Suppression of primary tumor growth and the progression to metastasis withp53 adenovirus in human prostate cancer

Purpose: Numerous advances have been made in gene therapy approaches for th e treatment of solid tumors, including prostate cancer. While treatment of the primary tumor has been well investigated, little information is availab le regarding gene therapy techniques which might impact on the progression to metastatic disease. We investigate the ability of p53 adenovirus to supp ress not only primary tumor growth, but also the progression to metastatic disease. Mutation of the p53 tumor suppressor gene has been associated with the progression of prostate cancer. In this study, we utilized a metastati c model for human prostate cancer to determine if introduction of the wild- type p53 gene using an adenoviral vector (rAd-p53) impacted on primary tumo r growth as well as the progression to metastatic disease. Materials and Methods: For our studies, we used the human prostate cancer c ell line PC-3, which has a homozygous loss of p53 expression. Expression of exogenous p53 as well as p21 induction at various time points after infect ion with rAd-p53 was determined in vitro. In vivo studies were performed in nude mice following orthotopic (intraprostatic) injection of PC-3 cells. P rimary tumor growth as well as the progression to metastatic disease was as sessed following rAd-p53 treatment. Results: In vitro studies demonstrated high levels of p53 gene expression a s well as the induction of p21 gene expression. Infection of PC-3 cells wit h rAd-p53 resulted in marked growth inhibition, as well as wide-spread frag mentation of nuclei and secretion of nuclear matrix proteins into the cultu re medium consistent with the process of apoptosis. In vivo studies demonst rated that a single injection of rAd-p53 into an established orthotopic pro state tumor resulted not only in primary tumor growth suppression (treated = 97.5 +/- 25,3 mm.(3) versus control = 393.4 +/- 67.2 mm.(3); p = 0.0002) but also reduced the frequency of progression to metastatic disease (treate d = 8 of 19 versus control = 18 of 19; p = 0.001). Conclusion: These experiments demonstrate that a single injection of rAd-p5 3 into an established orthotopic prostate tumor results not only in suppres sion of primary tumor growth, but also in a reduction of the frequency of p rogression to metastatic disease. These results suggest that a rAd-p53 gene therapy strategy may be useful in the treatment; of human prostate cancer.