PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

DFMO和维甲酸在转基因小鼠模型中的作用 表达人乳头瘤病毒的宫颈癌：基因调控 改变，细胞增殖和其他替代终点生物标记物。 人乳头瘤病毒感染与许多特定的人类癌症有关。 肛门癌，食道病变等。然而，最清楚的是 与宫颈癌有关。 该项目的目标是开发一种动物模型，该模型 与人类疾病相似，开发出可能对治疗 预防这些特定形式的癌症，并了解 这种疾病发展的机制。该项目使用了HPV 宫颈癌发生的转基因模型。该模型的结果是 至少40%的动物发生浸润性宫颈癌 在30周内，至少有75%的小鼠出现高度不典型增生。这个 转基因小鼠正在接受DFMO和维甲酸的治疗。两个人 最有可能被检测的维甲酸是9-顺式维甲酸或4-顺式-维甲酸。 (羟基苯基)维甲酰胺。要使用的特定类维甲酸是 下定决心。另外一组缺乏HPV转基因的小鼠 或含有HPV转基因但未经雌二醇治疗的 包括在内。小鼠开始服用DFMO或维甲酸，当它们 都是12周大的，一直持续到研究结束。当 第1-3组动物为4周龄，每组8只小鼠 用BUDR测定小鼠的DNA合成水平 组织学上“正常”的粘膜以及对照组或 治疗过的小鼠。4-6组的组织学定义的病变正在 用于确定使用FISH的遗传损伤的频率 分析。

The Efficacy of DFMO And A Retinoid In A Transgenic Mouse Model For Cervical Cancer Expressing Human Papilloma Virus: Modulation of Genetic Alterations, Cell Proliferation and Other Surrogate Endpoint Biomarkers. HPV infection is associated with a number of specific human cancers e.g. anal cancer, lesions of the esophagus etc. However it is most clearly associated with cervical cancer. The goal of this project is the development of an animal model which parallels the human disease to develop agents which may be useful in prevention of these specific forms of cancer and in understanding the mechanisms of progression of this disease. This project employs an HPV transgenic model in which cervical cancer develops. The model results in the development of invasive cervical cancer in at least 40% of the animals and high grade dysplasia in at least 75% of the mice within 30 weeks. The transgenic mice are being treated with DFMO and with a retinoid. The two most likely retinoids to be examined are 9-cis retinoic acid or 4- (hydroxyphenyl)retinamide. The specific retinoid to be employed is being determined. An additional group of mice either lacking the HPV transgene or containing the HPV transgene but not treated with estradiol, is included. The mice ar being given DFMO or retinoid beginning when they are 12 weeks old and continuing until the end of the study. When the animals in groups 1-3 are 4 weeks of age eight mice from each group are being administered BuDR to determine the levels DNA synthesis in histologically "normal" mucosa as well as hyperplasia in control or treated mice. histologically defined lesions from groups 4-6 are being employed to determine the frequency of genetic lesions employing FISH analysis.