline on testing for carcinogenicity of pharmaceuticals; notice. Fed Regist 61: 43329-43300.
  • International Conference on Harmonisation (1998). Guidance on testing for carcinogenicity of pharmaceuticals. Fed Regist 63: 8983-8986.[Medline] [Order article via Infotrieve]
  • Jacks T., Remington L., Williams BO, Schmitt EM, Halachmi S., Bronson RT, Weinberg RA (1994). Tumor spectrum analysis in p53-mutant mice. Curr Biol 4: 1-7.[Medline] [Order article via Infotrieve]
  • Jaenisch R. (1988). Transgenic animals. Science 240: 1468-1474. 75. Jonckheere AR (1954). A distribution-free K sample test against ordered alternatives. Biometrika 41: 133-145.[Free Full Text]
  • Kemp C., Fee F., Balmain A. (1993). Allelotype analysis of mouse skin tumors using polymorphic microsatellites: Sequential genetic alterations on chromosomes 6, 7, and 11. Cancer Res 53: 6022-6027.[Abstract/Free Full Text]
  • Kemp CJ, Wheldon T., Balmain A (1994). p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat Genet 8: 66-69.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Klaassen CD, Eaton DL (1991). Principles of toxicology. In: Casarett and Doull's Toxicology, 4th ed, Amdur MO, Doull J, Klaassen CD (eds). Pergamon Press, Elsmsford, New York, pp 12-49.
  • Kress S., Konig J., Schweizer J., Lohrke H., Bauer-Hofmann R., Schwarz M. (1992). p53 mutations are absent from carcinogen-induced mouse liver tumors but occur in cell lines established from these tumors. Mol Carcinog 6: 148-158.[Web of Science][Medline] [Order article via Infotrieve]
  • Laird PW, Jaenisch R. (1996). The role of DNA methylation in cancer genetics and epigenetics. Annu Rev Genet 30: 441-464.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Leder A., Kuo A., Cardiff RD, Sinn E., Leder P. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: Effects of phorbol esters and retinoic acid. Proc Natl Acad Sci USA 87: 9178-9182.[Abstract/Free Full Text]
  • Lee JM, Abrahamson Jla, Bernstein A. (1994). DNA damage, oncogenesis and the p53 tumour-suppressor gene. Mutat Res 307: 573-581.[Web of Science][Medline] [Order article via Infotrieve]
  • Mahler JF, Flagler ND, Malarkey DE, Mann PC, Haseman JK, Eastin W. (1998). Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice. Toxicol Pathol 26: 501-511.[Abstract/Free Full Text]
  • Mahler JF, Stokes W., Mann P Takaoka M., Maronpot RP (1996). Spontaneous lesions in aging FVB/N mice. Toxicol Pathol 24: 710-716.[Abstract/Free Full Text]
  • Manam S., Storer RD, Prahalada S., Leander KR, Kraynak AR, Hammermeister CL, Joslyn DJ, Ledwith BJ, van Zwieten MJ, Bradley MO, Nichols WW (1992). Activation of the Ki-ras gene in spontaneous and chemically-induced lung tumors in CD-1 mice. Mol Carcinog 6: 68-75.[Web of Science][Medline] [Order article via Infotrieve]
  • Manam S., Storer RD, Prahalada S., Leander KR, Kraynak AK, Ledwith BJ, van Zwieten MJ, Bradley MO, Nichols WW (1992). Activation of the Ha-, Ki-, and N-ras genes in chemically induced liver tumors from CD-1 mice. Cancer Res 52: 3347-3352.[Abstract/Free Full Text]
  • Mao JH, Lindsay KA, Balmain A., Wheldon TE (1998). Stochastic modelling of tumorigenesis in p53 deficient mice. Br J Cancer 77: 243-252.[Web of Science][Medline] [Order article via Infotrieve]
  • Maronpot RR, Boorman GA (1996). The contribution of the mouse in hazard identification studies. Toxicol Pathol 24: 726-731.[Abstract/Free Full Text]
  • Marselos M., Vainio H. (1991). Carcinogenic properties of pharmaceutical agents evaluated in the IARC Monographs programme. Carcinogenesis 12: 1751-1766.[Abstract/Free Full Text]
  • Merlino G. (1994). Transgenic mice as models for tumorigenesis. Cancer Invest 12: 203-213.[Web of Science][Medline] [Order article via Infotrieve]
  • Mirsalis JC, Monforte JA, Winegar RA (1994). Transgenic animal models for measuring mutation in vivo. Crit Rev Toxicol 24: 255-280.[Web of Science][Medline] [Order article via Infotrieve]
  • Mitsumori, K., Koizzumi H., Nomura T., Yamamoto S. (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. Toxicol Pathol 26: 520-531.[Abstract/Free Full Text]
  • Mohr U., Lewkowski JP (1989). The Effect of Diet on Tumour Development in Animals. VEB Gustav Fischer Verlag, Jena, Germany.
  • Monastersky GM (1995). Transgenic mouse strategies: Embryology and animal science. In: Strategies in Transgenic Animal Science, Monastersky GM, Robl JM (eds). American Society for Microbiology Press, Washington, DC, pp 3-36.
  • Monastersky GM, Geistfeld JG (1997). The production and verification of transgenic mouse lines. Lab Anim 36: 36-40.
  • Monro AM (1994). Utility of two rodent species: Some arguments for and against. Proc Int Conf Harmonization 2: 293.
  • Moolgavkar SH, Knudson AG (1981). Mutation and cancer: A model for human carcinogenesis. J Natl Cancer Inst 66: 1037-1052.[Web of Science][Medline] [Order article via Infotrieve]
  • Moolgavkar SH, Luebeck EG (1990). Two-event model for carcinogenesis: Biological, mathematical, and statistical considerations. Risk Anal 10: 323-341.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Moolgavkar SH (1993). Cell proliferation and carcinogenesis models: General principles with illustrations from the rodent liver system. Environ Health Perspect 101(suppl 5): 91-94.
  • Munro IC, Lynch BS, Kittur A., Nestman ER (1995). Modulators of carcinogenesis. Regul Toxicol Pharmacol 21: 60-70.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • National Institute of Environmental Health Sciences (1998). http://ntp-server.niehs.nih.gov/htdocs/liason/factsheets/TGAnml.html.
  • Owens DM, Spalding JW, Tennant RW, Smart RC (1995). Genetic alterations cooperate with v-Ha-ras to accelerate multistage carcinogenesis in TG.AC transgenic mouse skin. Cancer Res 55: 3171-3178.[Abstract/Free Full Text]
  • Pattengale PK, Stewart TA, Leder A., Sinn E., Muller W., Tepler I., Schmidt E., Leder P. (1989). Pathology and molecular biology of spontaneous neoplasms occurring in transgenic mice carrying and expressing activated cellular oncogenes. Am J Pathol 135: 39-61.[Abstract]
  • Poole TM, Drinkwater NR (1996). Two genes abrogate the inhibition of murine hepatocarcinogenesis by ovarian hormones. Proc Natl Acad Sci USA 93: 5848-5853.[Abstract/Free Full Text]
  • Purdie CA, Harrison DJ, Peter A., Dobbie L., White S., Howie SE, Salter DM, Bird CC, Wyllie AH, Hooper ML, Clarke AR (1994). Tumour incidence, spectrum and ploidy in mice with a large deletion in the p53 gene. Oncogene 9: 603-609.[Web of Science][Medline] [Order article via Infotrieve]
  • Reiners JJ, Singh KP (1997). Susceptibility of 129/SvEv mice in two-stage carcinogenesis protocols to 12-o-tetradecanoylphorbol-13-acetate promotion. Carcinogenesis 18: 593-597.[Abstract/Free Full Text]
  • Robbins JH, Kraemer KH, Lutzner MA, Festoff BW, Coon HG (1974). Xeroderma pigmentosum. An inherited disease with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair. Ann Intern Med 80: 221-248.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Robinson D. (1998). The International Life Sciences Institute's role in the evaluation of alternative methodologies for the assessment of carcinogenic risk. Toxicol Pathol 26: 474-475.[Free Full Text]
  • Rodenhuis S., Slebos RJ, Boot AJ, Evers SG, Mooi WJ, Wagenaar SS, Van Bodegom PC, Bos JL ( 1988). Incidence and possible significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 48: 5738-5741.[Abstract/Free Full Text]
  • Rodenhuis S., Van de Wetering ML, Mooi WJ, Evers SG, Van Zandwijk N., Bos J. ( 1987). Mutational activation of the K-ras oncogene: A possible pathogenic factor in adenocarcinoma of the lung. N Engl J Med 317: 929-935.[Abstract]
  • Rumsby PC, Barrass NC, Phillimore HE, Evans JG (1991). Analysis of the Ha-ras oncogene in C3H/He mouse liver tumors derived spontaneously or induced with diethylnitrosamine or phenobarbitone. Carcinogenesis 12: 2331-2336.[Abstract/Free Full Text]
  • Sagartz JE, Curtiss SW, Bunch RT, Davila JC, Morris DL, Alden CL (1998). Phenobarbital does not promote hepatic tumorigenesis in a twenty-six-week bioassay in p53 heterozygous mice. Toxicol Pathol 26: 492-500.[Abstract/Free Full Text]
  • Saitoh A., Kimura M., Takahashi R., Yokoyama M., Nomua T., Izawa M., Sekiya T., Nishimura S., Katsuki M. (1990). Most tumors in transgenic mice with human c-Ha-ras gene contained somatically activated transgenes. Oncogene 5: 1195-1200.[Web of Science][Medline] [Order article via Infotrieve]
  • Sandgren EP, Quaife CJ, Pinkert CA, Palmiter RD, Brinster RL (1989). Oncogene-induced liver neoplasia in transgenic mice. Oncogene 4: 715-724.[Web of Science][Medline] [Order article via Infotrieve]
  • Sedivy JM, Joyner AL (1992). Gene Targeting. W. H. Freeman and Co, New York.
  • Sibilia M., Wagner EF (1995). Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269: 234-238.[Abstract/Free Full Text]
  • Siegel S. (1956). Nonparametric Statistics for the Behavioral Sciences. McGraw-Hill, New York, pp 116-127.
  • Simpson EM, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp JJ (1997). Genetic variation among 129 substrains and its importance for 'targeted mutagenesis' in mice. Nat Genet 16: 19-27.[Medline] [Order article via Infotrieve]
  • Spalding JW, French JE, Tice RR, Furedi-Machacek, M., Haseman JK, Tennant RW (1999). Development of a transgenic mouse model for carcinogenesis bioassays: Evaluation of chemically induced skin tumors in Tg.AC mice. Toxicol Sci 49: 241-254.[Abstract/Free Full Text]
  • Spalding JW, Momma J., Elwell MR, Tennant RW (1993). Chemically induced skin carcinogenesis in a transgenic mouse line (Tg.AC) carrying a v-Ha-ras gene. Carcinogenesis 14: 1335-1341.[Abstract/Free Full Text]
  • Stowers SJ, Glover P., Reynolds S., Boone L., Maranpot R., Anderson M. (1987). Activation of the K-ras proto-oncogene in lung tumors from rats and mice chronically-exposed to tetranitromethane. Cancer Res. 47: 3212-3219.[Abstract/Free Full Text]
  • Sundberg JP, Brown KS, Bedigan SR (1990). Ulcerative blepharitis and periorbital abcesses in BALB/cJ and BALB/cByJ mice. JAX Notes 443.
  • Swenberg JA (1995). Bioassay design and MTD setting: Old methods and new approaches. Regul Toxicol Pharmacol 21: 44-51.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Tada M., Omata M., Ohto M. ( 1990). Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 50: 1121-1124.[Abstract/Free Full Text]
  • Taketo M., Schroder AC, Mobraaten LE, Gunning KB, Hanten G., Fox RR, Roderick TH, Stewart CL, Lilly F., Hansen CT, Overbeek PA (1991). FVB/N: An inbred mouse strain preferable for transgenic analysis. Proc Natl Acad Sci USA 88: 1065-1069.
  • Tarone RE (1975). Tests for trend in life table analysis. Biometrika 62: 679-682.[Abstract/Free Full Text]
  • Tennant RW, French JE, Spalding JW (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ Health Perspect 103: 942-950.[Web of Science][Medline] [Order article via Infotrieve]
  • Tennant RW, Spalding J., French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and noncarcinogens. Mutat Res 365: 119-127.[Web of Science][Medline] [Order article via Infotrieve]
  • Tennant RW, Stasiewicz S., Mennear J. French JE, Spalding JW (1999). Genetically altered mouse models for carcinogen identification. In: Short- and Medium-Term Carcinogenicity Tests, Mutation Analysis, and Multistage Models in Risk Identification, McGregor D, Rice J, Venitt S (eds). IARC Scientific Publications No 146, International Agency for Research on Cancer, Lyon, France, pp 123-150.
  • Thomas RD (1997). Assessing risks to human health. In: Comprehensive Toxicology, Vol 2, Sipes IG, McQueen CA, Gandolfi AJ (eds). Elsevier, Oxford, England, pp 59-74.
  • Thompson KI, Rosenzweig BA, Sistare FD (1998). An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. II. A genotypic marker that predicts tumorigenic responsiveness. Toxicol Pathol 26: 548-555.[Abstract/Free Full Text]
  • Threadgill DW, Diugosz AA, Hansen LA, Tennenbaum T., Lichti U., Yee D., LaMantia C., Mourton T., Herrup K., Harris RC, Barnard JA, Yuspa JH, Coffey RJ, Mgnuson T. (1995). Targeted disruption of mouse EGF receptor: Effect of genetic background on mutant phenotype. Science 269: 230-234.[Abstract/Free Full Text]
  • van Oostrom Ctm, de Vries A., Verbeek SJ, van Kreijl CF, van Steeg H. (1994). Cloning and characterization of the mouse XPAC gene. Nucleic Acids Res 22: 11-14.[Abstract/Free Full Text]
  • van Steeg H., Klein H., Beems RB, van Kreijl CF (1998). Use of DNA repair-deficient XPA transgenic mice in short-term carcinogenicity testing. Toxicol Pathol 26: 742-749.[Abstract/Free Full Text]
  • Venkatachalam S., Shi YP, Jones SN, Vogel H., Bradley A., Pinkel D., Donehower LA (1998). Retention of wild-type p53 in tumors from p53 heterzygous mice: Reduction of p53 dosage can promote cancer formation. EMBO J 17: 4657-4667.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Walker CL (1996). Cancer susceptibility genes and molecular carcinogenesis. Mol Med Today 2: 364-365.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Watson J., Kelly K., Largen M., Taylor BA (1978). The genetic mapping of a defective LPS response gene in C3H/Hej mice. J Immunol 120: 422-424.[Abstract/Free Full Text]
  • Weaver JL, Contrera JF, Rosenzweig BA, Thompson KL, Faustino PJ, Strong JM, Ellison CD, Anderson LW, Prasanna HR, Long-Bradley PE, Lin KK, Zhang J., Sistare FD (1998). An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. I. Evidence for a confounding nonresponder phenotype. Toxicol Pathol 26: 532-540.[Abstract/Free Full Text]
  • Weisburger JH, Williams GM (1984). Bioassay of carcinogens: In vitro and in vivo tests. In: Chemical Carcinogens, Searle CE (ed). American Chemical Society, Washington, DC, pp 1323-1373.
  • Witham BA (1990). Coat colors of sublines of 129 mice. JAX Notes 441.
  • Wright JT, Hansen L., Mahler J., Szczesniak C., Spalding, JW (1995). Odontogenic tumours in the v-Ha-ras (Tg.AG) transgenic mouse. Arch Oral Biol 40: 631-638.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Yamamoto S., Hayashi Y., Mitsumori K., Nomura T. (1997). Rapid carcinogenicity testing system with transgenic mice harboring human prototype c-H-ras gene. Lab Anim Sci 47: 121-126.[Web of Science][Medline] [Order article via Infotrieve]
  • Yamamoto S., Mitsumori K., Kodama Y., Matsunuma N., Manabe S., Okamiya H., Suzuki H., Fukuda T., Sakamaki Y., Sunaga M., Nomura G., Hioki K., Wakana S., Nomura T., Hayashi Y. (1996). 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. Carcinogeriesis 17: 2455-2461.[CrossRef]
  • Yamamoto S., Urano K., Koizumi H., Wakana S., Hioki K., Mitsumori K., Kurokawa Y., Hayashi Y. (1998). Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing. Environ Health Perspect 106(suppl 1): 57-69.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • You M., Candrian U., Maranpot R., Anderson M. (1989). Activation of the K-ras protooncogenes in spontaneously occurring and chemically induced lung tumors of the strain A mouse. Proc Natl Acad Sci USA 86: 3070-3074.[Abstract/Free Full Text]
  • Yukawa K., Kikutani H., Imomoto T., Uehira M. Bin SH, Kagi KA, Yamamura KI, Kishimoto T. (1989). Strain dependency of b and T lymphoma development in immunoglobulin heavy chain enhancer (Em)-myc transgenic mice. J Exp Med 170: 711-726.[Abstract/Free Full Text]

Toxicologic Pathology, Vol. 28, No. 3, 482-499 (2000)
DOI: 10.1177/019262330002800320
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Toxicol SciHome page
C. Michel, C. Desdouets, M. Slaoui, K. R. Isaacs, R. A. Roberts, and E. Boitier
Diethylnitrosamine Initiation Does Not Alter Clofibric Acid Induced Hepatocarcinogenesis in the Rat
Toxicol. Sci., September 1, 2007; 99(1): 58 - 69.
[Abstract] [Full Text] [PDF]

Home page
 MutagenesisHome page
B. L. Parsons, R. R. Delongchamp, F. A. Beland, and R. H. Heflich
Levels of H-ras codon 61 CAA to AAA mutation: response to 4-ABP-treatment and Pms2-deficiency
Mutagenesis, January 1, 2006; 21(1): 29 - 34.
[Abstract] [Full Text] [PDF]

Home page
 International Journal of ToxicologyHome page
D. L. McCormick and R. Kavet
Animal Models for the Study of Childhood Leukemia: Considerations for Model Identification and Optimization to Identify Potential Risk Factors
International Journal of Toxicology, May 1, 2004; 23(3): 149 - 161.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
S. M. Cohen
Risk Assessment in the Genomic Era
Toxicol Pathol, January 1, 2004; 32(1_suppl): 3 - 8.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
K. Toyosawa, K. Tanaka, T. Imai, K. Yasuhara, T. Koujitani, M. Hirose, and K. Mitsumori
Mutation and Overexpression of the Transgene in Ethylnitrosourea-Induced Tumors in Mice Carrying a Human Prototype c-Ha-ras Gene
Toxicol Pathol, August 1, 2003; 31(5): 491 - 495.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
S. R. Payne and C. J. Kemp
p27 Kip1 (Cdkn1b)-Deficient Mice Are Susceptible to Chemical Carcinogenesis and May Be a Useful Model for Carcinogen Screening
Toxicol Pathol, June 1, 2003; 31(4): 355 - 363.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
S. Sehata, T. Maejima, M. Watanabe, S. Ogata, T. Makino, K. Tanaka, S. Manabe, and M. Takaoka
Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice
Toxicol Pathol, April 1, 2002; 30(3): 328 - 338.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
E. Floyd, P. Mann, G. Long, and R. Ochoa
The Trp53 Hemizygous Mouse in Pharmaceutical Development: Points to Consider for Pathologists
Toxicol Pathol, January 1, 2002; 30(1): 147 - 156.
[Abstract] [PDF]

Home page
 Toxicol SciHome page
S. M. Cohen, D. Robinson, and J. MacDonald
Alternative Models for Carcinogenicity Testing
Toxicol. Sci., November 1, 2001; 64(1): 14 - 19.
[Abstract] [Full Text] [PDF]

Home page
 International Journal of ToxicologyHome page
B. B. Curry III
Animal Models Used in Identifying Gender-Related Differences
International Journal of Toxicology, May 1, 2001; 20(3): 153 - 160.
[Abstract] [PDF]

Home page
 MutagenesisHome page
L. N. Healy, L. J. Pluta, R.A. James, D. B. Janszen, D. Torous, J. E. French, and L. Recio
Induction and time-dependent accumulation of micronuclei in peripheral blood of transgenic p53+/- mice, Tg.AC (v-Ha-ras) and parental wild-type (C57BL/6 and FVB/N) mice exposed to benzene by inhalation
Mutagenesis, March 1, 2001; 16(2): 163 - 168.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
S. W. Burchiel, C. M. Knall, J. W. Davis II, R. S. Paules, S. E. Boggs, and C. A. Afshari
Analysis of Genetic and Epigenetic Mechanisms of Toxicity: Potential Roles of Toxicogenomics and Proteomics in Toxicology
Toxicol. Sci., February 1, 2001; 59(2): 193 - 195.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol PatholHome page
R. D. Storer, J. E. French, J. Haseman, G. Hajian, E. K. Legrand, G. G. Long, L. A. Mixson, R. Ochoa, J. E. Sagartz, and K. A. Soper
p53 +/- Hemizygous Knockout Mouse: Overview of Available Data
Toxicol Pathol, January 1, 2001; 29(1_suppl): 30 - 50.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
T. Usui, M. Mutai, S. Hisada, M. Takoaka, K. A. Soper, B. Mccullough, and C. Alden
CB6F1-rasH2 Mouse: Overview of Available Data
Toxicol Pathol, January 1, 2001; 29(1_suppl): 90 - 108.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
S. Venkatachalam, S. D. Tyner, C. R. Pickering, S. Boley, L. Recio, J. E. French, and L. A. Donehower
Is p53 Haploinsufficient for Tumor Suppression? Implications for the p53+/- Mouse Model in Carcinogenicity Testing
Toxicol Pathol, January 1, 2001; 29(1_suppl): 147 - 154.
[Abstract] [PDF]

Home page
 Toxicol PatholHome page
S. M. Cohen
Alternative Models for Carcinogenicity Testing: Weight of Evidence Evaluations Across Models
Toxicol Pathol, January 1, 2001; 29(1_suppl): 183 - 190.
[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Gulezian, D.
Right arrow Articles by Neumann, D. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Gulezian, D.
Right arrow Articles by Neumann, D. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?