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Oncogenicity Evaluations of Chemopreventive Soy Components in p53^(+/–) (p53 knockout) Mice

Life Sciences Group, IIT Research Institute, Chicago, Illinois, USA

Robert L. Morrissey
Lawrence Arp

Pathology Associates, Chicago, Illinois, USA

Izet Kapetanovic
James A. Crowell

National Cancer Institute, Bethesda, Maryland, USA

David L. McCormick

Life Sciences Group, IIT Research Institute, Chicago, Illinois, USA

Correspondence: Address correspondence to David L. McCormick, PhD, IIT Research Institute, 10 West 35th Street, Chicago, Illinois 60616, USA. E-mail:dmccormick{at}iitri.org

Epidemiologic data suggest that soy consumption may protect against cancer induction in several tissues in humans. Although the soy components responsible for this activity remain unidentified, isoflavones (e.g., genistein) and protease inhibitors (e.g., Bowman-Birk inhibitor complex [BBIC]) demonstrate chemopreventive activity in several animal cancer models. As part of their preclinical development for cancer prevention, PTI G-2535 (a soy isoflavone mixture containing 45% genistein, 23% daidzein, and 4% glycitein) and BBIC were evaluated for oncogenicity in p53^(+/–) mice. In separate studies, groups of 25 p53^(+/–) mice/sex received daily gavage exposure to PTI G-2535 (0, 250, 1000, or 2500 mg/kg/day) or BBIC (0, 500, 1000, or 2000 mg/kg/day) for 6 months. The high doses of both PTI G-2535 and BBIC were limited by viscosity. p-Cresidine (400 mg/kg/day) served as a positive-control article in both studies. PTI G-2535 induced no gross toxicity in any animal, but did induce a dose-related suppression of body weight gain in male mice. Modest hematologic alterations and increased liver and spleen weights were seen in both sexes exposed to the isoflavone mixture. BBIC had no significant effect on body weight, food consumption, clinical pathology, or organ weights in either sex. Histopathologic evaluations demonstrated no increases in the incidence of either benign or malignant tumors in any group of p53^(+/–) mice exposed to PTI G-2535 or to BBIC. By contrast, the positive-control article, p-cresidine, induced urinary bladder cancers in both studies. Neither PTI G-2535 nor BBIC demonstrates any evidence of oncogenicity in the p53^(+/–) mouse model.

Key Words: Bowman-Birk Inhibitor • Cancer Chemopreventive Agent • Inhibitor • Isoflavone • Protease Oncogenicity Evaluation • Soy

International Journal of Toxicology, Vol. 25, No. 3, 219-228 (2006)
DOI: 10.1080/10915810600683366


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