DFMO/SULINDAC PHASE III

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。目的：腺瘤性息肉通常被认为是结直肠癌的前体，也是这些恶性肿瘤发展的致癌途径中相对较晚的替代物。病因学和实验研究已经确定了在疾病发病之前和发病过程中可定义的分子变化的关键性质，这些变化导致异常信号通路和生长控制缺陷。广泛的流行病学研究已经确定了许多影响腺瘤和结直肠癌发展的饮食和非饮食因素，包括定期摄入非甾体抗炎药（NSAIDs）。在一些动物模型中进行的实验干预表明，非甾体抗炎药以及多胺合成抑制剂二氟甲基鸟氨酸（DFMO）可以抑制包括腺瘤形成和结肠癌在内的癌变。我们和其他人已经进行了DFMO的I期，IIa期和IIb期临床化学预防试验，并在一系列研究中证实了其在降低DFMO剂量下结肠组织多胺含量的有效性，并且几乎完全没有副作用。非甾体抗炎药和舒林达克已被证明可引起FAP消退和偶发性相关息肉，其副作用已被广泛了解。关于这两种药物及其作为结肠直肠癌候选预防药物的潜在作用的现有数据与目前考虑用于人类使用的任何药物一样全面，它们代表了本提案的干预重点。我们已经接近完成了DFMO加舒林酸与安慰剂的IIb期联合试验，主要目标是研究扁平粘膜和腺瘤复发的各种病理标志物。我们建议将这一大组个体作为随机、安慰剂对照、DFMO加舒林酸的III期试验的先导，以确定这种组合是否能显著减少腺瘤性息肉的复发，并且安全。1.具体目标开展一项随机、双盲、安慰剂对照的三期临床化学预防试验，研究DFMO联合舒林酸降低新发性腺瘤性息肉的发生率。假设：这种候选化学预防药物的组合将使腺瘤性息肉的发生率降低50%或更高。合格的和复发的腺瘤将被收集、测量并存档，以供将来的研究。将测量所有随机参与者的饮食参数，并确定结直肠癌和息肉的家族史。2. 目的探讨多胺和前列腺素联合用药对扁平粘膜腺瘤形成率的影响。这些生化参数水平的变化也将被用作依从性的一种衡量标准，以及表明药物正在产生预期的生化调节。假设：治疗36个月后扁平黏膜多胺和前列腺素含量降低水平与腺瘤复发率相关。3. 确定在干预过程中随机分配到联合治疗的患者的副作用。假设：胃肠道和非胃肠道副作用，以及随机分组后的下降，在治疗组和安慰剂组之间没有区别。本研究的主要目的是减少腺瘤性结肠息肉的复发率，而不产生比安慰剂组更大的毒性。我们工作的总体目标是开发可在实践环境中使用的化学预防剂的安全组合，并补充当前的监测工作。

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. OBJECTIVES Adenomatous polyps are generally regarded as precursors to colorectal cancer and relatively late surrogates in the carcinogenic pathway to the development of these malignancies. Etiologic and experimental investigations have established the critical nature of definable molecular changes precedent to and during pathogenesis of the disease that leads to abnormal signaling pathways and defective growth control. Extensive epidemiologic studies have identified numerous dietary and non-dietary factors that affect adenoma and colorectal cancer development, including regular intake of non-steriodal anti-inflammatory drugs (NSAIDs). Experimental interventions in several animal models have demonstrated that NSAIDs as well as the polyamine synthesis inhibitor, difluoromethylornithine (DFMO), inhibit carcinogenesis including adenoma formation and colon cancer. We and others have performed Phase I, IIa and IIb clinical chemoprevention trials of DFMO and in a series of studies that have established its effectiveness in lowering the polyamine content of colorectal tissue at doses of DFMO that are almost completely free of side effects. The NSAID and sulindac has been shown to cause regression of FAP and sporadic associated polyps and its side effects profile is widely understood. The available data on these two agents and their potential role as candidate preventive agents for colorectal cancer is as comprehensive as for any agent(s) currently being considered for human use and they represent the intervention focus of this proposal. We have nearly completed accrual to our Phase IIb combination trial fo DFMO plus sulindac versus placebo in which the major goal was to study various pathobiologic markers in flat mucosa and incident adenoma recurrence. We propose to use this large group of individuals as a Vanguard for a randomized, placebo-controlled, phase III trial of DFMO plus sulindac to determine whether this combination can decrease substantially the recurrence of adenomatous polyps and do so safely. SPECIFIC AIMS 1. To conduct a randomized, double-blind, placebo-controlled phase III clinical chemoprevention trial of the combination of DFMO plus sulindac to decrease the rate of new adenomatous polyp formation. Hypothesis: This combination of candidate chemoprevention agents will lower the rate of adenomatous polyps by 50% or greater. Qualifying and recurrent adenomas will be collected, measured, and archived for future studies. Dietary parameters will be measured and family history of colorectal cancer and polyps will be determined in all randomized participants. 2. To correlate the effects of the combination on polyamine and prostaglandin contents in the flat mucosa to the rate of adenoma formation. The changes in the levels fo these biochemical parameters will also be used as one measure of compliance as well as an indication that the agent is producing the intended biochemical modulation. Hypothesis: The level of reduction of polyamine and prostaglandin contents of flat mucosa after 36 months of treatment will be correlated with the rate of adenoma recurrence. 3. To determine the side effects in patients randomized to the combination therapy over the course of the intervention. Hypothesis: Both GI and non-GI side effects, as well as drop-offs after randomization, will be no different between the treatment and placebo arms. The major objectives of this investigation are to reduce the recurrence rate of adenomatous colonic polyps without producing toxicity greater than seen in the placebo group. The overall goal of our work is to develop safe combinations of chemoprevention agents that can be used in the practice setting and complement current surveillance efforts.