El-Bayoumy Karam, Sinha Raghu
Institute for Cancer Prevention, American Health Foundation Cancer Center, 1 Dana Road, Valhalla, NY 10595, USA.
Mutat Res. 2004 Jul 13;551(1-2):181-97. doi: 10.1016/j.mrfmmm.2004.02.023.
Searching for optimal diets and for naturally occurring agents in routinely consumed foods that may inhibit cancer development, although challenging, constitutes a valuable and plausible approach to finding ways to control and prevent cancer. To date, the use of the micronutrient selenium in human clinical trials is limited but the outcome of these investigations indicates that selenium is one of the most promising agents. Data presented in this mini-review indicate that the dose and the form (structure) in which selenium is used are the most critical determinants of success in future clinical trials. The focus of this mini-review is on the mechanisms of mammary cancer chemoprevention by organoselenium compounds. Among the naturally occurring organoselenium compounds, Se-Methylselenocysteine is more efficacious than the most extensively studied forms, such as selenomethionine. However, we showed that synthetic organoselenium compounds can be tailored to achieve greater chemopreventive efficacy with minimal side effects by structural modifications; it is evident that synthetic agents are superior to the inorganic selenite, naturally occurring selenium compounds and their sulfur-containing analogs. We have demonstrated that 1,4-phenylenebis (methylene) selenocyanate (p-XSC) and its putative metabolite glutathione conjugate (p-XSeSG) are highly promising agents in the chemoprevention of mammary carcinogenesis in the 7,12-dimethylbenz[a]anthracene (DMBA)-rat mammary tumor model system. Both compounds inhibit the initiation phase of carcinogenesis by inhibiting DMBA-DNA adduct formation in the target organ in vivo. cDNA microarray analysis indicates that both selenium compounds alter genes in a manner that leads to inhibition of cell proliferation and induction of apoptosis; modulation of apoptosis and cell proliferation can account for chemoprevention during the post-initiation phase of mammary carcinogenesis. Using a rat mammary cancer cell line, we compared p-XSC and p-XSeSG as inhibitors of cell proliferation; depending on the selenium dose and time point selected, p-XSC was comparable to or better than p-XSeSG. Collectively, the results described here, suggest that the molecular targets modulated by organoselenium compounds are highly useful indicators of success in clinical cancer chemoprevention trials.
寻找最佳饮食以及日常食用食物中可能抑制癌症发展的天然成分，尽管具有挑战性，但却是寻找控制和预防癌症方法的一种有价值且合理的途径。迄今为止，微量营养素硒在人体临床试验中的应用有限，但这些研究结果表明，硒是最有前景的成分之一。本综述提供的数据表明，硒的使用剂量和形式（结构）是未来临床试验成功的最关键决定因素。本综述的重点是有机硒化合物预防乳腺癌的机制。在天然存在的有机硒化合物中，硒代甲基硒代半胱氨酸比研究最广泛的形式（如硒代蛋氨酸）更有效。然而，我们发现，通过结构修饰，合成有机硒化合物可以在副作用最小的情况下实现更高的化学预防效果；显然，合成剂优于无机亚硒酸盐、天然存在的硒化合物及其含硫类似物。我们已经证明，1,4 - 亚苯基双（亚甲基）硒氰酸盐（p - XSC）及其假定的代谢物谷胱甘肽共轭物（p - XSeSG）在7,12 - 二甲基苯并[a]蒽（DMBA）诱导的大鼠乳腺肿瘤模型系统中是预防乳腺癌发生的极有前景的成分。这两种化合物都通过抑制体内靶器官中DMBA - DNA加合物的形成来抑制致癌作用的起始阶段。cDNA微阵列分析表明，这两种硒化合物都以导致细胞增殖抑制和凋亡诱导的方式改变基因；凋亡和细胞增殖的调节可以解释乳腺癌发生起始后阶段的化学预防作用。使用大鼠乳腺癌细胞系，我们比较了p - XSC和p - XSeSG作为细胞增殖抑制剂的效果；根据所选的硒剂量和时间点，p - XSC与p - XSeSG相当或更好。总体而言，此处所述结果表明，有机硒化合物调节的分子靶点是临床癌症化学预防试验成功的非常有用的指标。
