IN-VIVO GENE-THERAPY WITH P53 OR P21 ADENOVIRUS FOR PROSTATE-CANCER

We introduced the gene for wild-type human p53 or p21, a critical down stream mediator of p53-induced growth suppression, into a p53-deficien t mouse prostate cancer cell Line using a recombinant adenoviral vecto r (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduc ed p53. Functional activity of viral-transduced p21 was demonstrated t hrough 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-depen dent kinase by approximately 65%, In vitro growth assays revealed sign ificantly higher growth suppression after Ad5CMV-p21 infection compare d to Ad5CMV-p53. In vivo studies in syngeneic male mice with establish ed s,c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that recei ved intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53, In addi tion, the survival of host animals bearing tumors that were infected w ith Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent f or prostate cancer,