Colorectal cancer is the second leading cause of cancer deaths in the United States making its prevention a major public health issue. Human colorectal tumorigenesis progresses through a series of well defined clinical and histopathological stages that range from small benign tumors to widely metastatic disease. This progression occurs over many years and is associated with the accumulation of multiple genetic changes that affect at least one oncogene and several tumor suppressor genes. It can be argued the early genetic changes in this process are the most important in terms of prevention and treatment. Mutation of the APC tumor suppressor gene is a early if not initiating event for the development of most sporadic colorectal tumors. Moreover, patients who inherit a mutated APC gene suffer from Familial Adenomatous Polyposis (FAP) which is characterized by the development of hundreds of benign colorectal tumors during their second to third decade of life. Likewise, MIN mice, which have a germline mutation of the murine homolog of APC (mAPC), develop multiple intestinal tumors. MIN mice are thus an excellent model for Human FAP at both the phenotypic and genetic levels. Furthermore, because MIN mice share a critical genetic defect with sporadic colorectal tumors, MIN tumors are a good model for colorectal tumorigenesis in the general population as well. We propose to use MIN mice for the rapid and cost effective evaluation of agents for the treatment and prevention of colorectal tumors. MIN mice have several advantages over chemical mutagen induced models of colorectal cancer where the genetic pathogenesis and relatedness to human disease is unclear. To evaluate this model system, we treated MIN mice with the Non Steroidal Anti-inflammatory Drug (NSAID) sulindac which has shown promise in the treatment of human FAP patients. Our preliminary data indicate that sulindac displays tumor suppressing effects in MIN mice similar to those observed in humans. Moreover, provocative information about the timing of sulindac dosage was obtained which would have been difficult to obtain in human studies. We propose to continue to explore the effectiveness and mechanism of sulindac tumor suppressive activities. In addition, we will evaluate other NSAIDs and promising unrelated compounds for their ability to prevent tumorigenesis in MIN mice. Finally, because only a fraction of the cells with mutant APC eventually go on to form tumors, we will attempt to identify other genetic changes that must accompany colorectal tumor formation. Identifying these changes will have important implications for the development of new preventions for colorectal tumors.
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