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.

Bovine lactoferrin, a multifunctional glycoprotein, has been shown to strongly inhibit development of azoxymethane (AOM)-induced rat colon tumors. Little, however, is known about the inhibitory mechanisms. We have demonstrated recently that lactoferrin enhances the expression of a member of the tumor necrosis factor receptor family, Fas, in the colon mucosa during both early and late stages of carcinogenesis. Thus, Fas could be involved in bovine lactoferrin-mediated inhibition of tumor development. To investigate this possibility, we studied the influence of bovine lactoferrin on Fas-mediated apoptosis with regard to expression of Fas, activation of caspase-8 and caspase-3, and DNA fragmentation in the colon mucosa of AOM-treated rats. Western blot analysis demonstrated a >2.5-fold increase in Fas protein expression, as well as elevation of the active forms of both caspase-8 and caspase-3. Immunohistochemical analysis revealed Fas-positive cells and apoptotic cells preferentially within the proximal colon region, clearly at the site of bovine lactoferrin-mediated tumor inhibition. These results suggest that apoptosis caused by elevated expression of Fas is involved in chemoprevention by lactoferrin of colon carcinogenesis.

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The acridinium ester 4-(2-succinimidyloxycarbonylethyl)phenyl-10-methylacridinium 9-carboxylate trifluoromethane sulfonate (AE), which reacts rapidly with alkaline hydrogen peroxide to produce light, has been used as a detection label in a number of assay procedures, including nucleic acid probe-based systems [Nelson et al. (1995) in Nonisotopic Probing, Blotting and Sequencing (Kricka, L. J., Ed.) pp 391-428, Academic Press, Inc., San Diego, CA]. We have synthesized a number of derivatives of this AE and characterized their chemiluminescent properties. These derivatives display significant differences in the kinetics of the chemiluminescence reaction as well as optimal pH for light production. These differences allow two or more derivatives to be simultaneously detected and quantitated in a single reaction vessel. Several of these derivatives have been covalently linked to nucleic acid probe molecules and have been further characterized in regard to chemiluminescence properties as well as hydrolysis of the ester bond in both single- and double-stranded conformations. On the basis of these properties, homogeneous assay formats utilizing DNA probes labeled with various AE derivatives were developed. Simultaneous detection and quantitation of Chlamydia trachomatis and Neisseria gonorrhoeae, the gag and pol regions of HIV, and wild-type and mutant HIV sequences was achieved with high sensitivity and discrimination.