Enhanced radiosensitivity of malignant glioma cells after adenoviral p53 transduction

Object. The goal of this study was to determine whether adenoviral vector-m ediated expression of human wildtype p53 can enhance the radiosensitivity o f malignant glioma cells that express native wild-type p53. The p53 gene is thought to function abnormally in the majority of malignant gliomas, although it has been demonstrated to be mutated in only approxima tely 30%. This has led to studies in which adenoviral transduction with wil dtype human p53 has been investigated in an attempt to slow tumor cell grow th. Recent studies suggest that reconstitution of wild-type p53 can render cells more susceptible to radiation-mediated death, primarily by p53-mediat ed apoptosis. Methods. Rat RT2 glioma cells were analyzed for native p53 status by revers e transcriptase-polymerase chain reaction and sequence analysis and for p53 expression by Western blot analysis. Clonogenic survival and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end la beling assay were used to characterize RT2 cell radiosensitivity and apopto sis, respectively, with and without prior transduction with p53-containing and control adenoviral vectors. Animal survival length was monitored after intracerebral implantation with transduced and nontransduced RT2 cells, wit h and without cranial radiation. The RT2 cells were demonstrated to express native rat wild-type p53 and to markedly overexpress human p53 following adenoviral p53 transduction. The c ombination of p53 transduction followed by radiation resulted in marked dec reases in RT2 cell survival and increases in apoptosis at radiation doses f rom 2 to 6 Gy. Animals receiving cranial radiation after intracerebral impl antation with RT2 cells previously transduced with p53 survived significant ly longer than control animals (p < 0.01). Conclusions. The ability to enhance the radiosensitivity of malignant gliom a cells that express wild-type p53 by using adenoviral transduction to indu ce overexpression of p53 offers hope for this approach as a therapeutic str ategy, not only in human gliomas that express mutant p53, but also in those that express wild-type p53.