Lahiri-Chatterjee M, Katiyar S K, Mohan R R, Agarwal R
Department of Dermatology, Skin Diseases Research Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Cancer Res. 1999 Feb 1;59(3):622-32.
In cancer chemoprevention studies, the identification of better antitumor-promoting agents is highly desired because they may have a wider applicability against the development of clinical cancers. Both epidemiological and animal studies have suggested that microchemicals present in the diet and several herbs and plants with diversified pharmacological properties are useful agents for the prevention of a wide variety of human cancers. Silymarin, a flavonoid isolated from milk thistle, is used clinically in Europe and Asia as an antihepatotoxic agent, largely due to its strong antioxidant activity. Because most antioxidants afford protection against tumor promotion, in this study, we assessed the protective effect of silymarin on tumor promotion in the SENCAR mouse skin tumorigenesis model. Application of silymarin prior to each 12-O-tetradecanoylphorbol 13-acetate (TPA) application resulted in a highly significant protection against tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated mouse skin. The protective effect of silymarin was evident in terms of reduction in tumor incidence (25, 40, and 75% protection, P < 0.001, X2 test), tumor multiplicity (76, 84, and 97% protection, 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 per application, respectively. To dissect out the stage specificity of silymarin 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 protective effect during stage I tumor promotion, showing 74% protection against tumor incidence (P < 0.001, X2 test), 92% protection against tumor multiplicity (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 promotion, silymarin showed 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 II protocols. In other studies, silymarin significantly inhibited: (a) TPA-induced skin edema, epidermal hyperplasia, and proliferating cell nuclear antigen-positive cells; (b) DNA synthesis; and (c) epidermal lipid peroxidation, the early markers of TPA-caused changes that are associated with tumor promotion. Taken together, these results suggest that silymarin possesses exceptionally high protective effects against tumor promotion, primarily targeted against stage I tumors, and that the mechanism of such effects may involve inhibition of promoter-induced edema, hyperplasia, proliferation index, and oxidant state.
在癌症化学预防研究中，人们迫切希望能鉴定出更好的抗肿瘤促进剂，因为它们可能对临床癌症的发生具有更广泛的适用性。流行病学和动物研究均表明，饮食中存在的微量化学物质以及几种具有多种药理特性的草药和植物是预防多种人类癌症的有用药物。水飞蓟素是从水飞蓟中分离出的一种黄酮类化合物，在欧洲和亚洲临床上用作抗肝毒素药物，主要是因其具有强大的抗氧化活性。由于大多数抗氧化剂都能预防肿瘤促进作用，因此在本研究中，我们评估了水飞蓟素在SENCAR小鼠皮肤肿瘤发生模型中对肿瘤促进的保护作用。在每次涂抹12-O-十四烷酰佛波醇-13-乙酸酯（TPA）之前涂抹水飞蓟素，对7,12-二甲基苯并(a)蒽引发的小鼠皮肤肿瘤促进具有高度显著的保护作用。水飞蓟素的保护作用在肿瘤发生率降低（保护率分别为25%、40%和75%，P<0.001，卡方检验）、肿瘤多发性降低（保护率分别为76%、84%和97%，P<0.001，Wilcoxon秩和检验）以及肿瘤体积减小（保护率分别为76%、94%和96%，P<0.001，Student t检验）方面很明显，每次涂抹的剂量分别为3、6和12毫克。为了剖析水飞蓟素对肿瘤促进的阶段特异性，我们接下来评估了其对肿瘤促进I期和II期的作用。在二甲基苯并(a)蒽引发的SENCAR小鼠皮肤肿瘤促进I期涂抹TPA之前或II期涂抹芫花素之前涂抹水飞蓟素，在肿瘤促进I期产生了极高的保护作用，对肿瘤发生率的保护率为74%（P<0.001，卡方检验），对肿瘤多发性的保护率为92%（P<0.001，Wilcoxon秩和检验），对肿瘤体积的保护率为96%（P<0.001，Student t检验）。关于肿瘤促进II期，水飞蓟素在肿瘤发生率、多发性和体积方面的保护率分别为26%、63%和54%。当在I期和II期方案中均应用时，也观察到了水飞蓟素与抗I期研究中类似的效果。在其他研究中，水飞蓟素显著抑制：(a)TPA诱导的皮肤水肿、表皮增生和增殖细胞核抗原阳性细胞；(b)DNA合成；以及(c)表皮脂质过氧化，这些是TPA引起的与肿瘤促进相关变化的早期标志物。综上所述，这些结果表明水飞蓟素对肿瘤促进具有极高的保护作用，主要针对I期肿瘤，并且这种作用机制可能涉及抑制促进剂诱导的水肿、增生、增殖指数和氧化状态。
