The overall goal in this PO1 renewal is to develop new anticancer drugs that are active specifically in solid tumors. In this application we propose to accomplish this by exploiting a major difference between normal and malignant tissues, namely, the presence in human solid tumors of regions of very low oxygenation, which are often associated with necrosis. Although this lower oxygenation is currently a negative prognostic factor for radiotherapy, for chemotherapy, and for malignant progression, it also provides a potentially powerful way to activate cytotoxic anticancer drugs exclusively in tumors. We propose three different strategies for exploiting these hypoxic regions in solid tumors to develop tumor-specific anticancer drugs. All three depend on the activation within hypoxic regions of nontoxic prodrugs into toxic drugs but by different mechanisms. One project will design, synthesize, and provide the necessary physicochemical evaluation of the drugs for each of the three strategies. A second project will evaluate prodrugs activated to cytotoxic agents by the nonpathogenic obligate anaerobe C. sporogenes genetically engineered to express specific prodrug-activating enzymes. These anaerobes colonize the necrotic areas of solid tumors, express the prodrug-activating enzymes in these regions, and consequently activate systemically delivered prodrugs to the cytotoxic drugs specifically in the tumors. A third project will continue our mechanism-based development of a superior analog of the clinically active hypoxic cytotoxin tirapazamine (TPZ), which was developed by us and which is showing success in clinical trials. The rational development of an improved TPZ analog depends on the extensive knowledge we have gained in understanding the properties of drugs affecting their in vivo activity. A fourth project is designed to exploit the fact that hypoxic cells in tumors have elevated levels and activity of the transcription factor HIF-1, which transactivates many genes that become specifically expressed in the hypoxic regions. We will screen for drugs that are conditionally lethal to cells withhigh HIF-1 activity. An important advantage of our strategy is that though we are targeting tumor cells in general, we expect the maximum cell killing to be against the hypoxic cells of the tumor, which are known to be those resistant to standard therapy.
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