Chemoprevention of murine urinary bladder carcinogenesis

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DESCRIPTION (provided by applicant): The incidence of bladder cancer in the United States is increasing with 57,400 new cases projected for the year 2003. The majority of bladder tumors present as superficial papillary transitional cell carcinomas and recurrence rates approach 88% at 15 years. New approaches, including chemoprevention, are needed to reduce morbidity from this disease. Our study proposes to evaluate the hypothesis that two classes of agents - a cyclooxygenase-2 inhibitor and a quinolone antibiotic - either alone or in combination, have chemopreventive activity against superficial bladder cancer. Both these agents have been widely used with minimal toxicity, making them attractive for chemoprevention studies in humans. The first specific aim will study the in vitro effects of these agents on a panel of human bladder cancer cells with varying invasive and metastatic potential in order to obtain insights regarding activity against different grades of human bladder tumors. The second specific aim will evaluate the agents' chemopreventive efficacy in vivo. For these studies, we will use the transgenic mouse model in which development of papillary tumors in the bladder is driven by the presence of mutant Ha-ras. The tumors in this model mimic the tumors seen in patients who are considered candidates for chemoprevention studies. We will use MRI to image and monitor the tumors within the bladder of the animals since this will provide a rapid method to assess the efficacy of the chemopreventive agents. The third specific aim will determine the effects of the chemopreventive agents on tissue pathology and will address the hypothesis that the agents will prevent or inhibit the growth of tumors by inhibiting cell proliferation, inducing apoptosis, or both. We believe that this application will meet the stated goals of the program announcement to evaluate new chemopreventive agents, test strategies to prevent cancer in persons/animals at increased genetic risk, and to develop innovative animal models to mimic the human cancer process in order to expedite research in cancer prevention.