Chemoprevention of Chemically-Induced Bladder Cancers

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DESCRIPTION (provided by applicant): Numerous epidemiological studies have established a strong association between cigarette smoking and urinary bladder cancer. The overall goals of this proposal are to evaluate chemopreventive agents and surrogate markers for future clinical trials to prevent cancers in former smokers. The chemically induced urinary bladder cancer model that will be used will allow the correlation of changes in surrogate endpoints with the ability of the agent(s) to inhibit bladder carcinogenesis. The first specific aim will evaluate three classes of chemopreventive agents (lipoxygenase inhibitor, farnesyl transferase inhibitor (FTI), and COX-2 inhibitor) either alone or in combination for efficacy in the prevention of bladder cancers. The agents are esculetin, R115777, and celecoxib, respectively. The second specific aim will measure the expression of survivin in urinary bladder lesions and in urine of rats treated with the carcinogen OH-BBN and/or chemopreventive agents. The rationale for using survivin as a molecular marker/predictor in these studies is twofold. First, increased expression of survivin in cancer versus normal tissues is contributed by associated Ras and secondly, survivin provides a highly sensitive and specific marker of onset and progression of bladder cancer. This is particularly relevant for the chemopreventive experiments with the farnesyl transferase inhibitor R115777 and suggests that monitoring the modulation of survivin expression during this study may provide a molecular indicator of Ras-dependent transformation. The third specific aim will initially determine the effect of R115777 on gene expression profiles as assessed by Affymetrix gene chip analysis to establish new biomarkers that are involved in urinary bladder carcinogenesis and modulatable by chemopreventive agents. The hypothesis is that farnesyl transferase inhibitors will prevent chemically-induced urinary bladder cancers by modulating the expression of genes associated with apoptosis and cell cycle regulation pathways. Depending on the results in the FTI treated rats, additional profiles can be assessed in the celecoxib and esculetin treated animals.