CLINICAL TRIAL: DFMO/SULINDAC PHASE III

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 腺瘤性息肉通常被认为是结直肠癌的先兆，并在致癌途径中相对较晚地替代这些恶性肿瘤的发展。病因学和实验研究已经确定了可确定的分子变化的关键性质，这些变化在疾病发病之前和发病过程中导致异常的信号通路和缺陷的生长控制。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生的饮食和非饮食因素，包括定期摄入非甾体抗炎药(NSAIDs)。在几个动物模型中的实验干预已经证明，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症发生。我们和其他人进行了DFMO的I、IIa和IIb期临床化学预防试验，并在一系列研究中证实了DFMO在降低大肠组织多胺含量方面的有效性，这些剂量的DFMO几乎完全没有副作用。非甾体抗炎药和舒林酸已被证明可导致FAP和散发性相关性息肉的消退，其副作用已被广泛了解。

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. 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.