Restoration of wild-type p53 function in human tumors: strategies for efficient cancer therapy.
The p53 tumor suppressor gene is mutated in around 50% of all human tumors. Most mutations inactivate p53's specific DNA binding, resulting in failure to activate transcription of p53 target genes. As a consequence, mutant p53 is unable to trigger a p53-dependent biological response, that is cell cycle arrest and apoptosis. Many tumors express high levels of nonfunctional mutant p53. Several strategies for restoration of wild-type p53 function in tumors have been designed. Wild-type p53 reconstitution by adenovirus-mediated gene transfer has shown antitumor efficacy in clinical trials. Screening of chemical libraries has allowed identification of small molecules that reactivate mutant p53 and trigger mutant p53-dependent apoptosis. These novel strategies raise hopes for more efficient cancer therapy.
Wiman
Klas G
KG
Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, SE-171 76 Stockholm, Sweden.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D004273:DNA, Neoplasm / Q000378:metabolism; D003673:Defective Viruses / Q000235:genetics; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D017921:Mastadenovirus / Q000235:genetics; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000628:therapy; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C402665:CP 31398