DIFFERENTIAL SENSITIVITY OF P53(-) AND P53(-INDUCED RADIOSENSITIZATION AND OVERRIDE OF G(2) DELAY() CELLS TO CAFFEINE)

Most drug discovery efforts have focused on finding new DNA-damaging a gents to kill tumor cells preferentially. An alternative approach is t o find ways to increase tumor-specific killing by modifying tumor-spec ific responses to that damage. In this report, we ask whether cells la cking the G(1)-S arrest in response to X-rays are more sensitive to X- ray damage when treated with agents that override G(2)-M arrest. Mouse embryonic fibroblasts genetically matched to be (+) or (-) p53 and ra t embryonic fibroblasts (+) or (-) for wild-type p53 function were irr adiated with and without caffeine, a known checkpoint inhibitor. At lo w doses (500 phr), caffeine caused selective radiosensitization in the p53((-)) cells. At this low dose (where no effect was seen in p53((+) ) cells), the p53((-)) cells showed a 50% reduction in the size of the G(2)-M arrest. At higher doses (2 mM caffeine), where sensitization w as seen in both p53((+)) and p53((-)) cells, the radiosensitization an d the G(2)-M override were more pronounced in the p53((-)) cells, The greater caffeine-induced radiosensitization in p53((-)) . cells sugges ts that p53, already shown to control the G(1)-S checkpoint, may also influence aspects of G(2)-M arrest. These data indicate an opportunity for therapeutic gain by combining DNA-damaging agents with compounds that disrupt G(2)-M arrest in tumors lacking functional p53.