Therapeutic exploitation of checkpoint defects in cancer cells lacking p53 function.
Cytotoxic agents form the basis of most cancer therapies. These agents primarily affect rapidly proliferating cells, so their use incurs morbidity associated with damage to tissues such as bone marrow and gastrointestinal mucosa. Clinical outcome would be improved if it were possible to develop therapeutics with more specific activity against p53-deficient cancers, which account for over 50% of all cases. p53 deficiency alters the cellular response to DNA damage in that it leaves cells with attenuated DNA damage checkpoint controls and a reduced propensity for apoptotic cell death. Thus, the DNA repair capacity of these cells is reduced but survival is increased. This promotes genomic instability and contributes to the resistance of p53-deficient cells to cytotoxic agents. Disabling the residual G(2) checkpoint function of p53-deficient cells may favour cell death following DNA damage. Several potential strategies for G(2) checkpoint abrogation show promise for the specific sensitization of cancer cells. Here we detail how the G(2) DNA damage checkpoint is influenced by p53 status and how the loss of p53 function in cancer cells can be exploited to enhance the cytotoxicity of anti-cancer agents.
Dixon
Helen
H
Cancer Research UK Molecular Oncology Laboratory, University of Oxford Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford UK.
Norbury
Chris J
CJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics*; D000071877:Checkpoint Kinase 1; D003603:Cytotoxins / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D015195:Drug Design; D016195:G2 Phase / Q000187:drug effects / Q000235:genetics; D018816:Genes, cdc / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000628:therapy; D011494:Protein Kinases / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D000970:Antineoplastic Agents; D003603:Cytotoxins; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1