PRECLINICAL EVALUATION OF INTERMEDIATE ENDPOINTS

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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.