DFMO AND SULINDAC

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在美国，结肠癌和直肠癌是癌症相关死亡的第二大常见原因。目前，治愈这种癌症的最大希望在于早期发现并在早期手术切除肿瘤。因此，在改进早期检测方法和确定危险因素方面作出了很大努力。已经出现的最重要的危险因素是结肠腺瘤性息肉。目前的证据支持大多数结肠癌通过腺瘤-癌序列的理论。临床观察表明，有息肉的人结肠粘膜发生癌症的可能性比没有息肉的人要大得多。大量的实验室实验表明，包括结肠在内的许多器官的癌症发展过程依赖于鸟氨酸脱羧酶（ODC）的活性，即随后的多胺合成。这些证据表明，改变结肠中多胺的水平可以降低患癌症的风险。也有证据表明，服用实验性药物二氟甲基鸟氨酸（DFMO）可降低结肠中多胺的水平。这项工作的总体目标是开发一种有效和安全的组合来预防结肠癌。动物模型研究表明，这一目标是可行的，特别是DFMO和非甾体抗炎药（NSAIDS）是有效的。我们对这两种化合物都有相当丰富的临床经验，最近在结肠癌风险增加的受试者中完成了临床化学预防试验：I期（非甾体抗炎药、布洛芬）和IIa/b期（DFMO）。测定结肠黏膜相应的生化指标，并证实其有调节作用。动物实验表明，通过不同机制作用的药物组合比单独使用任何一种药物更有效，并且在我们使用这些化合物的临床化学预防试验中取得了令人鼓舞的结果（调节生化效应和无/低毒），这表明应该进行使用这些药物组合的有限试验。因此，在目前的研究中，我们提出了一项随机的IIb期临床化学预防试验，即DFMO 0.20 gm/M2/day与舒林酸（克林瑞）150 mg/day联合使用。具体目的是：(1)测量DFMO加舒林酸（Clinoril）与安慰剂在调节一组与结直肠肿瘤特别相关的替代终点生物标志物（SEB）方面的疗效。在扁平粘膜活检中，通过免疫过氧化物酶定量测量组织病理学和评估非诱导的细胞凋亡、增殖（Ki67）和瘤前（CEA、唾液酰- tn、p53、bcl-2）特征；多胺和PGE2水平也将被确定为两种药物的生化效应的估计；(2)确定平坦粘膜中SEB的调节与间发性腺瘤的发展之间的关系，从而验证一种或多种对腺瘤病理的替代性质

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer of the colon and rectum is the second most prevalent cause of cancer-related deaths in the United States. Currently, the best hope for cure of this type of cancer lies with early detection and surgical removal of the tumor at an early stage. Accordingly, much effort has been directed toward improving early detection methods and identifying risk factors. The most important risk factor which has emerged is the adenomatous colon polyp. Current evidence supports the theory that most colon cancers pass through an adenoma-carcinoma sequence. Clinical observations indicate that the potential of colonic mucosa to develop cancer is much greater in people with polyps than without. Extensive laboratory experimentation has demonstrated that the process of cancer development in many organs, including the colon, is dependent on the activity of the enzyme ornithine decarboxylate (ODC), the the subsequent synthesis of polyamines. These is evidence which indicates that alteration in the level of polyamines in the colon can reduce the risk for cancer. Evidence is also available that the level of polyamines in the colon may be decreased by giving the experimental drug difluoromethylornithine (DFMO). The overall goal of this work is to develop an effective and safe combination that will prevent colon cancer. Studies in animal models have demonstrated that such a goal is feasible and that, in particular, DFMO and non-steroidal anti-inflammatory agents (NSAIDS) are efficacious. We have considerable clinical experience with both these compounds and recently have completed clinical chemoprevention trials in subjects at increased risk for colon cancer: phase I (the NSAID, Ibuprofen) and phase IIa/b (DFMO). Appropriate biochemical markers were measured in colonic mucosa and modulation was demonstrated. The demonstration in animals that combinations of agents acting through different mechanisms are more effective than either agent alone and the encouraging results (modulation of biochemical effect and no/low toxicity) in our clinical chemoprevention trials with these compounds suggests that a limited trial using a combination of these drugs should be undertaken. In the current study, therefore, we propose a randomized phase IIb clinical chemoprevention trial of the combination of DFMO 0.20 gm/M2/day and sulindac (Clinoril) 150 mg/day. The specific aims are: (1) to measure the efficacy of DFMO plus sulindac (Clinoril) versus placebo in modulating a panel of surrogate endpoint biomarkers (SEB) of particular relevance in colorectal neoplasia. Several measurements of quantitative histopathology and assessment of uninduced apoptosis, proliferative (Ki67) and preneoplastic (CEA, sialyl-TN, p53, bcl-2) features by immunoperoxidase will be done in biopsies of flat mucosa; polyamine and PGE2 levels will also be determined as estimate of biochemical effect by the two agents; and (2) to determine the relationship between the modulation of SEB in flat mucosa to the development of interval incident adenomas, thereby validating the surrogate nature of one or more against adenoma pathology