Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice.

Adachi, Tamiko; Kuwamura, Yuki; Fujiwara, Toshihisa; Tanimoto, Noriaki; Nishimura, Toshiaki; Koguchi, Atsushi; Kobayashi, Kinji; Sasaki, Yoshifumi; Yamaguchi, Chisato; Honda, Tatsuya; Kawashima, K; Yuasa, Hirofumi; Yamamura, Takaaki; Inui, Toshiya

doi:10.2131/jts.27.147

Cited by 5 publications

(2 citation statements)

References 8 publications

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“…The historical incidence of background tumors in p53 + / – knockout mice is relatively low, the highest being subcutaneous sarcomas (1% males; 3.37% females), lymphomas (1.7% males; 2.9% females), and osteosarcomas (0.5% males; 0.7% females) (Storer et al 2001). In addition, tumors in multiple tissues, including the lung, thymus, forestomach, skin, bone marrow, and spleen, were noted 26 weeks after treatment of rasH2 mice with a single dose of MNU at 75 mg/kg (Adachi et al 2002).…”

Section: Resultsmentioning

confidence: 99%

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Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53⁺^/– Mouse

et al. 2005

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Studies conducted under the auspices of International Life Sciences Institute (ILSI) have suggested that an alternative mouse carcinogenicity study may be substituted for the traditional 2-year mouse bioassay typically conducted to support the development of drug candidates. The purpose of this study was to characterize the carcinogenic potential of N-methyl-N-nitrosourea (MNU), a DNA alkylating agent, in p53+/- knockout mice to determine its suitability as a positive control agent in an alternative carcinogenicity model. p53+/- knockout mice were administered a single oral dose of 90 mg/kg and maintained for up to 13 weeks prior to evaluation of neoplasms. Treatment was generally well tolerated; however, 4 of 30 mice died between the days of 75 and 92 due to neoplasms. MNU-related macroscopic observations included enlargement of the thymus, spleen, mandibular and mesenteric lymph nodes; and pale liver, heart, kidney, and bone marrow, which correlated with the diagnosis of lymphoma of the hematopoietic system, noted in the thymus of all affected animals and in the spleen, liver, lungs, and kidneys of some animals. Other treatment-related single neoplasms included a squamous-cell carcinoma in the nonglandular stomach and leiomyosarcoma in the glandular stomach. Non-neoplastic proliferative lesions included acanthosis and hyperkeratosis in the nonglandular stomach, focal papillary hyperplasia of the nonglandular stomach, glandular hyperplasia of the stomach, and adenomatous hyperplasia of the duodenum or ileum. The increased incidence of neoplastic and proliferative changes in MNU-treated mice suggests MNU could serve as a positive control in alternative carcinogenicity studies conducted in p53+/- knockout mice.

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Section: Resultsmentioning

confidence: 99%

“…In addition, tumors in multiple tissues, including the lung, thymus, forestomach, skin, bone marrow, and spleen, were noted 26 weeks after treatment of rasH2 mice with a single dose of MNU at 75 mg/kg (Adachi et al 2002).…”

Section: Macroscopic Pathology and Proliferative Lesionsmentioning

confidence: 99%

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53⁺^/– Mouse

et al. 2005

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Preclinical Safety Testing and Assessment of Veterinary Pharmaceuticals and Pharmacovigilance

Woodward¹

2009

Veterinary Pharmacovigilance

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Use of a standardized JaCVAM in vivo rat comet assay protocol to assess the genotoxicity of three coded test compounds; ampicillin trihydrate, 1,2-dimethylhydrazine dihydrochloride, and N-nitrosodimethylamine

McNamee

Bellier

2015

Mutation Research/Genetic Toxicology and Environmental Mutagene

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As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), our laboratory examined ampicillin trihydrate (AMP), 1,2-dimethylhydrazine dihydrochloride (DMH), and N-nitrosodimethylamine (NDA) using a standard comet assay validation protocol (v14.2) developed by the JaCVAM validation management team (VMT). Coded samples were received by our laboratory along with basic MSDS information. Solubility analysis and range-finding experiments of the coded test compounds were conducted for dose selection. Animal dosing schedules, the comet assay processing and analysis, and statistical analysis were conducted in accordance with the standard protocol. Based upon our blinded evaluation, AMP was not found to exhibit evidence of genotoxicity in either the rat liver or stomach. However, both NDA and DMH were observed to cause a significant increase in % tail DNA in the rat liver at all dose levels tested. While acute hepatoxicity was observed for these compounds in the high dose group, in the investigators opinion there were a sufficient number of consistently damaged/measurable cells at the medium and low dose groups to judge these compounds as genotoxic. There was no evidence of genotoxicity from either NDA or DMH in the rat stomach. In conclusion, our laboratory observed increased DNA damage from two blinded test compounds in rat liver (later identified as genotoxic carcinogens), while no evidence of genotoxicity was observed for the third blinded test compound (later identified as a non-genotoxic, non-carcinogen). This data supports the use of a standardized protocol of the in vivo comet assay as a cost-effective alternative genotoxicity assay for regulatory testing purposes.

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Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice.

Cited by 5 publications

References 8 publications

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53⁺^/– Mouse

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53⁺^/– Mouse

Preclinical Safety Testing and Assessment of Veterinary Pharmaceuticals and Pharmacovigilance

Use of a standardized JaCVAM in vivo rat comet assay protocol to assess the genotoxicity of three coded test compounds; ampicillin trihydrate, 1,2-dimethylhydrazine dihydrochloride, and N-nitrosodimethylamine

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Twenty-six week carcinogenicity study of ampicillin in CB6F1-TgrasH2 mice.

Cited by 5 publications

References 8 publications

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53+/– Mouse

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53+/– Mouse

Preclinical Safety Testing and Assessment of Veterinary Pharmaceuticals and Pharmacovigilance

Use of a standardized JaCVAM in vivo rat comet assay protocol to assess the genotoxicity of three coded test compounds; ampicillin trihydrate, 1,2-dimethylhydrazine dihydrochloride, and N-nitrosodimethylamine

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Product

Resources

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Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53⁺^/– Mouse

Studies Evaluating the Utility of N-Methyl-N-Nitrosourea as a Positive Control in Carcinogenicity Studies in the p53⁺^/– Mouse