Prevention of mouse lung tumors by budesonide and its modulation of biomarkers
Prevention of mouse lung tumors by budesonide and its modulation of biomarkers
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DOI：
10.1093/carcin/23.7.1185
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发表时间：
2002-07-01
期刊：
影响因子：
4.7
通讯作者：
Tao, LH
中科院分区：
文献类型：
--
作者：
Pereira, MA;Li, YZ;Tao, LH
化学预防药物有可能降低肺癌的发病率和死亡率。可以通过应用替代终点生物标记物来加速这些药物的开发，这些生物标记物可以证明化学预防效果。本研究进一步研究了布地奈德对小鼠肺部肿瘤的预防作用，并测定了其对生物标志物的影响。A系雌性小鼠给予氨基甲酸乙烯酯(16 mg/kg)诱发肺癌，每周1次，连续2周。4周后，小鼠开始连续给予0.6、1.2或2.4 mg/kg的布地奈德，直到第20周处死。布地奈德使肺癌的多发性分别下降了25%、58%和82%，且呈剂量依赖性。在第4、10或16周开始给予布地奈德(2.4 mg/kg饮食)，在第20周时肿瘤多样性分别减少82、66和30%。在第4-20周或20-35周给予2.4 mg/kg布地奈德并在第35周处死小鼠，虽然这两种治疗方案都能减少肿瘤的大小和腺瘤向癌症的进展，但并未显著降低肿瘤产量。因此，布地奈德延缓了肺癌的出现，并减少了它们的生长和癌变。为了确定有限暴露于布地奈德对生物标志物的影响，在第35周死亡前仅给药7天。布地奈德使肺腺瘤、肺癌、肺实质和支气管呼吸道的增殖细胞核抗原标记分别减少87.6%、59.0%、41.1%和25.4%。布地奈德还能提高p21和p27基因的蛋白水平，提高p21基因的mRNA水平。因此，布地奈德的短期治疗调节了肺肿瘤的生物和分子终点，这些终点可能被进一步开发为其在肺部的临床化学预防效果的生物标志物。
Chemopreventive drugs have the potential to decrease the morbidity and mortality of lung cancer. The development of these drugs could be expedited by the application of surrogate end-point biomarkers that demonstrate chemopreventive efficacy. In this study, the ability of budesonide to prevent lung tumors in mice was characterized further and its effects on biomarkers were determined. Lung tumors were induced in female strain A mice by vinyl carbamate (16 mg/kg) administered once weekly for 2 consecutive weeks. Four weeks later the mice started to receive 0.6, 1.2 or 2.4 mg/kg budesonide continually in the diet until killed at week 20. Budesonide caused a dose-dependent decrease in the multiplicity of lung tumors of 25, 58 and 82%, respectively. Budesonide (2.4 mg/kg diet) administered starting at weeks 4, 10 or 16, decreased tumor multiplicity by 82, 66 and 30% at week 20. Administering 2.4 mg/kg budesonide at weeks 4-20 or 20-35 and killing the mice at week 35 did not significantly decrease the yield of tumors, although both treatment regimens did decrease the size of the tumors and the progression of adenomas to carcinomas. Thus, budesonide delayed the appearance of lung tumors and decreased their growth and progression to carcinomas. To determine the effect of limited exposure to budesonide on biomarkers, it was administered for only 7 days prior to death at week 35. Budesonide decreased the proliferating cell nuclear antigen labeling in lung adenomas, carcinomas, parenchyma and bronchial airways by 87.6, 59.0, 41.1 and 25.4%, respectively. Budesonide treatment also increased the protein level of the p21 and p27 genes and increased the mRNA level of p21. Thus, short-term treatment with budesonide modulated biological and molecular end-points in lung tumors that might be developed further as biomarkers for its clinical chemopreventive efficacy in the lung.