DFMO AND SULINDAC

点击翻译按钮获取中文摘要

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