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Specific mechanisms are at various stages of development, although the drug candidates that will be identified through this grant should have considerable potential for clinical application. The grant will fund, in part, other mechanisms that also have potential for clinical application. We use a three-prong approach to accomplish our goal of developing a "means to prevent and eliminate cancer". First, we use molecular biological methods to determine the changes in gene expression and the consequences of these changes in cancer development. Second, we use chemical approaches to produce agents that will affect gene expression or protein function to determine their effects in cancer. Third, we use classical preclinical and clinical procedures to evaluate the effects of these mechanisms on tumor growth and metastasis. During the present year we will determine whether changes in protein kinase C-dependent gene expression lead to tumor suppression in human cervical cancer cells. Also during this year, we will determine the effects of the chemical agents that have been developed to inhibit vascular endothelial growth factor (VEGF) on various steps of the neoplastic process. These agents will be evaluated for their therapeutic effects in human tumor xenografts. Last year, we performed the first ever clinical trial of a molecularly targeted drug in patients with advanced malignancies. 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