Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review.
Dietary chemoprevention strategies for induction of phase II xenobiotic-metabolizing enzymes in lung carcinogenesis: A review.
复制标题
DOI：
10.1016/j.lungcan.2009.01.002
复制
发表时间：
2009-08
期刊：
影响因子：
5.3
通讯作者：
Spivack, Simon D.
中科院分区：
文献类型：
--
作者：
Tan, Xiang-Lin;Spivack, Simon D.
肺癌是美国男性和女性癌症死亡的主要原因，也是一个日益严重的全球性问题。根据最近的大型流行病学研究，预防肺癌与较高的水果和蔬菜摄入量有关。肺癌化学预防的一项策略侧重于使用药物通过上调解毒 II 相酶来调节烟草、环境和内源性致癌物的代谢和处置。我们总结了大量证据，表明 II 相酶（尤其是谷胱甘肽 S-转移酶）的诱导在针对肺癌发生的化学保护中发挥直接作用。 Keap1-Nrf2 复合物调节抗氧化反应元件 (ARE) 信号通路的参与已被确定为多个系统中化学预防 II 期诱导剂的关键分子靶点。对 II 相酶诱导的监测已导致新型化学预防剂的鉴定，例如异硫氰酸萝卜硫素和 1,2-二硫醇-3-硫酮。然而，目前还没有药物在人类细胞系统或临床试验中显示出明显的益处。替代策略包括： (a) 使用中间癌症生物标志物作为人体试验的终点； (b) 用于人类 II 期基因诱导表达的高通量小分子发现方法； (c) 考虑药物遗传学以及靶肺组织中的药代动力学和药效学的综合方法。这些方法可能会产生更有效的策略，即使用已被证实具有人类活性的化合物来进行定制的化学预防工作。
Lung cancer is the leading cause of cancer mortality for men and women in the United States and is a growing worldwide problem. Protection against lung cancer is associated with higher dietary intake of fruits and vegetables, according to recent large epidemiologic studies. One strategy for lung cancer chemoprevention focuses on the use of agents to modulate the metabolism and disposition of tobacco, environmental and endogenous carcinogens through upregulation of detoxifying phase II enzymes. We summarize the substantial evidence that suggests that induction of phase II enzymes, particularly the glutathione S-transferases, plays a direct role in chemoprotection against lung carcinogenesis. The engagement of the Keap1–Nrf2 complex regulating the antioxidant response element (ARE) signaling pathway has been identified as a key molecular target of chemopreventive phase II inducers in several systems. Monitoring of phase II enzyme induction has led to identification of novel chemopreventive agents such as the isothiocyanate sulforaphane, and the 1,2-dithiole-3-thiones. However, no agents have yet demonstrated clear benefit in human cell systems, or in clinical trials. Alternative strategies include: (a) using intermediate cancer biomarkers for the endpoint in human trials; (b) high-throughput small molecule discovery approaches for induced expression of human phase II genes; and (c) integrative approaches that consider pharmacogenetics, along with pharmacokinetics and pharmacodynamics in target lung tissue. These approaches may lead to a more effective strategy of tailored chemoprevention efforts using compounds with proven human activity.
登录
查看更多内容
影响因子：
10.3
作者：
HALPERN, MT;GILLESPIE, BW;WARNER, KE
通讯作者：
WARNER, KE
影响因子：
4.2
作者：
Hakim, IA;Harris, RB;Talbot, W
通讯作者：
Talbot, W
影响因子：
11.2
作者：
Cauchi, Stephane;Han, Weiguo;Spivack, Simon D.
通讯作者：
Spivack, Simon D.
影响因子：
4.7
作者：
Basten, GP;Bao, YP;Williamson, G
通讯作者：
Williamson, G
影响因子：
3.8
作者：
Aoki, Y;Sato, H;Yamamoto, M
通讯作者：
Yamamoto, M