The Tg.AC (v-Ha-ras) transgenic mouse model provides a reporter phenotype of skin papillomas in response to either genotoxic or nongenotoxic carcinogens. In common with the conventional bioassay, the Tg.AC model responds to known human carcinogens and does not respond to noncarcinogens. It also does not respond to most chemicals that are positive in conventional bioassays principally at sites of high spontaneous tumor incidence. The mechanism of response of the Tg.AC model is related to the structure and genomic position of the transgene and the induction of transgene expression through specific mediated interactions between the chemicals and target cells in the skin.
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Ras transgene expression in TG-AC mice treated with benzo[a]pyrene.
Biol Pharm Bull
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Division of Toxicology, College of Pharmacy, SungKyunKwan University, Chunchun-dong, Suwon, Kyonggi-do, South Korea.
Transgene expression and skin tumorigenicity were investigated in transgenic TG-AC mice carrying the v-Ha-ras after treatment with benzo[a]pyrene (BP). Animals treated with 40 microg BP (x2/week/mouse) showed 100% tumor response after 25 weeks, as did 40% of the mice treated with 20 microg BP but 10 microg BP did not produce a tumor response. In the case of animals treated with 40 microg BP for 25 weeks, most of the tumors were proven to be carcinomas (80%, 4 out of 5 mice), and all tumors were shown to be positive in terms of transgene expression detected by in situ hybridization.
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Cancer Sci
February 2003
Otsuka Pharmaceutical Factory Inc., Muya-cho, Naruto, Tokushima 772-8601.
Article Synopsis
- TPA application to transgenic mice resulted in high tumor incidence, with rates increasing steadily over 9 weeks.
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Inducible nitric oxide synthase mRNA is upregulated in skin tumors of v-ha-ras transgenic TG-AC mice treated with 12-o-tetradecanoylphorbol-13-acetate.
Biol Pharm Bull
July 2000
Division of' Toxicology, College of Pharmacy, SungKyunKwan University, Suwon, Kyunggi-do, South Korea.
The correlation between the steady-state level of inducible nitric oxide synthase (iNOS) mRNA and skin tumors induced following treatment with 12-o-tetradecanoylphorbol-13-acetate (TPA) was investigated in transgenic TG-AC mice, which carry the v-Ha-ras oncogene fused to the promoter of the mouse embryonic alpha-like, zeta-globin gene. In animals treated with TPA (2.5 microg x 2/week, for 2 weeks), the increase of iNOS mRNA was locally confined only to the regions of papillomas, but not to the skin tissues surrounding the papillomas.
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Biochem Biophys Res Commun
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Ohio State University College of Medicine and Public Health, Department of Medical Microbiology and Immunology, Columbus 43210, USA.
One of the most frequently detected changes in human solid tumors is the mutation of the ras oncogene, which has been associated with production of angiogenic growth factors such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Using the v-Ha-ras Tg-AC transgenic mice and the background FVB/N strain of inbred mice, the pattern of expression of specific VEGF/VPF transcripts was characterized in major organs and in skin, papillomas, and carcinomas during multi-stage skin carcinogenesis. Three VEGF/VPF transcripts were found to be constitutively expressed in skin as well as the major organs in both mouse strains, which corresponded in size and sequence to previously reported murine VEGF120 with a bp size of 331, VEGF164 with a bp size of 333, and VEGF188 with a bp size of 407.
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Mol Carcinog
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National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
TG.AC mice (which carry a v-Ha-ras transgene) rapidly develop papillomas in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). Approximately 30% of the papillomas are associated with subsequent development of malignancies.
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