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Scott Department of Urology [J. A. E., S. J. H., I. S., J. W., T. L. T., G. Y., T. C. T.], Verna and Marrs McLean Department of Biochemistry [L. C-C., S. J. E., J. W. H.], Howard Hughes Medical Institute [S. J. E.], and Departments of Human and Molecular Genetics [S. J. E.], Cell Biology [T. C. T.], and Radiology [T. C. T.], Baylor College of Medicine, Houston, Texas 77030, and Gene Therapy Unit, Baxter Healthcare Corporation, Round Lake, Illinois 60073 [W-W. Z.]
We introduced the gene for wild-type human p53 or p21, a critical downstream mediator of p53-induced growth suppression, into a p53-deficient mouse prostate cancer cell line using a recombinant adenoviral vector (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduced p53. Functional activity of viral-transduced p21 was demonstrated through immunoprecipitation of cellular protein extracts, which showed that the viral-transduced p21 associates with cyclin-dependent kinase 2 and was sufficient to down-regulate the activity of the cyclin-dependent kinase by approximately 65%. In vitro growth assays revealed significantly higher growth suppression after Ad5CMV-p21 infection compared to Ad5CMV-p53. In vivo studies in syngeneic male mice with established s.c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that received intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53. In addition, the survival of host animals bearing tumors that were infected with Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent for prostate cancer.
1 Supported by NIH Grants SPORE P50-CA58204 and CA50588 and grants from the CaP Cure Foundation (to T. C. T.), the National Kidney Foundation (to J. A. E.), and the Welch Foundation (to J. W. H).
2 To whom requests for reprints should be addressed, at 6560 Fannin, Suite 1004, Houston, TX 77030. Phone: (713) 799-8718; Fax: (713) 799-8712; E-mail: timothyt@bcm.tmc.edu.
Received 7/17/95. Accepted 9/26/95.
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