Loss of p53 tumor suppressor gene function occurs in a majority of human cancers. Inactivation of p53 may be a crucial step in tumor development. Certain tumors and tumor cell lines contain an amplified MDM2 gene. MDM2 protein binds p53 protein in vitro and in vivo and can block the transactivation and growth suppressive functions of p53. Therefore, in tumors overexpressing MDM2, p53 activity presumably is lost by interaction with MDM2. Since wild-type p53 often is found in tumors or cell lines overexpressing MDM2, treatment of these tumors with an agent that disrupts the p53-MDM2 complex could restore normal levels of functional p53, leading to the inhibition of tumor growth.A domain of MDM2 that interacts with p53 has been identified and preliminary results indicate that this isolated domain binds both RNA and DNA random sequence oligonucleotides. The proposal is to use a random oligonucleotide selection strategy to identify specific RNA and DNA sequences or motifs that will bind MDM2 protein and block its interaction with p53 protein. Selected sequences will be analyzed to determine an appropriate sequence with minimal size for full activity. Ultimately, these oligonucleotides will be chemically modified to develop pharmacologically-suitable drug candidates.
