Adenovirus-mediated transfer of P53 augments hyperthermia-induced apoptosis in U251 glioma cells

Purpose: Hyperthermia kills glioma cells by inducing apoptosis and is there by an effective therapeutic modality for the treatment of malignant gliomas . However, cells harboring mutated p53 are refractory to hyperthermia-induc ed apoptosis. In this study, we assessed whether or not adenovirus (Adv)-me diated transduction of p53 overrides this resistant mechanism. Methods and Materials: We transduced the p53 wild-type tumor suppressor gen e into U251 glioma cells harboring mutated p53 using Adv vectors in combina tion with hyperthermia (43, 44.5 degreesC), and evaluated the degree of cel l death and apoptosis. Results: The percentage of cells that had died, as measured by trypan blue staining, among U251 cells infected with the Adv for p53 (Adv-p53) and trea ted with hyperthermia, was significantly higher than the percentage of cell s that had died among U251 cells infected with Adv-p53 and not treated with hyperthermia, or those infected with the control Adv for dE (Adv-dE) and t reated,vith hyperthermia. The degree of apoptosis, measured at 24 h after t reatment, in hyperthermia-treated U251 cells infected with Adv-p53 (43 degr eesC, 73%; 44.5 degreesC, 92%) was much higher than that infected with Adv- p53 (41%), or that infected with control Adv-dE and treated with hypertherm ia (43 degreesC, 1.3%; 44.5 degreesC, 19%). Treatment with combined hyperth ermia and Adv-p53 infection induced cleavage of caspase-3 in U251 cells. Conclusion: These results indicate that Adv-mediated transduction of p53 wo uld render glioma cells highly sensitive to hyperthermia. (C) 2001 Elsevier Science Inc.