Zhang Yuesheng, Munday Rex
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Mol Cancer Ther. 2008 Nov;7(11):3470-9. doi: 10.1158/1535-7163.MCT-08-0625.
Dithiolethiones are a well-known class of cancer chemopreventive agents; the key mechanism of action of dithiolethiones involves activation of Nrf2 signaling and induction of phase II enzymes. In the past, attention has been focused mainly on 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz), which showed ability as a wide-spectrum inhibitor of chemical carcinogenesis in preclinical models. However, clinical trials of oltipraz have shown questionable efficacy, and at the high doses employed in such studies, significant side effects were observed. Dithiolethiones that are markedly more effective and potent than oltipraz in both induction of phase II enzymes and inhibition of chemical carcinogenesis in preclinical studies have been identified, and these compounds have shown pronounced organ specificity in vivo. Further investigation of these compounds may lead to development of effective and safe agents for cancer prevention in humans.
二硫代硫酮是一类著名的癌症化学预防剂；二硫代硫酮的关键作用机制涉及Nrf2信号通路的激活和II期酶的诱导。过去，注意力主要集中在4-甲基-5-吡嗪基-3H-1,2-二硫代-3-硫酮（奥替普拉）上，它在临床前模型中显示出作为化学致癌作用的广谱抑制剂的能力。然而，奥替普拉的临床试验显示出可疑的疗效，并且在这类研究中使用的高剂量下，观察到了显著的副作用。在临床前研究中，已鉴定出在诱导II期酶和抑制化学致癌作用方面比奥替普拉明显更有效和更具效力的二硫代硫酮，并且这些化合物在体内表现出明显的器官特异性。对这些化合物的进一步研究可能会导致开发出对人类癌症预防有效且安全的药物。
