EFFICACY STUDIES OF CHEMOPREVENTIVE AGENTS

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。这个项目的目标是 一种与人类疾病相似的动物模型的建立 开发可能对预防这些特殊形式有用的试剂 以及对癌症进展机制的理解 疾病。该项目采用了HPV转基因模型，在该模型中， 癌症就会发展。该模型导致了侵袭性疾病的发展 至少40%的动物患有宫颈癌和高度不典型增生 至少75%的小鼠在30周内。转基因小鼠正在被 用DFMO和维甲酸治疗。两种最有可能的维甲酸 被检查的是9-顺式维甲酸或4-(羟基苯基)维甲酰胺。这个 具体使用的维甲酸正在确定中。一个额外的小组 缺乏HPV转基因或含有HPV转基因的小鼠 但没有用雌二醇治疗，包括在内。小鼠被给予了 DFMO或视黄醇，从12周龄开始，一直持续到 研究的结束。当1-3组的动物4周龄时 每组8只小鼠接受BUDR注射，以确定 在组织学上“正常”的粘膜中的DNA合成水平 对照组或治疗组小鼠的增生。组织学定义的病变 来自4-6组的基因被用来确定基因的频率 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.