Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence

Abstract

It is estimated that there will be >184,500 new cases of prostate cancer and 42,000 prostate cancer deaths in the United States this year. In the majority of patients diagnosed with prostate cancer, the disease will be too advanced for cure with standard medical treatment. New therapeutic strategies against advanced prostate cancer are desperately needed. As alterations in tumor-suppressor gene p16 are common in prostate cancer, one novel approach is gene therapy using a replication-deficient, E1/E3-deleted adenovirus type 5 containing a p16 under the control of a truncated Rous sarcoma virus promoter (AdRSVp16). In vitro, PC-3 cells that had been stably transfected with p16 expression vector under the control of an inducible promoter had a 70% reduction in cell number compared with the parental and control vector-transfected PC-3 cells. Similarly, AdRSVp16 significantly inhibited the growth of PPC-1 and PC-3 prostate cancer cells in culture. Furthermore, PPC-1 tumors grown in nude mice treated by a single injection of AdRSVp16 had a marked reduction in tumor size compared with untreated control-treated or viral control-treated PPC-1 tumors. Animals bearing tumors treated with AdRSVp16 also had longer survival. Adenovirally mediated expression of transgene was detected in xenograft tumors for at least 2 weeks. Taken together, these results suggest that AdRSVp16 should be considered for prostate cancer gene therapy in human clinical trials.