GENE-TRANSFER OF WILD-TYPE P53 RESULTS IN RESTORATION OF TUMOR-SUPPRESSOR FUNCTION IN A MEDULLOBLASTOMA CELL-LINE

The replacement of functional genes into cells that lack genes or have mutant genes is the basis of gene therapy. In cancer, where cells oft en have multiple genetic defects, the replacement of critical genes ma y suffice to suppress cell growth or induce cell death. The high frequ ency of mutations of the p53 tumor-suppressor gene in human cancers, i ncluding primary brain tumors, suggests that p53 plays a critical role in carcinogenesis and tumor progression. We report the successful tra nsfer of the wild-type p53 gene using a defective herpes simplex viral vector into a human medulloblastoma cell line containing a mutant cop y of p53. Upon gene transfer, we detected novel expression of wild-typ e p53 protein in the cells. In addition, the p53 protein was functiona lly active, since gene transfer resulted in increased levels of mdm2 p roteins and induced cell cycle arrest of the majority of transduced ce lls. To our knowledge, this is the first report of the use of this vec tor system to carry wild-type p53. We conclude that defective herpes s implex viral vectors can transfer and express p53 in human primary bra in tumor cells in vitro, restoring wild-type p53 tumor-suppressor func tions.