Arch Toxicol (2008) 82:655–663 DOI 10.1007/s00204-007-0271-9 123 GENOTOXICITY AND CARCINOGENICITY Diphenyl diselenide supplementation delays the development of N-nitroso-N-methylurea-induced mammary tumors Nilda Berenice de Vargas Barbosa · Cristina Wayne Nogueira · Temenouga N. Guecheva · Maria de Lourdes Bellinaso · João Batista Teixeira Rocha Received: 4 October 2007 / Accepted: 28 November 2007 / Published online: 12 December 2007  Springer-Verlag 2007 Abstract The eVect of dietary diphenyl diselenide (1 ppm) on N-nitroso-N-methylurea (NMU)-induced mam- mary carcinogenesis was examined in female Wistar rats. Beginning at 5 weeks of age, the animals were fed with either control or diphenyl-diselenide-supplied diets until the end of the study (210 days). At 50 days of age, mam- mary tumor was induced by the administration of three doses of NMU (50 mg/kg body wt, intraperitoneally) once a week for 3 weeks. In experimental trials, latency to tumor onset was extended in rats fed with diet supplemented with diphenyl diselenide (P < 0.05). The incidence and frequency of tumors were signiWcantly small in animals supplemented with diphenyl diselenide. However, the multiplicity of tumors was not altered by dietary diphenyl diselenide. Diphenyl diselenide supplementation also restored super- oxide dismutase (SOD) activity and vitamin C levels altered in the NMU group (P < 0.05). Our results suggest that diphenyl diselenide can be considered a chemopreven- tive agent, even when supplemented at a relatively low concentration. Keywords Mammary tumors · Chemoprophylaxis · Selenium · N-nitroso-N-methylurea Introduction Breast cancer is the second most frequent cause of cancer- related deaths in women (Schairer et al. 2004); however, its etiology remains obscure and primary prevention strategies are yet not available. Moreover, advances in therapy are limited and, consequently, alternatives need to be devel- oped for breast cancer control. Thus, the search for syn- thetic or natural chemical agents that inhibit and/or delay the preneoplasic events has received an increasing attention in cancer therapy. Selenium intake at low concentrations is recognized as essential in animal and human nutrition (Navarro-Alarcón and Lopes-Martinez 2000). In the form of selenocysteine, selenium is a component of a number of antioxidant enzymes, e.g. glutathione peroxidase and thioredoxin reductase (Rotruck et al. 1973; Arner and Holmgren 2000). Conversely, high doses of selenium can be cytotoxic via its ability to catalyze the oxidation of thiols and to generate free radicals (Barbosa et al. 1998; Nogueira et al. 2004). Of particular importance, this element has received consider- able attention for its possible role as an eVective, naturally occurring, anticarcinogenic agent, when used in both physi- ological and/or supranutritional concentrations (Fleming et al. 2001; Spallholz 2001; Letavayová et al. 2006). Thus, the mechanism involved in the anticarcinogenic activity of selenium seems to be, at least in part, associated with its antioxidant and pro-oxidative eVects (Das et al. 2004; Spallholz et al. 2004; Valko et al. 2006). Human epidemiological studies have clearly indicated that low selenium status is invariably associated with N. B. de Vargas Barbosa (&) Centro de Ciências da Saúde, Universidade Federal de Santa Maria -UNIPAMPA, Rua Domingos de Almeida, 3525 - São Miguel, Uruguaiana 97500-009, RS, Brazil e-mail: nvbarbosa@yahoo.com.br C. W. Nogueira · J. B. T. Rocha Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria 97105-900, Brazil T. N. Guecheva · M. de Lourdes Bellinaso UNIJUI, Ijuí, Brazil