Effects of Clofibrate in the CB6F1-TgHras2 Mice.

Aoki, Toyohiko; Imai, Toshio; Ando, Tomomi; Dodo, Tetsushi; Kerns, William; Motooka, Satoru; Tsukidate, Kazuo

doi:10.1293/tox.15.111

Cited by 2 publications

(3 citation statements)

References 23 publications

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“…For example, phenobarbital and sulfamethoxazole produce neoplasia in rodents by rodent-speci c mechanisms and are negative in the Tg rasH2 model (15,18). Tg rasH2 mice and conventional rodents produce liver neoplasms in response to the peroxisome proliferating agents clo brate and diethyl-hexyl-phthalate (2,9,16). These chemicals are not considered human carcinogens.…”

Section: Responses Of Tg Rash2 Mice To Chemical Agentsmentioning

confidence: 99%

“…Analyzing combined data from both sexes with data blocked by sex should be considered as a means of increasing power, and the advantages and disadvantages of doing so are discussed in detail in the next paragraph. Based on the results of these power simulations, the authors recommend using 20 to 25 mice/sex/group for 2 Three treatment groups and a negative control group are analyzed. 3 The prevalence of a treatment-related neoplasm increases proportionall y to the dosage administered.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the results of these power simulations, the authors recommend using 20 to 25 mice/sex/group for a Assumptions for these sample power simulations include: 1 A trend test is performed . 2 Three treatment groups and a negative control group are analyzed. 3 The prevalence of a treatment-related neoplasm increases proportionall y to the dosage administered.…”

Section: Introductionmentioning

confidence: 99%

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The Tg rasH2 Mouse in Cancer Hazard Identification

Morton¹,

Alden²,

Roth³

et al. 2002

Toxicol Pathol

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The Tg rasH2 transgenic mouse has been developed as an alternative to the lifetime mouse bioassay to predict the carcinogeni c potential of chemicals. Unlike the p53 / mouse, the Tg rasH2 mouse is sensitive to both genotoxic and nongenotoxi c carcinogens . The Tg rasH2 mouse, of cially designated CB6F1-TgN (RasH2), contains multiple copies of the human c-Ha-ras oncogen e and promoter within its genome. These mice develop spontaneou s and chemically induced neoplasms earlier in life and in greater numbers than wild-type mice, re ecting their enhanced sensitivity to neoplasia. The most common spontaneous neoplasms in control Tg rasH2 mice 8 to 9 months of age are lung adenomas and carcinomas (7.4% incidence), splenic hemangioma s and hemangiosarcoma s (5.4%), forestomach squamous cell papillomas and carcinomas (2.4%), and skin neoplasms (1.2%). Simulations have demonstrated that 20 to 25 mice/sex/treatment group are required to provide the assay with adequate statistical power. Four of 6 known or suspected human carcinogens tested in Tg rasH2 mice were positive in this assay. For 19 nonmutageni c agents testing positive in conventiona l rodent bioassays, 7 chemicals were positive, 10 chemicals were negative, and 2 were equivocal. None of the 10 nonmutageni c rodent carcinogen s that were negative in the Tg rasH2 mouse model are considered to be human carcinogens . All nonmutageni c chemicals that were negative in the conventiona l rodent bioassays were also negative in the Tg rasH2 model. Results for 15 of 18 mutageni c chemicals tested in Tg rasH2 mice agreed with the results of conventiona l rodent bioassays, and 3 results were equivocal. The Tg rasH2 mouse model appears to predict known or suspected human carcinogen s as well as the traditional mouse bioassay, but with fewer positive results for nongenotoxi c compounds that are not considered human carcinogens . The Tg rasH2 mouse model is the most thoroughly tested in vivo alternative to the lifetime mouse bioassay for nongenotoxi c compounds administered by oral or parenteral routes. The U.S. FDA Carcinogenicit y Assessment Committee has determined that the Tg rasH2 model has been adequately evaluated for consideration for carcinogenicity testing of pharmaceutica l candidates and its use could contribute to the weight of evidence for carcinogenicity assessment. The FDA will consider proposals to replace lifetime mouse carcinogenicity studies with 6-month Tg rasH2 mouse studies to support pharmaceutical registration on a case-by-cas e basis.

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Section: Responses Of Tg Rash2 Mice To Chemical Agentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Tg rasH2 Mouse in Cancer Hazard Identification

Morton¹,

Alden²,

Roth³

et al. 2002

Toxicol Pathol

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Current Status of Carcinogenicity Assessment of Peroxisome Proliferator-Activated Receptor Agonists by the US FDA and a Mode-of-Action Approach to the Carcinogenic Potential

Aoki

2007

J Toxicol Pathol

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Abstract:Since it has been revealed that PPAR (Peroxisome Proliferator-Activated Receptor) agonists induce various types of tumors in various organs and tissues in rodents, the US FDA has been requesting performance of 2-year carcinogenicity studies prior to initiation of clinical studies longer than 6 months, and does not accept data from alternative carcinogenicity studies such as those in transgenic mouse models, which are recommended in the ICH S1B guideline. In general, although PPAR agonists do not possess genotoxic potential, the tissue distribution of PPAR does correspond to the target organs and tissues of tumor induction, and carcinogenic potential is closely correlated with potency of PPAR agonistic effect. It is thus not possible to rule out the possibility that the mode of action (MOA) of tumorigenesis by PPAR agonists is receptor-mediated. The ILSI-HESI PPAR Agonist Project was organized and is currently conducting collaborative research to elucidate the MOA of PPAR agonist-induced carcinogenicity (for urinary bladder tumor, hemangioma/hemangiosarcoma, and fibrosarcoma/liposarcoma) and to evaluate the human relevance of the results of rodent bioassays of PPAR agonists. In this paper, carcinogenicity data on PPAR agonists disclosed by the CDER of the US FDA and current activities of the ILSI-HESI PPAR Agonist Project are explained, and the possible usefulness of transgenic mouse models, especially rasH2 mice, for assessing carcinogenic potential and the MOA of PPAR agonists are addressed. (J Toxicol Pathol 2007; 20: 197-202)

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Effects of Clofibrate in the CB6F1-TgHras2 Mice.

Cited by 2 publications

References 23 publications

The Tg rasH2 Mouse in Cancer Hazard Identification

The Tg rasH2 Mouse in Cancer Hazard Identification

Current Status of Carcinogenicity Assessment of Peroxisome Proliferator-Activated Receptor Agonists by the US FDA and a Mode-of-Action Approach to the Carcinogenic Potential

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