Preclinical Evaluation of Intermediate Endpoints

发起人将使用两种不同品系的小鼠，这两种小鼠 基因工程使其对结肠癌高度敏感。一 品系的小鼠会有APC基因的缺失，导致 分子表型与人类FAP相似。第二个品系的小鼠 小鼠会有MSH-2基因的缺失，导致分子 病理类似于人类HNPCC的一个子集。可与之媲美的饮食 在发达国家经常吃的，相对较高的脂肪和 钙含量相对较低，将被用来调节肿瘤 这些基因改变的小鼠的发病率和多样性。样本 将在不同的时间点从这些小鼠身上提取 动物或用姜黄素、芦丁、舒林酸或高钙治疗的动物 在这些不同的时间段，无论是结肠粘膜还是特定的 将对病变进行各种终点检查，包括DNA倍体， 核扩散状况、核形态计量[大小、形状、质地]、 核仁形态计量学、细胞角蛋白和黏附分子。在这种情况下 结肠粘膜，在出现大的离散病变之前， 对这些不同终端的单个地穴的分析应该是 受雇的。这些不同标记物的表达增加或减少将 与姜黄素、芦丁、 确定舒林酸和高钙是否具有调节特异性 化学标记物与长期的化学预防活动有关。 此外，这些研究还将产生这些高强度药物的治疗效果 这些模型中的优先预防药物非常接近 它们的人类同类。

The offeror will employ two different strains of mice which have been genetically engineered to be highly susceptible to colon tumor. One strain of mice will have a deletion in the APC gene, resulting in a molecular phenotype similar to human FAP. The second strain of mice of mice will have a deletion in the MSH-2 gene, resulting in a molecular pathology similar to a subset of human HNPCC. A diet comparable to that routinely eaten in the developed world, relatively high in fat and relatively low in calcium, will be employed to modulate the tumor incidence and multiplicity in these genotypically altered mice. Samples from these mice will be taken at various time points either from control animals or animals treated with curcumin, rutin, sulindac or high Calcium high vitamin D. At these various times either colonic mucosa or specific lesions will be examined for a variety of endpoints including DNA ploidy, Proliferation status, nuclear morphometry [size, shape, texture], nucleolar morphometry, cytokeratins and adhesion molecules. In the case of the colonic mucosae , prior to appearance of large discrete lesions, analysis of individual crypts for these various endpoints should be employed. Increased or decreased expression of these various markers will be compared with the final chemopreventive activity of curcumin, rutin, sulindac and high calcium to determine whether modulation of specific chemical markers is associated with long term chemopreventive activity. In addition the studies will yield the therapeutic efficacy of these high priority preventive agents in these models which closely approximate their human counterpart.