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Genotoxicity and Carcinogenicity Studies of Soy IsoflavonesOffice of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
Office of Preventive Oncology, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA
Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
SRI International, Menlo Park, California, USA
SRI International, Menlo Park, California, USA
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, 20892, USA
The potential cancer preventive efficacy of soy isoflavones is being investigated in preclinical and phase 1 clinical studies sponsored by the U.S. National Cancer Institute. Although 90-day oral toxicity studies with PTI G-2535 (an investigational soy isoflavone drug product) in rats and dogs, as well as teratology studies, indicated no signs of toxicity, there remains a mechanistic concern associated with the ability of isoflavones (i.e., genistein) to inhibit topoisomerase, possibly leading to DNA strand breaks. The present report describes results from two in vitro genotoxicity studies, one in vivo genotoxicity study, and a single carcinogenicity study conducted in p53 knockout mice. Bacterial mutagenesis experiments using six tester strains without metabolic activation revealed no evidence that PTI G-2535 was mutagenic. In similar experiments with exogenous metabolic activation there were statistically significant increases in revertants, but less than twofold, in a single (Salmonella typhimurium TA100) tester strain. Mouse lymphoma cell mutagenesis experiments conducted with and without metabolic activation revealed statistically significant increases in mutation frequency at PTI G-2535 concentrations
Key Words: Carcinogenicity • Chemoprevention • Genistein • Genotoxicity • Soy Isoflavones
International Journal of Toxicology, Vol. 21, No. 4,
277-285 (2002) This article has been cited by other articles:
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0.8 and 12 µg/ml, respectively; such increases were dose related and increases in the frequency of both small and large colonies were observed. A statistically significant increase in the frequency of micronucleated polychromatic erythrocytes was also seen 24 hours after treatment in male, but not female, mice who received 500 and 1000 mg/kg body weight PTI G-2535; however, such increases were small, were not dose related, and were not observed 48 hours after treatment. In contrast, dietary genistein had no effect on survival, weight gain, or the incidence or types of tumors that developed in cancer-prone rodents lacking the p53 tumor suppressor gene, p53 knockout mice. The apparent risk/benefit of isoflavone ingestion may ultimately depend on the dose and developmental timing of exposure. 
