Combination of PTEN gene therapy and radiation inhibits the growth of human prostate cancer xenografts.
The resistance of prostate cancers to radiation therapy has been linked to abnormalities in overexpression of Bcl-2, an oncogene associated with inhibition of apoptosis. In this study, we evaluated whether the combination of the overexpression of phosphatase and tensin homolog (PTEN), a protein known to inhibit Bcl-2 expression, and radiation therapy would inhibit proliferation of Bcl-2-expressing human prostate cancer cells inoculated into the subcutis of athymic mice. Compared with either treatment alone, the combination of adenoviral vector-expressed PTEN (AdPTEN) and radiation (5 Gy) significantly inhibited xenograft tumor growth. Median tumor size on day 48 was 1030 mm3 in untreated controls, 656 mm3 in mice treated with radiation (5 Gy) alone, 640 mm3 in mice treated with AdPTEN alone, and 253 mm3 in mice treated with the combination (p<0.001). Treatment was well tolerated in all cases. Combination treatment also enhanced apoptosis (p=0.048), inhibited cellular proliferation (p=0.005), and inhibited tumor-induced neovascularity (p=0.030). Interestingly, this treatment increased apoptosis not only in tumor cells but also in tumor-associated endothelial cells. Together, these findings indicate that AdPTEN strongly inhibits the growth of human prostate tumors, especially when combined with radiation therapy, and that this effect is mediated by the induction of apoptosis and by the inhibition of angiogenesis and cellular proliferation.
Anai
Satoshi
S
Department of Urology, University of Florida, Gainesville 32610, USA.
Goodison
Steve
S
Shiverick
Kathleen
K
Iczkowski
Kenneth
K
Tanaka
Motoyoshi
M
Rosser
Charles J
CJ
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000502:physiology / Q000528:radiation effects; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000532:radiotherapy / Q000628:therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D019253:Proto-Oncogene Proteins c-bcl-2; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human