Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20852.
Cancer Prev Res (Phila). 2014 Feb;7(2):246-54. doi: 10.1158/1940-6207.CAPR-13-0164. Epub 2013 Dec 17.
Urinary bladder cancer prevention studies were performed with the nonsteroidal anti-inflammatory drugs (NSAID) naproxen (a standard NSAID with a good cardiovascular profile), sulindac, and their nitric oxide (NO) derivatives. In addition, the effects of the ornithine decarboxylase inhibitor, difluoromethylornithine (DFMO), alone or combined with a suboptimal dose of naproxen or sulindac was examined. Agents were evaluated at their human equivalent doses (HED), as well as at lower doses. In the hydroxybutyl(butyl)nitrosamine (OH-BBN) model of urinary bladder cancer, naproxen (400 or 75 ppm) and sulindac (400 ppm) reduced the incidence of large bladder cancers by 82%, 68%, and 44%, respectively, when the agents were initially given 3 months after the final dose of the carcinogen; microscopic cancers already existed. NO-naproxen was highly effective, whereas NO-sulindac was inactive. To further compare naproxen and NO-naproxen, we examined their effects on gene expression in rat livers following a 7-day exposure. Limited, but similar, gene expression changes in the liver were induced by both agents, implying that the primary effects of both are mediated by the parent NSAID. When agents were initiated 2 weeks after the last administration of OH-BBN, DFMO at 1,000 ppm had limited activity, a low dose of naproxen (75 ppm) and sulindac (150 ppm) were highly and marginally effective. Combining DFMO with suboptimal doses of naproxen had minimal effects, whereas the combination of DMFO and sulindac was more active than either agent alone. Thus, naproxen and NO-naproxen were highly effective, whereas sulindac was moderately effective in the OH-BBN model at their HEDs.
进行了非甾体抗炎药（NSAID）萘普生（具有良好心血管特征的标准 NSAID）、舒林酸及其一氧化氮（NO）衍生物的膀胱癌预防研究。此外，还研究了单独使用鸟氨酸脱羧酶抑制剂二氟甲基鸟氨酸（DFMO）或与萘普生或舒林酸的亚最佳剂量联合使用的效果。以人类等效剂量（HED）以及较低剂量评估了这些药物。在羟基丁基（丁基）亚硝胺（OH-BBN）膀胱癌模型中，萘普生（400 或 75ppm）和舒林酸（400ppm）在最初给予致癌剂最后一次剂量后 3 个月时，分别将大膀胱癌的发生率降低了 82%、68%和 44%；此时已经存在显微镜下的癌症。NO-萘普生非常有效，而 NO-舒林酸则无效。为了进一步比较萘普生和 NO-萘普生，我们检查了它们在大鼠肝脏中 7 天暴露后的基因表达情况。两种药物都引起了有限但相似的肝脏基因表达变化，这表明两种药物的主要作用都是由母体 NSAID 介导的。当在最后一次给予 OH-BBN 后 2 周开始使用药物时，1000ppm 的 DFMO 活性有限，低剂量的萘普生（75ppm）和舒林酸（150ppm）高度有效，略有效。将 DFMO 与亚最佳剂量的萘普生联合使用效果甚微，而将 DFMO 与舒林酸联合使用的效果比单独使用任何一种药物都更有效。因此，在 HED 下，萘普生和 NO-萘普生的效果非常显著，而舒林酸在 OH-BBN 模型中则具有中度效果。
