Molecular therapy with recombinant p53 adenovirus in an androgen-independent, metastatic human prostate cancer model.
The lethal phenotypes of advanced prostate cancer are androgen independent (AI) and metastatic to the axial skeleton. Our laboratory has developed an AI mouse model of metastatic human prostate cancer. In this communication, we report the development of tumor suppressor gene therapy in this AI and metastatic (C4-2) cancer model. By using recombinant adenovirus as a delivery vehicle, we introduced a wild-type p53 tumor suppressor gene into prostate cancer cell lines. Despite a silent mutation at codon 152 of the p53 gene, C4-2 cells express functional, but low, levels of p53 protein. However, the other prostatic cell lines, PC-3 and DU145, have a deletion mutation and two point mutations of the p53 gene, respectively. In vitro studies showed that cell growth, as measured by the thymidine incorporation assay, was inhibited in the C4-2, PC-3, and DU145 cells infected with wild-type p53 adenovirus in comparison to control viruses. Recombinant wild-type p53 adenovirus inhibited prostate tumor growth and its production of prostate-specific antigen (PSA) when injected into C4-2 tumors in nude mice. All p53-treated mice were tumor free as long as 12 weeks after cessation of the 8-week treatment regimen. Two of 8 p53-treated mice developed small tumors growing at distant sites after a prolonged period of follow-up observation. Moreover, other AI prostate cancer cells, PC-3 and DU145, treated with Ad5-CMV-p53 failed to develop into tumors in vivo. This gene therapy strategy may be used against AI prostatic cancer regardless of p53 gene mutation status.
Ko
S C
SC
Urology Research Laboratory, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Gotoh
A
A
Thalmann
G N
GN
Zhau
H E
HE
Johnston
D A
DA
Zhang
W W
WW
Kao
C
C
Chung
L W
LW
D000260:Adenoviruses, Human / Q000235:genetics*; D000728:Androgens / Q000502:physiology; D000818:Animals; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D016158:Genes, p53 / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D000728:Androgens; D016159:Tumor Suppressor Protein p53; D017430:Prostate-Specific Antigen