TY - JOUR
T1 - Transcription-controlled gene therapy against tumor angiogenesis
AU - Greenberger, Shoshana
AU - Shaish, Aviv
AU - Varda-Bloom, Nira
AU - Levanon, Keren
AU - Breitbart, Eyal
AU - Goldberg, Iris
AU - Barshack, Iris
AU - Hodish, Israel
AU - Yaacov, Niva
AU - Bangio, Livnat
AU - Goncharov, Tanya
AU - Wallach, David
AU - Harats, Dror
PY - 2004/4
Y1 - 2004/4
N2 - A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell-specific apoptosis, using adenoviral vector-mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-α. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1-based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.
AB - A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell-specific apoptosis, using adenoviral vector-mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-α. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1-based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.
UR - http://www.scopus.com/inward/record.url?scp=11144354459&partnerID=8YFLogxK
U2 - 10.1172/JCI200420007
DO - 10.1172/JCI200420007
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C2 - 15057308
AN - SCOPUS:11144354459
SN - 0021-9738
VL - 113
SP - 1017
EP - 1024
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -