Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지

Recent Progress in Transgenic Mouse Models as an Alternative Carcinogenicity Bioassay

형질전환 마우스 모델 발암성 평가의 최신 지견

  • Son Woo-Chan (Huntingdon Life Sciences, Pathology, Woolley Road, Alconbury) ;
  • Kim Bae-Hwan (Pre-clinical Research Center, AMOREPACIFIC R&D CENTER) ;
  • Jang Dong-Deuk (Division of Toxicological Research, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Kim Chull-Kyu (Division of Toxicological Research, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Han Beom-Seok (Division of Toxicological Research, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Kim Jong-Choon (Department of Toxicology, College of Veterinary Medicine, Chonnam National University) ;
  • Kang Boo-Hyon (Korean Institute of Toxicology, KRICT) ;
  • Lee Je-Bong (Division of Agricultural safety, National Institute of Agricultural Science and Technology, RDA) ;
  • Choi Yang-Kyu (Lab. of Animal Model Evaluation, Korea Research Institute of Bioscience and Biotechnology (KRIBB)) ;
  • Kim Hyoung-Chin (Lab. of Animal Model Evaluation, Korea Research Institute of Bioscience and Biotechnology (KRIBB))
  • 손우찬 ;
  • 김배환 ((주)태평양 기술연구원 전임상연구센타) ;
  • 장동덕 (국립독성연구원 독성연구부) ;
  • 김철규 (국립독성연구원 독성연구부) ;
  • 한범석 (국립독성연구원 독성연구부) ;
  • 김종춘 (전남대학교 수의과대학 독성학교실) ;
  • 강부현 (한국화학연구원 안전성평가연구소) ;
  • 이제봉 (농촌진흥청 농업과학기술원) ;
  • 최양규 (한국생명공학연구원 질환동물모델평가연구실) ;
  • 김형진 (한국생명공학연구원 질환동물모델평가연구실)
  • Published : 2005.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Transgenic mouse models have been introduced and accepted by regulatory bodies as an alternative to carcinogenicity assay models to predict and evaluate chemical carcinogens. The recent research outcomes in transgenic mouse models have made progressive advances in the understanding of chemical carcinogenesis and the evaluation of potential human carcinogens. However, these models still remain to be insufficient assay systems although the insufficiencies have been recognised and are being resolved. Based on up to date information from literature, this review article intends to understand currently accepted transgenic mouse models, issues arising from study design, interpretation of the study, results of validation project and their cancer prediction rate, and further perspectives of cancer assay models from the regulatory view point.

Keywords

References

  1. Albert, R., French, J., Maronpot, R., Spalding, J. and Tennant, R. (1996): Mechanism of skin tumorigenesis by contact sensitizers: The effect of the corticosteroid fluocinolone acetonide on inflammation and tumor induction by 2,4dinitro-1-fluorobenzene in the skin of the Tg.AC (v-Ha-ras) mouse. Environmental Health Perspectives, 104, 1062-1068 https://doi.org/10.2307/3433118
  2. Berg, R.J.W., De Vries, A., Van Steeg, H. and De Gruijl, F.R. (1997): Relative susceptibilities of XPA knockout mice, and their heterozygous, and wild-type littermates to UVB-induced skin cancer. Cancer Res., 57, 581-584
  3. Bucher, J.R. (1998): Update on National Toxicology Program (NTP) assays with genetically altered or 'Transgenic' mice. Environmental Health Perspectives., 106, 619-622. http://ntp.niehs.nih.gov/ https://doi.org/10.2307/3434087
  4. DeGeorge, J. (2001): Regulatory perspective on application of the transgenic alternatives in pharmaceutical development. Presented at the annual meeting of the society of toxicologic pathologists, Orlendo, FL
  5. de Vries, A., Van Oostrum, C.T.M., Hofhuis, F.M.A., Dortant, P.M., Berg, R.J.W., De Gruijl, F.R., Wester, P.W., Van Kreijl, C.F., Capel, P.J.A., Van Steeg, H. and Verbeek, S.J. (1995): Increased susceptability to ultraviolet-B and carcinogenesis of mice lacking the DNA excision repair gene Xpa. Nature, 337, 169-173 https://doi.org/10.1038/337169a0
  6. de Vries, A., Van Oostrum, C.T.M., Hofhuis, F.M.A., Dortant, P.M., Beems, R.B., Berg, R.J.W., Van Kreijl, C.F., Capel, P.J.A. and Van Steeg, H. (1997): Spontaneous liver tumours and benzo[a]pyrene-induced lymphomas in Xpa deficient mice. Molec. Carcinogen., 19, 46-53. https://doi.org/10.1002/(SICI)1098-2744(199705)19:1<46::AID-MC7>3.0.CO;2-L
  7. de Vries, A., van Steeg, A. and Opperhuizen. (2004). RIVM report 340700001/2004, Transgenic mice as alternatives in carcinogenicity testing: current status, Netherlands
  8. Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery, C.A.J., Butel, J.S. and Bradley, A. (1992): Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature, 356, 215-221 https://doi.org/10.1038/356215a0
  9. Eastin, W.C., Haseman, J.K., Mahler, J.F. and Bucher J.R. (1998): The National Toxicology program evaluation of genetically altered mice as predictive models for identifying carcinogens. Toxicol. Pathol., 26, 461-473 https://doi.org/10.1177/019262339802600401
  10. Floyd, E., Mann, P., Long, G. and Ochoa, R. (2002): The Trp53 hemizygous mouse in pharmaceutical development: points to consider for pathologists. Toxicol. Pathol., 30, 147-156 https://doi.org/10.1080/01926230252824860
  11. French, J., Haseman, J., Donehower, L., Hajian, G., LeGrand, E., Long, G., Ochoa, R., Sagartz, J., Mixon, L., Soper, K. and Storer, R. (2000): The P53+/- heterozygous knockout mouse model for short-term carcinogenicity testing. ILSI/HESI workshop on evaluation of alternative methods for carcinogenicity testing, Leesburg, VA
  12. Hansen, L.A. and Tennant, R.W. (1994): Follicular origin of epidermal papillomas in v-Ha-ras transgenic TG.AC mouse skin. Proc. Natl. Acad Sci USA, 91, 7822-7826 https://doi.org/10.1073/pnas.91.16.7822
  13. Hansen, L.A., Trempus, C.S., Mahler, J.F. and Tennant, R.W. (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 https://doi.org/10.1093/carcin/17.9.1825
  14. Hansen, L.A., Spalding, J.W., French, J.E. and Tennant, R.W. (1994): A transgenic mouse model (TG.AC) for skin carcinogenesis: Inducible transgene expression as a second critical event. In McClain, R.M., Slaga, T.J., LeBoeuf, R. and Pitot, H. (eds.), Growth Factors and Tumor Promotion: Implications for Risk Assessment, Vol. 391. Wile-Liss, Barton Creek, Texas, pp. 223-235
  15. Harvey, M., McArthur, M.J., Montgomery, C.A.J., Butel, J.S., Bradley, A. and Donehower, L.A. (1993a): Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat. Genet., 5, 225-229 https://doi.org/10.1038/ng1193-225
  16. Harvey, M., McArthur, M.J., Montgomery, C.A.J., Bradley, A. and Donehower, L.A. (1993b): Genetic background alters the spectrum of tumors that develop in p53-deficient mice. FASEB J., 7, 938-943 https://doi.org/10.1096/fasebj.7.10.8344491
  17. http://hesi.ilsi.org, ILSI HESI ACT:Alternatives to Carcinogenicity Testing
  18. http://ntp.niehs.nih.gov/, Bucher, J R. Update on National Toxicology Program (NTP) assays with genetically altered or 'Transgenic' mice
  19. http://www.item.fraunhofer.de/reni. ACT: Alternatives to Carcinogenicity Testing
  20. ICH (1997): Guidance on safety testing for carcinogenicity of pharmaceuticals. Fed. Reg., 63, 8983-8986
  21. ICH (1998): Expert working group on safety, Guidance for industry S1B testing for carcinogenicity of pharmaceuticals
  22. Jacobson-Krarn, D., Sistare F.D. and Jacobs, A.C. (2004): Use of transgenic mice in carcinogenicity hazard assessment. Toxicol. Pathol., 32(Suppl. 1), 49-52 https://doi.org/10.1080/01926230490424761
  23. Leder, A., Kuo, A., Cardiff, R.D., Sinn, E. and 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 https://doi.org/10.1073/pnas.87.23.9178
  24. Linda, B.A., Woutersen, R.A., Bruijntjes, J.P., Benthem, J.V., van den Berg, J.A.H., Monbaliu, J., Thoolen, B.J.J.M., Beems, R.B. and van Kreijl, C.F. (2004): Evaluation of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies with haloperidol, reserpine, phenacetin, and d-mannitol. Toxicol. Pathol., 32, 192-201 https://doi.org/10.1080/01926230490274344
  25. MacDonald, J., French, J.E., Gerson, R.J., Goodman, G.J., Inoue, T., Jacobs, A., Kasper, P., Keller, D., Lavin, A., Long, G., McCullough, B., Sistare, F.D., Storer, R. and van der laan, J.W. (2004): The utility of genetically modified mouse assays for identifying human carcinogens: a basic understanding and path forward. Toxicol. Sci., 77, 188-194 https://doi.org/10.1093/toxsci/kfh037
  26. Maronpot, M.M., Fox, T., Malarkey, D.E. and Goldworthy, T. (1995): Mutations in the ras proto-oncogene:Clues to etiology and molecular pathogenesis of mouse liver tumors. Toxicology, 101, 125-156 https://doi.org/10.1016/0300-483X(95)03112-S
  27. Mastorides, S. and Maronpot, R.R. (2002): Carcinogenesis. In: Handbook of toxicologic pathology. 2nd ed. Ed Haschek, W.M., Rousseaux, C.G., Wallig, M.A., pp. 83-122
  28. Morton, D., Alden, C.L., Roth, A.J. and Usui, T., (2002): The Tg rasH2 mouse in cancer hazard identification. Toxicol. Pathol., 30, 139-146 https://doi.org/10.1080/01926230252824851
  29. Nylander-French, L. and French, J. (1998): Tripropylene glycol diacrylate, but not ethyl acrylate, induces skin tumors in a twenty week short term tumorigenesis study in Tg.AC (v-Ha-ras) mice. Toxico. Pathol., 26, 476-483 https://doi.org/10.1177/019262339802600403
  30. Ochoa R. (2002): Pathology issues in the design of toxicology studies. In: Handbook of toxicologic pathology. 2nd ed. Ed Haschek, W.M., Rousseaux, C.G., Wallig, M.A., pp. 307-326
  31. Pritchard, J.B., French, J.E., Davis, B.J. and Haseman, J.K. (2003): The role of transgenic mouse models in carcinogen identification. Environ. Health. Prospect., 111, 1-11
  32. Recio, L., Boley, S., Everitt, J., James, R.A., Janszen, D., Healy, L., Roberts, K., Walker, D., Pluta, L. and French, J.E. (2000): Cancer bioassay and genotoxicity of inhaled benzene in $p53^{+/-} $ and C57B16 mice. Toxicologist, 54, 222
  33. Robinson, D.E. and MacDonald, J.S. (2001): Background and frame work for ILSI's collaborative evaluation program on alternative models for carcinogenicity assessment. Toxicol. Pathol., 29(Suppl), 13-19 https://doi.org/10.1080/019262301753178438
  34. Sanders, J.M., Burka, L.T., Chanas, B. and Matthews, H.B. (2001): Comparative xenobiotic metabolism between Tg.AC and $p53^{+/-} $ genetically altered mice and their respective wild types. Toxicol. Sci., 61, 54-61 https://doi.org/10.1093/toxsci/61.1.54
  35. Storer, R.D., French, J.E., Haseman, J., Hajian, G., LeGrand, E.K., Long, G.G., Mixon, L.A., Ochoa, R., Sagartz, J.E. and Soperm K.A. (2001): $p53^{+/-} $ hemizygous knockout mouse: overview of the available data. Toxicol. Pathol., 29(Suppl), 30-50 https://doi.org/10.1080/019262301753178465
  36. Spalding, J.W., Momma, J., Elwell, M.R. and Tennant, R.W. (1993): Chemical induced skin carcinogenesis in a transgenic mouse line (TG.AC) carrying a v-Ha-ras gene. Carcinogenesis, 14, 1335-1341 https://doi.org/10.1093/carcin/14.7.1335
  37. Suemizu, H., Ohnishi, Y., Maruyama, C., Tomisawa, M., Muguruma, K., Hioki, K., Usui, T., Kimura, M., Tamaoki, N. and Nomura, T. (2002): Molecular biological studies in the rasH2 transgenic mouse. In: Workshop on the evaluation of alternative methods for carcinogenicity testing. International Life Sciences Institute, Washington, DC
  38. Takaoka, M., Sehata, S., Maejima, T., Imai, T., Torii, M., Satoh, H., Toyosawa, K., Tanakamaru, Z.-Y., Adachi, T., Hisada, S., Ueda, M., Ogasawara, H., Matsumoto, M., Kobayashi, K., Mutai, M. and Usui, T. (2003): Interlaboratory comparison of short-term carcinogenicity studies using $CB6F_1 $-rasH2 transgenic mice. Toxieol. Pathol., 31, 191-199 https://doi.org/10.1080/01926230390183670
  39. Tennant, R.W., French, J.E. and Spalding, J.W. (1995): Identification of chemical carcinogens and assessing potential risk in short term bioassays using transgenic mouse models. Environ. Health. Perspeet., 103, 942-950 https://doi.org/10.2307/3432740
  40. Tennant, R.W., Spalding, J.W. and French, J.E. (1996): Evaluation of transgenic mouse bioassays for identifying carcinogens and non-carcinogens. Mut. Res., 395, 119-127 https://doi.org/10.1016/S0165-1110(96)90016-0
  41. Van Oostrum, C.T.M., Boeve, M., Van den Berg, J., de Vries, A., Dolle, M.E.T., Beems, R.B., Van Kreijl, C.F., Vijg, J. and Van Steeg, H. (1999): The effect of heterozygous loss of p53 on benzo a pyrene-induced mutations and tumours in DNA repair-deficient Xpa mice. Environ. Mol. Mutagen., 34, 124-30 https://doi.org/10.1002/(SICI)1098-2280(1999)34:2/3<124::AID-EM11>3.0.CO;2-F
  42. Watanabe, K. (2004): Research and development of the Tg rasH2 mice model. Presented at the seminar at Huntingdon Life Sciences, Huntingdon, UK