Franklin Michael R, Moos Philip J, El-Sayed Wael M, Aboul-Fadl Tarek, Roberts Jeanette C
University of Utah, Department of Pharmacology and Toxicology, Salt Lake City, UT 84112, USA.
Chem Biol Interact. 2007 Jul 20;168(3):211-20. doi: 10.1016/j.cbi.2007.04.012. Epub 2007 May 4.
The efficacy of a series of 2-aryl/alkyl selenazolidine-4(R)-carboxylic acids (SCAs) in reducing NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]-induced lung adenomas in female A/J mice, a model for tobacco-related lung tumorigenesis, has been investigated. With selenazolidines in the diet for 1 month prior to carcinogen administration and during the subsequent 4 months of tumor development, 2-butylSCA, 2-cyclohexylSCA, 2-phenylSCA and 2-oxoSCA were chemopreventive, significantly reducing mean lung tumor numbers from the 10.9 of unsupplemented controls to 4.7, 5.3, 2.8 and 4.7, respectively. When selenazolidine supplementation began three days after carcinogen administration (i.e., post-initiation), 2-butylSCA, 2-cyclohexylSCA, and 2-oxoSCA were chemopreventive. In both regimens, selenocystine was also chemopreventive. In the post-initiation protocol, but with intervention at a precancerous stage (13 days), whole genome expression analysis of lung RNA identified six gene transcripts that weakly correlated with the efficacy of tumor reduction by the four selenocompounds at 4 months. None of these genes were among those identified to be influenced by chemopreventive selenium compounds in human lung cancer cell lines. When supplementation was for 1 month-prior until 3 days-after carcinogen administration, 2-butylSCA, and 2-phenylSCA were chemopreventive but selenocystine was ineffective. Both 2-butylSCA and 2-phenylSCA retained their chemopreventive activity (44% and 40% tumor number reduction, respectively), when the supplementation was shortened and restricted to a pre-initiation period (days -9 to -2). With supplementation spanning 2 days-prior until 3 days-after NNK, reductions in tumor numbers by 2-phenylSCA (26%) and 2-butylSCA (17%) did not achieve statistical significance. Thus, several 2-aryl/alkyl selenazolidines possess chemopreventive activity against NNK-induced lung tumors, and variously demonstrate pre-initiation and post-initiation efficacy.
在烟草相关肺癌发生模型——雌性A/J小鼠中，研究了一系列2-芳基/烷基硒唑烷-4（R）-羧酸（SCA）在减少NNK[4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮]诱导的肺腺瘤方面的功效。在给予致癌物之前，先在饮食中添加硒唑烷1个月，并在随后4个月的肿瘤发展期持续添加，2-丁基SCA、2-环己基SCA、2-苯基SCA和2-氧代SCA具有化学预防作用，可将平均肺肿瘤数量从未补充组的10.9分别显著减少至4.7、5.3、2.8和4.7。当在给予致癌物三天后（即启动后）开始补充硒唑烷时，2-丁基SCA、2-环己基SCA和2-氧代SCA具有化学预防作用。在这两种方案中，硒代胱氨酸也具有化学预防作用。在启动后方案中，但在癌前阶段（第13天）进行干预时，对肺RNA进行全基因组表达分析，确定了六个基因转录本，它们与这四种硒化合物在4个月时减少肿瘤的功效呈弱相关。这些基因均不在已确定的受化学预防硒化合物影响的人肺癌细胞系基因之列。当在给予致癌物前1个月直至给予后3天进行补充时，2-丁基SCA和2-苯基SCA具有化学预防作用，但硒代胱氨酸无效。当补充时间缩短并限制在启动前期（第-9天至-2天）时，2-丁基SCA和2-苯基SCA均保留了其化学预防活性（分别减少44%和40%的肿瘤数量）。在NNK前2天直至后3天进行补充时，2-苯基SCA（26%）和2-丁基SCA（17%）减少肿瘤数量的效果未达到统计学显著水平。因此，几种2-芳基/烷基硒唑烷对NNK诱导的肺肿瘤具有化学预防活性，并分别表现出启动前和启动后的功效。
