Lack of Carcinogenicity of Reserpine in Transgenic Mice Carrying a Human Prototype c-Ha-ras Gene (RasH2 Mice)

Abstract

The present study was conducted as part of an international collaborative project organized by the International Life Sciences Institute Health and Environmental Sciences Institute (ILSI-HESI project). Transgenic CB6F1 mice carrying copies of human prototype c-Ha-ras gene, CB6F1-Tg- rasH2 (rasH2) mice, were utilized as an alternative test system to a standard 2-year bioassay for carcinogenicity assessment. The antihypertensive drug reserpine, a non-genotoxic rodent carcinogen (putative non-human carcinogen), was used as a test compound for validation of these transgenic mice. Reserpine was administered to rasH2 mice at dietary concentrations of 0, 2.5, 5 and 10 ppm and to non-transgenic littermates (non-Tg) at dietary concentrations of 0 and 10 ppm for 26 consecutive weeks. The rasH2 and non-Tg mice receiving basal diet alone in the same way acted as a corresponding control. A single intraperitoneal injection of N-methyl- N-nitrosourea (MNU) to rasH2 mice served as a positive control. All surviving animals were sacrificed 26 weeks later and subjected to histopathological examination. Alveolar/bronchiolar adenoma and carcinoma of the lung, hemangiomas and hemangiosarcomas of the spleen, and papilloma of the forestomach were sporadically detected in rasH2 mice fed either the reserpine-containing diet or basal diet. No specific hyperplastic or neoplastic lesions due to reserpine were detected. In MNU-treated mice, however, thymic and/or systemic malignant lymphomas and squamous cell papilloma and/or carcinoma in the forestomach were commonly detected in both males and females with low survival rates suggesting the sensitivity of assay conditions. In conclusion, no carcinogenicity of reserpine was identified in rasH2 mice under the present experimental conditions.