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

Debie J. Hoivik

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Jane S. Allen

Jane Allen Consulting, Inc., Raleigh, North Carolina, USA

Henry G. Wall

Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA

James B. Nold
Richard T. Miller
Michael J. Santostefano

GlaxoSmithKline, Safety Assessment, Research Triangle Park, North Carolina, USA

Correspondence: Address correspondence to Debie J. Hoivik, GlaxoSmithKline, Safety Assessment, 5 Moore Drive, Research Triangle Park, NC 27709, USA. E-mail:debie.j.hoivik{at}gsk.com

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.

Key Words: Carcinogenicity • MNU • Neoplasms • N-methyl-N-nitrosourea • p53+/– Mice • Proliferative

International Journal of Toxicology, Vol. 24, No. 5, 349-356 (2005)
DOI: 10.1080/10915810500210385
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