EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS IN ANIMAL MOD

化学预防剂在动物模型中的药效研究

• 批准号: 6346796
• 负责人: Clinton Julian Grubbs
• 金额: $ 53.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6346796
• 关键词: biomarker; cancer prevention; carcinogenesis; cell cycle proteins; chemoprevention; difluoromethylornithine; disease /disorder model; drug screening /evaluation; enzyme inhibitors; estradiol; hairless mouse; nitric oxide synthase; nonsteroidal antiinflammatory agent; skin neoplasms; telomerase; ultraviolet radiation

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).

鉴于非黑色素瘤皮肤癌的发病率相对较高且不断增加，迫切需要开发用于测试潜在化学预防剂的动物模型。 事实上，紫外线诱导的小鼠皮肤致癌模型已经存在了至少20年。 这就是SKH（无毛老鼠）。 这种小鼠品系是无毛的，这是由于在14号染色体上的“有毛”位点插入了逆转录病毒。 在纯合隐性小鼠中，紫外线暴露诱导表皮的皮肤癌和前驱病变（例如非典型增生和原位癌）。本研究主要检查化学预防药物对肿瘤形态学终点的影响，但我们正在检查数量更有限的潜在替代终点生物标志物，以了解这些药物对其的调节作用。 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激酶。 例如细胞周期蛋白D1 B）DNA合成的测量（BudR或PCNA）; C）端粒酶。 这些终点有助于定量分析。 1)采用SKH无毛小鼠模型，检查三种药物在治疗前即刻或治疗后10周开始化学预防治疗。 这些试剂（2甲氧基雌二醇、iNOS抑制剂、NSAID和DFMO）将全部在饲料中施用; 2）仅使用两种有效试剂来确定它们是否可以调节潜在生物标志物（例如细胞周期蛋白（例如PCNA）、细胞周期蛋白水平和端粒酶活性）的表达。