SELECTIVE RADIOSENSITIZATION OF P53-DEFICIENT CELLS BY CAFFEINE-MEDIATED ACTIVATION OF P34(CDC2) KINASE

The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because th e p53 tumor suppressor gene is a critical component for induction of a poptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both t he G(1)/S and G(2)/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arre st at the G(1) checkpoint is mediated by p53-dependent induction of p2 1(WAF1/CIP1), whereas the G(2) arrest involves inactivation of p34(cdc 2) kinase. following DNA damage, p53-deficient cells fail to arrest at G(1) and accumulate at the G(2)/M transition. We demonstrate that abr ogation of G(2) arrest by caffeine-mediated activation of p34(cdc2) ki nase results in the selective sensitization of p53-deficient primary a nd tumor cells to irradiation-induced apoptosis. These data suggest th at pharmacologic activation of p34(cdc2) kinase may be a useful therap eutic strategy for circumventing the resistance of p53-deficient cance rs to genotoxic anticancer agents.