Judd W. Moul

Recombinant adenovirus vector expressing wildtype p53 is a potent inhibitor of prostate cancer cell proliferation

OBJECTIVES A recombinant adenovirus vector (AdWTp53) expressing wild-type p53 was evaluated for its cell growth inhibitory effects on metastatic human prostate cancer cells. METHODS Human prostate cancer cells LNCaP, DU145, PC3, 1LN, and DUPro-1 were infected with AdWTp53 vector and expression of exogenous p53 in these cells was analyzed by immunoprecipitation and western blot assays. The cell growth inhibitory effects of AdWTp53 were determined by counting cell number on a hemocytometer or by crystal violet staining of cells after infection with AdWTp53. The p53-regulated gene WAF1 and DNA fragmentation were also analyzed in prostate cancer cells infected with AdWTp53. RESULTS High levels of the AdWTp53 vector-derived p53 protein were present in metastatic prostate cancer cells, and the p53-regulated gene WAF1 was induced in these cells. Infection of these tumor cell lines with AdWTp53 vector resulted in severe growth inhibition and cell death in comparison to untreated or control adenovirus vector-infected cells. Furthermore, fragmentation of genomic DNA, a property associated with apoptosis, was also observed in prostate cancer cells infected with AdWTp53. CONCLUSIONS AdWTp53 vector exhibited a potent inhibitory effect on the growth of all of human metastatic prostate cancer cells, and both cytostatic and cytotoxic effects of AdWTp53 were observed. The induction of p53-regulated gene WAF1 in AdWTp53-infected prostate cancer cells suggests the involvement of cellular p53 pathway in the cell growth inhibition. These results provide a molecular basis for further evaluation of antitumorigenic effects of AdWTp53 vector in animal models of prostate cancer.

Molecular Genetics and Markers of Progression

Prostate cancer (CaP) is the most common solid tumor in American males (1). The wide spectrum of biological behavior (2) exhibited by prostatic neoplasms poses the difficulty of predicting the clinical course in the individual patient (3,4). Because of increasing public awareness and screening efforts, the enhanced incidence has translated into a large increase in the use of radical prostatectomy as well as four other treatment modalities for localized disease (5). With this incremental rise in surgical intervention has come the frustrating realization of the inability to predict organ-confined disease and clinical outcome for a given patient (5, 6). Traditional markers, such as grade, clinical stage, and pretreatment prostate-specific antigen (PSA), are of limited prognostic value for individual men. There is clearly a need to recognize and develop molecular and genetic biomarkers to improve prognostication and the management of the patient with clinically localized CaP. As with other common human neoplasia (7), the search for molecular genetic markers to better define the genesis and progression of CaP, is the key focus for cancer research investigations worldwide.