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Gene transfer of wild-type p53 results in restoration of tumor-suppressor function in a medulloblastoma cell line

From the Department of Neurology and the Cotzias Laboratory of Neuro-Oncology (Drs. Rosenfeld and Dalmau, and P. Meneses) and the Department of Pathology (Drs. Drobnjak and Cordon-Cardo), Memorial Sloan-Kettering Cancer Center, and the Laboratory of Neurobiology and Behavior (Dr. Kaplitt), The Rockefeller University, New York, NY.
Supported in part by NIH grant 1 K08 NS 01625-01 (M.R.R.), ACS grant 94-18 (J.D.), and NCI grants CA-47538 and CA-47179 (C.C.-C.).
Presented in part at the annual meeting of the American Academy of Neurology, Washington, DC, May 1994.
Received November 11, 1994. Accepted in final form January 9, 1995.
Address correspondence and reprint requests to Dr. Myrna R. Rosenfeld, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

The replacement of functional genes into cells that lack genes or have mutant genes is the basis of gene therapy.In cancer, where cells often have multiple genetic defects, the replacement of critical genes may suffice to suppress cell growth or induce cell death. The high frequency of mutations of the p53 tumor-suppressor gene in human cancers, including primary brain tumors, suggests that p53 plays a critical role in carcinogenesis and tumor progression. We report the successful transfer of the wild-type p53 gene using a defective herpes simplex viral vector into a human medulloblastoma cell line containing a mutant copy of p53. Upon gene transfer, we detected novel expression of wild-type p53 protein in the cells. In addition, the p53 protein was functionally active, since gene transfer resulted in increased levels of mdm2 proteins and induced cell cycle arrest of the majority of transduced cells. To our knowledge, this is the first report of the use of this vector system to carry wild-type p53. We conclude that defective herpes simplex viral vectors can transfer and express p53 in human primary brain tumor cells in vitro, restoring wild-type p53 tumor-suppressor functions.

NEUROLOGY 1995;45: 1533-1539

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