This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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