Suppression of primary tumor growth and the progression to metastasis with p53 adenovirus in human prostate cancer.
OBJECTIVE
Numerous advances have been made in gene therapy approaches for the treatment of solid tumors, including prostate cancer. While treatment of the primary tumor has been well investigated, little information is available regarding gene therapy techniques which might impact on the progression to metastatic disease. We investigate the ability of p53 adenovirus to suppress 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 metastatic model for human prostate cancer to determine if introduction of the wild-type p53 gene using an adenoviral vector (rAd-p53) impacted on primary tumor growth as well as the progression to metastatic disease.


METHODS
For our studies, we used the human prostate cancer cell 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 infection with rAd-p53 was determined in vitro. In vivo studies were performed in nude mice following orthotopic (intraprostatic) injection of PC-3 cells. Primary tumor growth as well as the progression to metastatic disease was assessed following rAd-p53 treatment.


RESULTS
In vitro studies demonstrated high levels of p53 gene expression as well as the induction of p21 gene expression. Infection of PC-3 cells with rAd-p53 resulted in marked growth inhibition, as well as wide-spread fragmentation of nuclei and secretion of nuclear matrix proteins into the culture medium consistent with the process of apoptosis. In vivo studies demonstrated that a single injection of rAd-p53 into an established orthotopic prostate 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 (treated = 8 of 19 versus control = 18 of 19; p = 0.001).


CONCLUSIONS
These experiments demonstrate that a single injection of rAd-p53 into an established orthotopic prostate tumor results not only in suppression of primary tumor growth, but also in a reduction of the frequency of progression to metastatic disease. These results suggest that a rAd-p53 gene therapy strategy may be useful in the treatment of human prostate cancer.
Eastham
J A
JA
Departments of Urology, Pathology and Biochemistry/Molecular Biology, Louisiana State University Medical Center, Shreveport 71130-3932, USA.
Grafton
W
W
Martin
C M
CM
Williams
B J
BJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D034961:Antigens, Nuclear; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D002467:Cell Nucleus / Q000648:ultrastructure; D016009:Chi-Square Distribution; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009687:Nuclear Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D014407:Tumor Cells, Cultured
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)