TY - JOUR
T1 - Adenoviral vector-mediated mRTVP-1 gene therapy for prostate cancer
AU - Satoh, Takefumi
AU - Timme, Terry L.
AU - Saika, Takashi
AU - Ebara, Shin
AU - Yang, Guang
AU - Wang, Jianxiang
AU - Ren, Chengzhen
AU - Kusaka, Nobuyuki
AU - Mouraviev, Vladimir
AU - Thompson, Timothy C.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2003/1
Y1 - 2003/1
N2 - 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 Adβgal-injected tumors at two time points after injection with two different vector doses (p ≤ 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p ≤ 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 Adβgal, 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 Adβgal 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.
AB - 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 Adβgal-injected tumors at two time points after injection with two different vector doses (p ≤ 0.01 at 7 and 14 days). Spontaneous metastasis to lung was also significantly reduced (p ≤ 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 Adβgal, 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 Adβgal 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.
UR - http://www.scopus.com/inward/record.url?scp=0037260825&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037260825&partnerID=8YFLogxK
U2 - 10.1089/104303403321070793
DO - 10.1089/104303403321070793
M3 - Article
C2 - 12614561
AN - SCOPUS:0037260825
SN - 1043-0342
VL - 14
SP - 91
EP - 101
JO - Human gene therapy
JF - Human gene therapy
IS - 2
ER -