Oligonucleotides that Block p53 and mdm2 Interaction

Loss of p53 tumor suppressor gene function occurs in a majority of human cancers. Inactivationof p53 may be a crucial step in tumor development. Certain tumors and tumor cell lines contain anamplified MDM2 gene. MDM2 protein binds p53 protein in vitro and in vivo and can block thetransactivation 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 tumorsor cell lines overexpressing MDM2, treatment of these tumors with an agent that disrupts thep53-MDM2 complex could restore normal levels of functional p53, leading to the inhibition of tumorgrowth. A domain of MDM2 that interacts with p53 has been identified and preliminary results indicatethat this isolated domain binds both RNA and DNA random sequence oligonucleotides. The research isto use a random oligonucleotide selection strategy to identify specific RNA and DNA sequences or motifsthat will bind MDM2 protein and block its interaction with p53 protein. Selected sequences will beanalyzed to determine an appropriate sequence with minimal size for full activity. Ultimately, theseoligonucleotides will be chemically modified to develop pharmacologically-suitable drug candidates.