Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

Torrey, Carla E.; Wall, Henry G.; Campbell, James A.; Kwanyuen, Puntipa; Hoivik, Debie J.; Miller, Richard T.; Allen, Jane S.; Jayo, Manuel J.; Selinger, Krzysztof; Santostefano, Michael J.

doi:10.1080/10915810500208199

Cited by 9 publications

(19 citation statements)

References 27 publications

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“…There may also be strain-specific differences in the mechanism of PPAR-induced carcinogenesis that may have led to a nonprototypical liver response. Recent data from our laboratory indicates that clofibrate is hepatocarcinogenic in rasH2 mice after 6 months of exposure (Nesfield et al 2005a) and produced papillomas in Tg.AC mice after dermal application (Torrey et al 2005a), but is noncarcinogenic in neonatal mice up to 1-year after treatment on litter days 9 and 16 (Nesfield et al 2005b) or in Tg.AC after 6 months of oral exposure (Torrey et al 2005b).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

et al. 2005

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This study was conducted as part of International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to p53+/- heterozygous mice for a minimum of 26 weeks. p-Cresidine, a urinary bladder carcinogen, was given orally at 400 mg/kg/day as a positive control. Initial clofibrate doses were 50, 250, and 400 mg/kg/day for males and 50, 200, and 500 mg/kg/day for females. Due to unexpected mortality during the first week of dosing, clofibrate doses were lowered to 25, 75, and 100 mg/kg/day for males and 25, 75, and 125 mg/kg/day for females. Clinical signs and mortality were greater in p53+/- than wild-type (WT) mice. With the exception of liver weights, no marked differences in any other parameters either between the sexes or between WT and p53+/- mice were noted. Moderate increases in liver weights noted in WT males given 100 mg/kg/day clofibrate were not associated with any microscopic changes. No neoplastic response was observed in p53+/- mice after 6 months of exposure to clofibrate at doses up to 100 mg/kg/day for males and 125 mg/kg/day for females. Transitional-cell hyperplasia and carcinoma of the urinary bladder were noted in both sexes given p-cresidine, demonstrating that the p53+/- mouse responded to a known mouse carcinogen as expected. Clofibrate produced non-neoplastic findings in the adrenals, pancreas, and prostate, whereas p-cresidine affected the kidney, liver, pancreas, and spleen.

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Section: Resultsmentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

et al. 2005

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“…Interestingly, several PPAR␣ agonists have been shown to induce ras (12,20). In addition, transgenic mice overexpressing ras or carrying a mutant ras demonstrate a decrease in tumor latency following chronic PPAR␣ agonist treatment (40,51,52). Currently, the relative contributions of ras and c-myc in Wy-14,643-induced cellular proliferation are not known; however, it is likely that both play an integral role in hepatocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation

Shah

Morimura

Yang

et al. 2007

Molecular and Cellular Biology

248

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“…Recent data from our laboratory indicate that clofibrate produced papillomas in Tg.AC mice after dermal application (Torrey et al 2005b) but is noncarcinogenic in p53 +/– mice after 6 months of exposure (Torrey et al 2005a) or in neonatal mice up to 1 year after treatment on litter days 9 and 16 (Nesfield et al 2005) or in Tg.AC after 6 months of oral exposure (Torrey et al 2005c). These data suggest that clofibrate was tumorgenic in most animal models that detect nongenotoxic carcinogens.…”

Section: Resultsmentioning

confidence: 99%

“…For example, the PPAR α agonists fenofibrate and clofibrate induce liver tumors in mice at doses of ≥60 mg/kg/day and ≥200 mg/kg/day, respectively (NDA 1993). Recent data from our laboratory indicate that clofibrate is produced papillomas in Tg.AC mice after dermal application (Torrey et al 2005b) but is noncarcinogenic in p53 + / – mice after 6 months of exposure (Torrey et al 2005a) or in neonatal mice up to 1 year after treatment on litter days 9 and 16 (Nesfield et al 2005) or in Tg.AC after 6 months of oral exposure (Torrey et al 2005c). However, humans are resistant to peroxisomal proliferation and presumably the development of hepatocarcinomas after exposure to PPAR α igands (Klaunig et al 2003).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse

et al. 2005

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The purpose of the study was to support of the International Life Sciences Institute (ILSI) alternative carcinogenicity models initiative to evaluate the carcinogenic potential of the nongenotoxic carcinogen, clofibrate, a peroxisome proliferator-activated receptor (PPAR) alpha agonist, following oral administration to rasH2 mice. Peroxisome proliferators are one of the most widely studied of the nongenotoxic carcinogens and have diverse industrial and therapeutic uses (Gonzalez et al. J. Nat. Cancer Inst. 90: 1702-1709, 1998); however, the nongenotoxic mechanism of carcinogenicity is currently unknown. Male mice were administered doses of clofibrate at 50, 100, or 200 mg/kg/day and female mice were administered doses of 50, 150, or 250 mg/kg/day by oral gavage at 10 ml/kg for 27 weeks. In addition, rasH2 male and female mice were treated with N-nitroso-N-methylurea (NMU). Nontransgenic male and female mice were treated with 200 and 250 mg/kg/day, respectively, of clofibrate. The NMU-treated mice were given a single intraperitoneal dose of 75 mg/kg, which was followed by a 90-day observation period; all others were sacrificed after 6 months of daily dosing. Hepatocellular neoplasms were observed in clofibrate-treated rasH2 male mice after 6 months of treatment but not in nontransgenic males or females. Clofibrate treatment (250 mg/kg/day) of female rasH2 mice was associated with a slight increase in the incidence of various neoplasms (harderian gland, lungs, skin, spleen, tail, thymus, and uterus) compared with untreated transgenic mice and with similarly treated nontransgenic mice. Non-neoplastic changes were found in the liver of transgenic and nontransgenic mice of both sexes and in the kidneys of male mice. NMU produced findings are consistent with previous studies. The data suggest that the rasH2 mice are a good model for testing epigenetic carcinogens in a shorter timeframe than conventional mouse carcinogenicity bioassays.

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Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

Cited by 9 publications

References 27 publications

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation

Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse

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Evaluation of the Carcinogenic Potential of Clofibrate in the FVB/Tg.AC Mouse After Dermal Application—Part II

Cited by 9 publications

References 27 publications

Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the p53+/− Mouse

Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation

Evaluation of the Carcinogenic Potential of Clofibrate in the rasH2 Mouse

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Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse

Evaluation of the Carcinogenic Potential of Clofibrate in the p53⁺^/⁻ Mouse