Alyaqoub Fadel S, Liu Yue, Tao Lianhui, Steele Vernon E, Lubet Ronald A, Pereira Michael A
Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio, USA.
Mol Carcinog. 2008 Mar;47(3):165-71. doi: 10.1002/mc.20383.
Bexarotene has demonstrated chemopreventive and therapeutic efficacy towards mouse lung tumors. Using specimens from our published study that demonstrated the efficacy of bexarotene, we report herein its ability to modulate mRNA expression of genes in both lung and lung tumors. Strain A/J mice were administered vinyl carbamate to induce lung tumors. This was followed by 200 mg/kg body weight of bexarotene administered by oral gavage during Wks 4-25 or 23-25. The mice were sacrificed at Wk 25. The expression of 26 genes was decreased in lung tumors, whereas only two genes, Apolipoprotein D and CYP26b, had their mRNA expression increased by bexarotene. Genes with increased mRNA expression in untreated lung tumors include: epiregulin and kininogen-1 (increased by more than 40-fold) and Caspase-3, Cyclin D1, DNA methyltransferase 3a (Dnmt-3a), E-prostanoid 3 receptor (EP3), c-myc, surfactant protein-C, and survivin (increased by 1.7- to 3.6-fold). Bexarotene decreased the mRNA expression of Caspase-3, Dnmt-3a, EP3, and survivin, as well as the expression of the Cyclin E1, estrogen receptor-alpha, and iNOS genes. Bexarotene had a greater effect in decreasing the expression of Caspase-3, Cyclin E1, Dnmt-3a, EP3, iNOS, and survivin, when administered to mice with established tumors than when administered to mice while tumors were emerging. In summary, bexarotene modulated mRNA expression of genes in mouse lung tumors, being more effective in established tumors than in emerging tumors, suggesting that modulation of expression could be useful as a biomarker for the therapeutic and chemopreventive activity of the drug, especially in established tumors.
贝沙罗汀已在小鼠肺癌中展现出化学预防和治疗功效。利用我们已发表研究中的标本（该研究证明了贝沙罗汀的功效），我们在此报告其调节肺组织和肺肿瘤中基因mRNA表达的能力。向A/J品系小鼠给予氨基甲酸乙烯酯以诱导肺肿瘤。随后在第4 - 25周或第23 - 25周期间，通过口服灌胃给予200mg/kg体重的贝沙罗汀。在第25周处死小鼠。肺肿瘤中26个基因的表达降低，而仅有两个基因，即载脂蛋白D和CYP26b，其mRNA表达因贝沙罗汀而增加。在未处理的肺肿瘤中mRNA表达增加的基因包括：表皮调节素和激肽原-1（增加超过40倍）以及半胱天冬酶-3、细胞周期蛋白D1、DNA甲基转移酶3a（Dnmt-3a）、E-前列腺素3受体（EP3）、c- myc、表面活性蛋白-C和生存素（增加1.7至3.6倍）。贝沙罗汀降低了半胱天冬酶-3、Dnmt-3a、EP3和生存素的mRNA表达，以及细胞周期蛋白E1、雌激素受体α和诱导型一氧化氮合酶（iNOS）基因的表达。当给予已形成肿瘤的小鼠时，贝沙罗汀在降低半胱天冬酶-3、细胞周期蛋白E1、Dnmt-3a、EP3、iNOS和生存素的表达方面比在肿瘤形成过程中给予小鼠时具有更大的作用。总之，贝沙罗汀调节小鼠肺肿瘤中基因的mRNA表达，在已形成的肿瘤中比在肿瘤形成过程中更有效，这表明表达调节可能作为该药物治疗和化学预防活性的生物标志物是有用的，尤其是在已形成的肿瘤中。
