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 downstream mediator of p53-induced growth suppression, into a p53-deficient mouse prostate cancer cell line using a recombinant adenoviral vector (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduced p53. Functional activity of viral-transduced p21 was demonstrated through 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-dependent kinase by approximately 65%. In vitro growth assays revealed significantly higher growth suppression after Ad5CMV-p21 infection compared to Ad5CMV-p53. In vivo studies in syngeneic male mice with established s.c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that received intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53. In addition, the survival of host animals bearing tumors that were infected with Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent for prostate cancer.
Eastham
J A
JA
Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030, USA.
Hall
S J
SJ
Sehgal
I
I
Wang
J
J
Timme
T L
TL
Yang
G
G
Connell-Crowley
L
L
Elledge
S J
SJ
Zhang
W W
WW
Harper
J W
JW
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D047428:Protein Kinase Inhibitors; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047428:Protein Kinase Inhibitors