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Restoring p53-dependent tumor suppression Wang W; Rastinejad F; El-Deiry WSCancer Biol Ther 2003[Jul]; 2 (4 Suppl 1): S55-63p53 represents an ideal target for anti-cancer drug design, because p53 is mutated in more than half of human tumors. Most of the remaining tumors, although carrying wild-type p53, have defects in the p53-mediated apoptotic pathway. Activation of p53 activity by either chemotherapy or radiotherapy induces p53-dependent apoptosis in tumor cells with wild-type p53. Supplying exogenous wild-type p53 in cancer cells by gene delivery is effective in suppressing tumor growth of both mutant and wild-type p53-containing tumors. Blockage of p53 degradation pathways either by overexpression of ARF or interruption of MDM2:p53 interaction is effective in inducing p53 triggered tumor cell death. Since unlike most other tumor suppressor genes, mutant p53 is over expressed in tumor cells, a promising approach involves restoring tumor-suppressing function to mutant p53. The activity of the mutant p53 in tumor cells is restorable based on the fact that PAb241 antibody against the carboxy-terminus of p53 and peptides corresponding to the p53 carboxy-terminus can restore specific DNA-binding ability to some mutant p53 proteins. High throughout screening of chemical libraries has led to the identification of a group of small synthetic molecules such as CP-31398, which can restore p53 function to mutant p53 by stabilizing the active conformation of the protein that is destabilized in many mutants. Subsequent identification of PRIMA-1 provides further evidence to the possibility of developing anti-cancer drugs that may rescue mutant p53. Further understanding of the mechanisms by which CP-31398 and PRIMA-1 restore p53 activity may not only lead to discovery of more potent analogs but may also suggest new strategies for p53-targeting in tumor therapy.|Antineoplastic Agents/pharmacology[MESH]|Aza Compounds/pharmacology[MESH]|Bridged Bicyclo Compounds, Heterocyclic/pharmacology[MESH]|Genes, Tumor Suppressor[MESH]|Genes, p53[MESH]|Humans[MESH]|Models, Biological[MESH]|Models, Chemical[MESH]|Mutation[MESH]|Neoplasms/*genetics/*therapy[MESH]|Peptides/chemistry[MESH]|Protein Conformation[MESH]|Pyrimidines/pharmacology[MESH]|Transcription, Genetic[MESH]|Tumor Suppressor Protein p53/*metabolism[MESH] |
