Fractionated gamma-irradiation renders tumour cells more responsive to apoptotic signals through CD95

Signals through the CD95 surface receptor can specifically induce apoptosis . Some tumour cell lines are sensitive to CD95 signals, and insensitive cel ls can be converted to a sensitive phenotype if given appropriate treatment . To determine whether the apoptotic response of tumour cells to signalling through CD95 might be enhanced by ionizing irradiation, carcinoma cells we re treated with either single-dose or fractionated gamma-irradiation. The r esponse to treatment with an agonist anti-CD95 antibody was enhanced by pre treatment with either a single large dose or daily fractionated radiation. Fractionated irradiation induced cumulative and prolonged up-regulation of CD95 expression in cell lines bearing functional p53. Since two of four cel l lines exhibiting heightened responsiveness to CD95-mediated signals follo wing fractionated irradiation express mutant p53 and displayed little or no up-regulation of CD95, enhanced responsiveness did not correlate with p53 status and CD95 up-regulation. Continuous inhibition of CD95/CD95-ligand in teractions during fractionated irradiation provided no protective effect to cells, arguing that autologous CD95/CD95-ligand interactions did not contr ibute to the direct lethal effect of irradiation. We conclude that fraction ated gamma-irradiation provides an extended period of time when carcinoma c ells are more responsive to CD95-mediated signals in vitro.