The mdm2 oncogene has been shown to be amplified or overexpressed in human cancers, about 50 percent of breast cancers, 40-60 percent of osteosarcomas, 30 percent of soft tissue sarcomas, and 60 percent of gliomas. It also has been suggested that mdm2 levels are associated with poor prognosis of several human cancers. The mdm2 oncoprotein binds to the p53 tumor suppressor protein and serves as a negative regulator of p53. The p53 tumor suppressor also has an important role in cancer therapy, with p53-mediated apoptosis being a major mechanism of action for many clinically used cancer chemotherapeutic agents and radiation therapy. Therefore, the negative regulation of p53 by mdm2 may limit the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. The investigators hypothesize that, by inhibiting mdm2 expression, the mdm2 oncoprotein level will be reduced and the mdm2 negative feed-back inhibition of p53 will be diminished, resulting in a significant increase of functional p53 levels that will modulate p53-mediated therapeutic effects. The overall objective of this grant application is to investigate the functions of mdm2 oncogene in tumor growth and the potential value of mdm2 as a drug target for cancer therapy. The following Specific Aims will be examined: 1). To determine the role of mdm2 in tumor growth by inhibiting mdm2 expression in in vivo models of human cancers; 2). To determine whether mdm2 inhibition activates p53 and induces apoptosis and whether these effects result in tumor growth inhibition in vivo; 3). To determine whether there are in vivo synergistically therapeutic effects between mdm2 inhibition and DNA damaging agents; and 4). To determine whether mdm2 inhibition has specific effects on key host tissues that are often sites of toxicity induced by cancer chemotherapy. When these specific aims have been accomplished, it will be possible in future studies to investigate the role of mdm2 in tumor development in humans and, ultimately, determine the usefulness of mdm2 as a target for new drug design for human cancer therapy.
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