A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model

In cancer chemoprevention studies, the identification of better antitumor-p romoting agents is highly desired because they may have a wider applicabili ty against the development of clinical cancers. Both epidemiological and an imal studies have suggested that microchemicals present in the diet and sev eral herbs and plants,with diversified pharmacological properties are usefu l agents for the prevention of a wide variety of human cancers. Silymarin, a flavonoid isolated from milk thistle, is used clinically in Europe and As ia as an antihepatotoxic agent, largely due to its strong antioxidant activ ity. Because most antioxidants afford protection against tumor promotion, i n this study, we assessed the protective effect of silymarin on tumor promo tion in the SENCAR mouse skin tumorigenesis model. Application of silymarin prior to each 12-O-tetradecanoylphorbol 13-acetate (TPA) application resul ted in a highly significant protection against tumor promotion in 7,12-dime thylbenz(a)anthracene-initiate mouse skin. The protective effect of silymar in was evident in terms of reduction in tumor incidence (25, 40, and 75% pr otection) P < 0.001, X-2 test), tumor multiplicity (76, 84, and 97% protect ion, P < 0.001, Wilcoxon rank sum test), and tumor volume (76, 94, and 96% protection, P < 0.001, Student's t test) at the doses of 3, 6, and 12 mg pe r application, respectively. To dissect out the stage specificity of silyma rin against tumor promotion, we next assessed its effect against both stage I and stage II of tumor promotion. Application of silymarin prior to that of TPA in stage I or mezerein in stage II tumor promotion in dimethylbenz(a )anthracene-initiated SENCAR mouse skin resulted in an exceptionally high p rotective effect during stage I tumor promotion, showing 74% protection aga inst tumor incidence (P < 0.001, X-2 test), 92% protection against tumor mu ltiplicity (P < 0.001, Wilcoxon rank sum test), and 96% protection against tumor volume (P < 0.001, Student's t test). With regard to stage II tumor p romotion, silymarin show ed 26, 63, and 54% protection in tumor incidence, multiplicity, and volume, respectively. Similar effect of silymarin to that in anti-stage I studies, were also observed when applied during both stage I and stage IT protocols. In other studies, silymarin significantly inhibi ted: ia) TPA-induced skin edema, epidermal hyperplasia, and proliferating c ell nuclear antigen-positive cells; (b) DNA synthesis; and (c) epidermal li pid peroxidation, the early markers of TPA-caused changes that are associat ed with tumor promotion. Taken together, these results suggest that silymar in possesses exceptionally high protective effects against tumor promotion, primarily targeted against stage I tumors, and that the mechanism of such effects mag involve inhibition of promoter-induced edema, hyperplasia, prol iferation index, and oxidant state.