ADENOVIRUS-MEDIATED P53 GENE-TRANSFER SUPPRESSES GROWTH OF HUMAN GLIOBLASTOMA CELLS IN-VITRO AND IN-VIVO

Alterations in the p53 tumor-suppressor gene occur in 35-60% of human glioblastomas, and re-introduction of p53 can suppress neoplastic grow th. To evaluate the potential for p53 gene therapy of glioblastoma, we have analyzed the response of human glioblastoma cell lines in vitro and in vivo to experimental therapy with replication-deficient recombi nant adenoviruses encoding wild-type p53 (rAd-p53). Western blot analy ses showed high-level expression of p53 protein after treatment with r Ad-p53, and transgene expression was dependent on promoter strength. A p53-specific dose-dependent inhibition of in vitro cellular prolifera tion was observed in 5 of 6 cell lines, and growth inhibition correspo nded to adenovirus-mediated gene transfer and expression. p53-specific cell death was quantitated by release of the lactate dehydrogenase en zyme. Fragmentation of DNA into nucleosomal oligomers and the occurren ce of a hypodiploid cell population detected by flow cytometry provide d evidence for apoptosis. Studies in nude mice demonstrated that ex vi vo infection with rAd-p53 suppressed the tumorigenic potential of huma n glioblastoma cells. Furthermore, direct injection of rAd-p53 into es tablished s.c. xenografts inhibited tumor growth. Our observations sug gest that re-introduction of wild-type p53 may have potential clinical utility for gene therapy of glioblastoma.