Differential Sensitivity of p53(-) and p53(+) Cells to Caffeine-induced Radiosensitization and Override of G2 Delay

摘要: Most drug discovery efforts have focused on finding new DNA-damaging agents to kill tumor cells preferentially. An alternative approach is find ways increase tumor-specific killing by modifying responses that damage. In this report, we ask whether lacking the G1-S arrest in response X-rays are more sensitive X-ray damage when treated with override G2-M arrest. Mouse embryonic fibroblasts genetically matched be (+) or (-) p53 and rat for wild-type function were irradiated without caffeine, a known checkpoint inhibitor. At low doses (500 µm), caffeine caused selective radiosensitization p53(-) cells. dose (where no effect was seen p53(+) cells), showed 50% reduction size of higher (2 mm caffeine), where sensitization both cells, pronounced The greater caffeine-induced suggests p53, already shown control checkpoint, may also influence aspects These data indicate an opportunity therapeutic gain combining compounds disrupt tumors functional p53.