Increasing attention is being paid to the possibility of applying cancer chemopreventive agents for individuals at high risk of neoplastic development. For this purpose by natural compounds have practical advantages with regard to availability, suitability for oral application, regulatory approval and mechanisms of action. Candidate substances such as phytochemicals present in foods and their derivatives have been identified by a combination of epidemiological and experimental studies. Plant constituents include vitamin derivatives, phenolic and flavonoid agents, organic sulfur compounds, isothiocyanates, curcumins, fatty acids and d-limonene. Examples of compounds from animals are unsaturated fatty acids and lactoferrin. Recent studies have indicated that mechanisms underlying chemopreventive potential may be combinations of anti-oxidant, anti-inflammatory, immune-enhancing, and anti-hormone effects, with modification of drug-metabolizing enzymes, influence on the cell cycle and cell differentiation, induction of apoptosis and suppression of proliferation and angiogenesis playing roles in the initiation and secondary modification stages of neoplastic development. Accordingly, natural agents are advantageous for application to humans because of their combined mild mechanism. Here we review naturally occurring compounds useful for cancer chemprevention based on in vivo studies with reference to their structures, sources and mechanisms of action.

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Transgenic animals carrying human c-Ha-ras proto-oncogene, vHa-ras transgenic mice, pim-1 transgenic mice and several knockout mice deficient of tumor suppressor genes, such as p53, have been shown to exhibit increased carcinogen susceptibility. As a result, studies into practical application and medium-term screening of environmental carcinogens are under way. Given the advantages of rat models characterized by larger organ size, abundant information regarding preneoplasias and virus-free constitution, we have concentrated on the generation of transgenic rats bearing copies of the human c-Ha-ras proto-oncogene and shown the Hras128 strain to be extremely sensitive to the induction of mammary carcinomas, and to a lesser extent, lesions in the urinary bladder, esophagus and skin. In most, if not all, the mammary cancers mutations of the transgene but not the endogenous H-ras gene are present, appearing to occur early in the process of tumorigenesis, which involves proliferation of cells in TEB and intraductal hyperplasia before carcinomas arise. Preliminary findings suggest that this is independent of endogenous ovarian hormones, although inhibited by soy isoflavones and promoted by atrazine and nonylphenols. Although further studies of the mechanisms are clearly necessary, the model appears to have great potential for screening purposes, not only for modifiers active in the breast, but also other organs where tumors characterized by ras gene mutations develop. (Cancer Sci 2005; 96: 309-316)

With the aim of developing a medium-term assay for screening of environmental carcinogens, we exposed mammary carcinogen sensitive human c-Ha-ras proto-oncogene transgenic (Hras128) rats to various carcinogens, including compounds that do not normally induce mammary tumors. Seven-week-old Hras128 rats and wild-type littermates received administrations of 3-methylcholanthrene (3-MC), benzo[a]pyrene (B[a]P), anthracene, pyrene, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), dimethylarsinic acid (DMA), diethylnitrosamine (DEN) or azoxymethane (AOM) and were sacrificed at week 12 (females) (at week 10 for the 3-MC group) or week 20 (males). Female Hras128 rats receiving NNK, DEN, or DMA showed a significant increase in mammary tumor incidence and/or multiplicity compared to the respective values with olive oil or deionized distilled water (DDW) vehicles. In male Hras128 rats, a significant increase in mammary tumors was also observed in groups administered 3-MC, B[a]P, anthracene, IQ, and NNK. Mutations of transgenes were observed in codons 12 and/or 61 in the induced tumors by PCR-RFLP except in the DEN group in female and in the MeIQx group in male Hras128 rats. Thus various carcinogens, not necessarily limited to those normally targeting the breast, were found to induce mammary carcinomas in Hras128 rats, especially in females, pointing to potential use for medium-term screening.