• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Early detection and non-steroidal anti-inflammatory drug chemoprevention of colorectal cancer.
【24h】

Early detection and non-steroidal anti-inflammatory drug chemoprevention of colorectal cancer.

机译：大肠癌的早期发现和非甾体抗炎药的化学预防。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Early detection and removal of pre-cancerous adenomas and polyps through endoscopic techniques remains the most effective method for reducing the morbidity and mortality associated with colorectal cancer (CRC). Aberrant crypt foci (ACF) are microscopic surface abnormalities that are putative precursors to adenomas and CRC. ACF exhibit similar histological and molecular abnormalities to adenomas and CRC and potentially represent useful biomarkers of cancer risk. We examined ACF from subjects undergoing screening colonoscopies. Notably, no patients included in the study had a concurrent colon cancer. Genomic DNA, isolated by laser capture microdissection, was prepared from ACF and adjacent normal colonic epithelium. We show that K-ras mutations, promoter hypermethylation of RASSF1A, hMLH1 and MGMT, and microsatellite instability (MSI) can all be detected in ACF in the absence of synchronous colon tumors and are not accompanied by field effects into the surrounding epithelium. Also, all ACF with MGMT hypermethylation displayed an MSI-low phenotype. These lesions may be precursors to MSI-low CRC, providing a potential early biomarker to assess the effects of cancer prevention strategies.;Chemoprevention has emerged as a complementary and even first-line strategy in high-risk subjects for the prevention of CRC, using agents that target cancer-associated pathways to delay, prevent or reverse the development of adenomas. Among the most promising chemopreventive approaches are non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit the COX-1 and -2 enzymes and can induce apoptosis in colon cancer cells through multiple mechanisms. We show that the NSAID sulindac significantly inhibits small intestinal tumors in ApcMin/+ mice, but actually increases colon tumor multiplicity. Importantly, p21WAF1/cip1 and PPARgamma expression were absent in colon tumors from sulindac-treated mice, suggesting that loss of these proteins is necessary for drug resistance. These observations may be translatable to designing novel clinical therapies utilizing combinations of agents that target multiple molecular pathways to overcome sulindac resistance. We also show that the NSAID ibuprofen inhibits nuclear beta-catenin expression in human sporadic colon adenomas as well as in colon cancer cell lines. These data demonstrate that this drug can target a key pathway associated with colon carcinogenesis and may be a good candidate for future clinical trials for CRC chemoprevention.
机译：通过内窥镜技术及早发现和去除癌前腺瘤和息肉仍然是降低与大肠癌（CRC）相关的发病率和死亡率的最有效方法。异常隐窝灶（ACF）是微观表面异常，是腺瘤和CRC的假定前兆。 ACF表现出与腺瘤和CRC相似的组织学和分子异常，并可能代表有用的癌症风险生物标志物。我们检查了接受筛选结肠镜检查的受试者的ACF。值得注意的是，研究中没有患者并发结肠癌。通过ACF和邻近的正常结肠上皮制备通过激光捕获显微切割分离的基因组DNA。我们显示K-ras突变，RASSF1A，hMLH1和MGMT的启动子高甲基化，以及微卫星不稳定性（MSI）都可以在没有同步结肠肿瘤的情况下在ACF中检测到，并且不伴随着对周围上皮的场效应。此外，所有具有MGMT高度甲基化的ACF均显示MSI低表型。这些病变可能是MSI低CRC的前体，为评估癌症预防策略的效果提供了潜在的早期生物标志物。化学预防已成为高风险受试者预防CRC的补充甚至一线策略，使用靶向癌症相关途径的药物可延缓，预防或逆转腺瘤的发展。非甾体抗炎药（NSAIDs）是最有前途的化学预防方法之一，它可以抑制COX-1和-2酶并可以通过多种机制诱导结肠癌细胞的凋亡。我们显示，NSAID舒林酸可显着抑制ApcMin / +小鼠中的小肠肿瘤，但实际上会增加结肠肿瘤的多重性。重要的是，舒林酸治疗小鼠的结肠肿瘤中不存在p21WAF1 / cip1和PPARγ的表达，这表明这些蛋白质的丢失对于耐药性是必需的。这些观察结果可转化为利用靶向多种分子途径以克服舒林酸耐药性的药物组合设计新颖的临床疗法。我们还显示，NSAID布洛芬抑制人零星结肠腺瘤以及结肠癌细胞系中的核β-连环蛋白表达。这些数据表明，该药物可以靶向与结肠癌发生有关的关键途径，并且可能是CRC化学预防未来临床试验的良好候选者。

著录项

  • 作者

    Greenspan, Emily Joy.;

  • 作者单位

    University of Connecticut.;

  • 授予单位 University of Connecticut.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 163 p.
  • 总页数 163
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号