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Laboratory of Biological Chemistry [C. Y., A. P.] and Gene Therapy Unit, Laboratory of Cardiovascular Science [C. C., M. C. C.], Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, and Laboratorio di Patologia Vascolare, Instituto Dermopatico Dell'Immacolata, 00167 Roma, Italy [C. C.]
The use of replication-deficient adenoviral vectors in gene therapy may become a powerful method to achieve efficient but safe transfer of antitumor agents. Introduction of the wild-type p53 gene into tumor cells has, in general, been associated with growth suppression. In this study, infection of androgen-independent human prostate Tsu-pr1 cells lacking functional p53 alleles resulted in high levels of p53 protein within 10–15 h. Cells infected with AdCMV.p53 detached from the substratum, condensed, and exhibited fragmentation of nuclear DNA into nucleosomal units consistent with the process of apoptosis. These effects were evident within 24 h after infection, and the majority of cells had undergone apoptosis by 48 h, whereas cells infected with AdCMV.NLSßGal continued to proliferate. Uninfected or AdCMV.NLSßGal-infected Tsu-pr1 cells formed tumors in nude mice within 3 weeks after implantation, whereas AdCMV.p53-infected cells failed to form tumors during this period. Therefore, adenoviral-mediated antitumor therapy using the p53 gene is an efficient method to inhibit prostate tumor growth, and agents that target the cellular programmed cell death pathway may be useful in clinical applications.
1 To whom requests for reprints should be addressed, at Laboratory of Biological Chemistry, National Institute on Aging, Gerontology Research Center, 4940 Eastern Avenue, Baltimore, MD 21224.
Received 6/19/95. Accepted 7/24/95.
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