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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors
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15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors

机译：15-羟前列腺素脱氢酶失活作为对塞来昔布化学预防结肠肿瘤的抗性机制

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摘要

Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE_2 levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.
机译：前列腺素合成的COX-2癌基因的药物抑制剂可防止人类结肠癌前癌的发展。但是，对治疗的抵抗力很普遍。在这项研究中，我们表明，COX-2抑制剂塞来昔布的腺瘤预防活性需要同时存在15-羟基前列腺素脱氢酶（15-PGDH）肿瘤抑制基因，并且15-PGDH表达的丧失会赋予塞来昔布抗肿瘤效应。我们首先证明在基因缺乏15-PGDH的小鼠中塞来昔布的腺瘤预防活性被废除。在FVB小鼠中，塞来昔布预防了85％的乙氧基甲烷诱导的肿瘤（> 1 mm），但在阻止15-PGDH的动物中诱导肿瘤的作用上基本上没有作用。实际上，用塞来昔布治疗的15-PGDH空动物比未用塞来昔布的WT小鼠产生更多的肿瘤。在丧失肿瘤预防活性的同时，塞来昔布介导的结肠PGE_2水平的抑制在15-PGDH-null与WT小鼠中也明显减弱。最后，如鼠模型所预测的那样，结肠15-PGDH水平低的人也表现出塞来昔布抗性。具体而言，在结肠腺瘤预防试验中，在所有测试的病例中，在接受塞来昔布治疗的同时出现新的腺瘤的人也被发现结肠15-PGDH水平较低。

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  • 作者

    Min Yan; Seung-Jae Myung; Stephen P. Fink; Earl Lawrence; James Lutterbaugh; Peiying Yang; Xiaohua Zhou; Danielle Liu; Ronald M. Rerko; Joseph Willis; Dawn Dawson; Hsin-Hsiung Tai; Jill S. Bamholtz-Sloan; Robert A. Newman; Monica M. Bertagnolli; Sanford D. Markowitz;

  • 作者单位

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106 Department of Medicine, Long Island Jewish Medical Center, Hyde Park, NY 11004;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106 Division of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Korea;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106 Howard Hughes Medical Institute, Cleveland, OH 44106;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106 Howard Hughes Medical Institute, Cleveland, OH 44106;

    University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106 Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44106;

    Departments of Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106;

    Departments of Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106;

    Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536;

    Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106;

    University of Texas M. D. Anderson Cancer Center, Houston, TX 77030;

    Division of Surgical Oncology, Brigham and Women's Hospital, Boston, MA 02115;

    Departments of Medicine Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106 Howard Hughes Medical Institute, Cleveland, OH 44106;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    colon cancer; 15-PGDH;

    机译：结肠癌;15-PGDH;

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