EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS IN ANIMAL MOD

鉴于非黑色素瘤皮肤癌的发病率相对较高且不断增加，迫切需要开发动物模型来测试潜在的化学预防药物。事实上，紫外线诱导小鼠皮肤癌的模型已经存在了至少20年。这是SKH(无毛老鼠)。由于在14号染色体上的“有毛”位置插入逆转录病毒，该小鼠品系是无毛的。在纯合子隐性小鼠中，紫外线暴露会诱发皮肤癌和来自表皮的前驱病变(如不典型增生和原位癌)。这项研究主要考察了化学保护剂对肿瘤形态终点的影响，但我们正在检测更有限数量的潜在替代终点生物标记物，以了解这些药物对它们的调节作用。终点包括：a)各种细胞周期调节蛋白，即细胞周期蛋白及其相关的激酶。例如，Cyclin D1，B)DNA合成的测量(BUDR或PCNA)；C)端粒酶。这些终点有助于进行量化分析。1)采用SKH无毛小鼠模型，检测三种药物在化疗前或治疗后10周开始化学预防治疗。这些药物(2甲氧基雌二醇、iNOS抑制剂、非甾体抗炎药和DFMO)都将在饲料中使用；2)只使用两种有效的药物来确定它们是否可以调节潜在生物标记物的表达(例如，细胞周期蛋白(例如，增殖细胞核抗原)、细胞周期蛋白水平和端粒酶活性)。

In view of the relatively high and increasing prevalence of nonmelanoma skin cancer, the development of animal models for testing potential chemopreventive agents is urgent. In fact a model of UV-induced skin carcinogenesis in mice has existed for at least 20 years. This is the SKH (hairless mouse). This mouse strain is hairless due to the insertion of a retrovirus at the "haired" locus on chromosome 14. In homozygous recessive mice UV exposure induces skin carcinomas and precursor lesions (e.g. atypical hyperplasias and carcinoma in situ) from the epidermis. This study examines the effects of chemopreventives primarily on tumor morphological endpoints however we are examining a more limited number of potential surrogate endpoint biomarkers for their modulation by these agents. Endpoints include: A) Various cell cycle regulated proteins i.e. cyclins and their related kinases. e.g. Cyclin D1 B) Measures of DNA synthesis(BudR or PCNA) ; C) Telomerase . These endpoints lend themselves to quantitative analysis. 1) To employ the SKH hairless mouse model to examine three agents starting chemopreventive treatment either immediately prior to following or 10 weeks following treatment with the agents. These agents ( 2 methoxy estradiol, iNOS inhibitor, NSAID, and DFMO) will all be administered in feed; 2) To employ only two of the effective agents to determine whether they can modulate expression of potential biomarkers (e.g. cell cycle proteins (e.g. PCNA),cyclin levels and telomerase activity).