EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS

DFMO和类维生素A在转基因小鼠模型中的功效 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志物。 HPV感染与许多特定的人类癌症有关，例如， 肛门癌，食道病变等，但它是最清楚的 与宫颈癌有关。 该项目的目标是 开发一种与人类疾病相似的动物模型， 开发可用于预防这些特定形式的药物 以及了解癌症进展的机制， 疾病 该项目采用HPV转基因模型，其中宫颈癌发生率为100%。 癌症发展。 该模型导致了侵入性的发展 至少40%的动物发生宫颈癌， 至少75%的小鼠在30周内死亡 这些转基因小鼠 用DFMO和维甲酸治疗。 两种最有可能 检查的是9-顺式视黄酸或4-（羟基苯基）视黄酰胺。 的 目前正在确定使用的具体类维生素A。 另外一组 缺乏HPV转基因或含有HPV转基因的小鼠 但未用雌二醇处理的。 这些老鼠被给予 DFMO或维甲酸开始时，他们是12周龄，并继续，直到 研究的结束。 当组1-3中的动物为4周龄时， 对每组的8只小鼠施用BuDR以测定 组织学上“正常”粘膜的DNA合成水平以及 在对照或治疗的小鼠中的增生。 组织学定义的病变 从组4-6被用来确定遗传频率 病变采用FISH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 are 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.