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N-Methyl-N-Nitrosourea (MNU): A Positive Control Chemical for p53+/– Mouse Carcinogenicity Studies

¹ Pfizer, Groton, Connecticut, USA
² Pfizer, Kalamazoo, Missouri, USA

Correspondence: Address correspondence to: Daniel Morton, Pfizer, MS 8275–1345, Eastern Point Road, Groton, CT 06340 USA; e-mail:dan.g.morton{at}pfizer.com.

This study evaluated the effects of a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU) in citrate buffer (pH 4.5) at a dose of 75 mg/kg in thirty male and thirty female p53+/– mice followed by a six-month observation period. Fifteen control mice per sex received a single intraperitoneal injection of citrate buffer. Fifty-six of sixty mice treated with MNU died or were sacrificed before the end of the observation period. Twenty-four males and twenty-seven females treated with MNU developed malignant lymphoma of the thymus; of these, twenty-three males and twenty-seven females had corresponding enlargement or masses in the thymus at necropsy. Lymphoblasts in thymic lymphomas stained positively for mouse CD3 antigen, indicating a T-cell lineage. One control female mouse had malignant lymphoma of the spleen that did not involve the thymus. Nine males and five females treated with MNU had adenomas or adenocarcinomas of the small intestine, whereas no intestinal neoplasms were observed in control mice. These findings support the use of a single dose of MNU as a positive control chemical in six-month p53+/– mouse carcinogenicity studies and suggest that examination of the thymus alone is sufficient to evaluate the validity of the model system.

Key Words: intestinal adenoma/adenocarcinoma • carcinogenicity • lymphoma • N-methyl-N-nitrosourea • p53+/– mouse • thymus

Abbreviations: MNU, N-methyl-N-nitrosourea • p53+/– mouse, B6.129-Trp53^tmlBrdN5 heterozygous mouse • U.S. FDA, United States Food and Drug Administration

This version was published on December 1, 2008

Toxicologic Pathology, Vol. 36, No. 7, 926-931 (2008)
DOI: 10.1177/0192623308324959


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