Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer.
We previously identified the mouse RTVP-1 (mRTVP-1; related to testes-specific, vespid, and pathogenesis proteins) gene as a direct target of p53 with proapoptotic activities in various cancer cell lines, including prostate cancer. To test the therapeutic potential of mRTVP-1 we constructed an adenoviral vector capable of efficient transduction and expression of mRTVP-1 (AdmRTVP-1) and used this vector in an orthotopic, metastatic mouse model of prostate cancer. A single intratumoral administration of AdmRTVP-1 gene therapy significantly reduced primary tumor wet weight compared with control Adbetagal-injected tumors at two time points after injection with two different vector doses (p < or = 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p < or = 0.02). Evaluation of treated tumors revealed increased apoptosis and lower microvessel density counts. In a rat aortic ring sprouting assay, AdmRTVP-1 inhibited endothelial cell sprouting compared with Adbetagal, confirming its antiangiogenic activity. These therapeutic activities were associated with a significant increase in survival from 22.9 to 26.8 days (p = 0.003) in this aggressive model of prostate cancer. Interestingly, there were significant increases in the infiltration of tumor-associated macrophages, dendritic cells, and CD8+ T cells, which persisted at 14 days posttreatment in the AdmRTVP-1-treated tumors compared with Adbetagal control-treated tumors. In addition, significantly increased natural killer and cytotoxic T lymphocyte activities were demonstrated in the mice with AdmRTVP-1-treated tumors. The unique therapeutic properties of AdmRTVP-1 gene therapy demonstrated in this study provide new opportunities for gene and immunotherapy of prostate cancer and potentially other malignancies.
Satoh
Takefumi
T
Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
Timme
Terry L
TL
Saika
Takashi
T
Ebara
Shin
S
Yang
Guang
G
Wang
Jianxiang
J
Ren
Chengzhen
C
Kusaka
Nobuyuki
N
Mouraviev
Vladimir
V
Thompson
Timothy C
TC
D000256:Adenoviridae; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051381:Rats; D014407:Tumor Cells, Cultured
C094538:GLIPR1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins