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

Gulezian, Donna; Jacobson‐Kram, David; McCullough, Carol; Olson, Harry M.; Recio, Leslie; Robinson, Denise E.; Storer, Richard D.; Tennant, Raymond W.; Ward, Jerrold M.; Neumann, David

doi:10.1177/019262330002800320

Cited by 68 publications

(57 citation statements)

References 105 publications

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“…Transgenic and null mutant ('knockout') animal models also offer an important opportunity to identify and study both carcinogens and chemopreventive agents [196,197]. The analysis of the available data on transgenic and mutant mice has shown that only few models represent examples of life span extension [195].…”

Section: Effect Of Genetic Modifications Of Aging On Carcinogenesismentioning

confidence: 99%

The relationship between aging and carcinogenesis: a critical appraisal

Anisimov

2003

Critical Reviews in Oncology/Hematology

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The incidence of cancer increases with age in humans and in laboratory animals alike. There are different patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer by several mechanisms: (1) tissue accumulation of cells in late stages of carcinogenesis; (2) alterations in homeostasis, in particular, alterations in immune and endocrine system and (3) telomere instability linking aging and increased cancer risk. Increased susceptibility to the effects of tumor promoters is found both in aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Available evidence supporting the relevance of replicative senescence of human cells and telomere biology to human cancer seems quite strong, however, the evidence linking cellular senescence to human aging is controversial and required additional stuidies. Data on the acceleration of aging by carcinogenic agents as well as on increased cancer risk in patients with

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Section: Effect Of Genetic Modifications Of Aging On Carcinogenesismentioning

confidence: 99%

The relationship between aging and carcinogenesis: a critical appraisal

Anisimov

2003

Critical Reviews in Oncology/Hematology

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“…The lines proposed bear altered forms of genes that are known to be mutated in certain human cancers. The Tg.AC line carries an activated form of the v-Ha-ras oncogene, the p53 heterozygote KO possesses an inactivated copy of the p53 tumor suppressor gene, the rasH2 transgenic mouse bears the human c-Ha-ras gene, and the XPA heterozygote KO mouse is deficient in nucleotide excision repair (69). The ras family of oncogenes is activated by point mutations, and such activation has been implicated in various human and animal cancers (70).…”

Section: Application Of Gem For Drug Development and Safety Testmentioning

confidence: 99%

Mouse phenogenomics, toolbox for functional annotation of human genome

Kim¹,

Shin²,

Seong³

2010

BMB Reports

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Mouse models are crucial for the functional annotation of human genome. Gene modification techniques including gene targeting and gene trap in mouse have provided powerful tools in the form of genetically engineered mice (GEM) for understanding the molecular pathogenesis of human diseases. Several international consortium and programs are under way to deliver mutations in every gene in mouse genome. The information from studying these GEM can be shared through international collaboration. However, there are many limitations in utility because not all human genes are knocked out in mouse and they are not yet phenotypically characterized by standardized ways which is required for sharing and evaluating data from GEM. The recent improvement in mouse genetics has now moved the bottleneck in mouse functional genomics from the production of GEM to the systematic mouse phenotype analysis of GEM. Enhanced, reproducible and comprehensive mouse phenotype analysis has thus emerged as a prerequisite for effectively engaging the phenotyping bottleneck. In this review, current information on systematic mouse phenotype analysis and an issue-oriented perspective will be provided. [BMB reports 2010; 43(2): 79-90]

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“…The p53 +/7 mice have a low incidence of spontaneous tumours up to 9 months but rates increased substantially thereafter. Thus, the p53 +/7 knockout mouse offers a phenotypically stable carcinogenicity model, developing tumours during the 6-month study period only in response to genotoxic agents (10). Although more sensitive and showing a shorter latent period for tumours, the single functional gene in the p53 +/7 mouse model allows some nucleotide excision repair of DNA damage relative to homozygous p53 7/7 knockout mice, but the reduced ability of p53 +/7 mice to repair DNA damage is an additional possible origin for the earlier and more frequent appearance of tumours in these mice, compared to wild-type mice (11).…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling of p53+/‐ Knockout and Wild‐type Mice Following Diethylstilbestrol Administration

et al. 2004

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SummaryStudies with clastogenic carcinogen diethylstilbestrol (DES) resulted in a broad of spectrum of toxic and carcinogenic effects in humans and rodents, but the cellular and molecular mechanism(s) by which it induces cancer is not clear. To identify putative genetic targets for p53 in vivo, we applied the cDNA macroarray gene expression profiles associated with apoptosis by comparing p53 +/7 knockout mice and wild-type mice on the kidney and uterus of female mice. p53 +/7 knockout mice and wild-type mice were treated with DES (500 mmole kg 71 ) or vehicle i.p once daily for 4 days. Total RNAs were obtained from kidney and uterus of both control and DES-treated. The signal intensities of individual gene spots on the membrane were quantified and normalized to the expression level of the GAPDH gene as an internal control. Our results demonstrated that 16 genes; bad, bax, bcl-2, bcl-w, bcl-x, caspase-3, caspase-7, caspase-8, c-myc, E124, GADD45, mdm2, NKkb1, p53, p21, Rb and trail were up-regulated and six genes; caspase-1, caspase-2, DR5, E2F1, FasL and iNOS did not changed in response to DES treatment in wild-type mice compared to p53 +/7 knockout mice. Most genes are involved in cell cycle regulation, signal transduction, apoptosis, or transcription. The greatest changes were seen in bad, bcl-x, mdm2, p53 and p21 gene expression in wild-type mice compared to p53 +/7 knockout mice. In comparing p53 and p21 gene expression in wild-type mice and p53 +/7 knockout mice, there was an 4.4-fold vs. 1.8-fold; 8-fold vs. 5.2-fold for kidney and16-fold vs. 5.5-fold; 2.1-fold vs. 8.3-fold for uterus samples increase in induction (respectively). RT-PCR and densitometric analysis was used to confirm the biggest changes of p21, p53 and bax genes. Using this approach, we have identified apoptosis associated genes regulated in response to DES and have revealed putative differences between the isogenic parent strain and p53 +/7 knockout mice, which will contribute to a better understanding of toxicity/carcinogenicity mechanisms in this model.

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

Cited by 68 publications

References 105 publications

The relationship between aging and carcinogenesis: a critical appraisal

The relationship between aging and carcinogenesis: a critical appraisal

Mouse phenogenomics, toolbox for functional annotation of human genome

Gene Expression Profiling of p53+/‐ Knockout and Wild‐type Mice Following Diethylstilbestrol Administration

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