Transcription-controlled gene therapy against tumor angiogenesis.
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-alpha. 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.
Greenberger
Shoshana
S
Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, Israel.
Shaish
Aviv
A
Varda-Bloom
Nira
N
Levanon
Keren
K
Breitbart
Eyal
E
Goldberg
Iris
I
Barshack
Iris
I
Hodish
Israel
I
Yaacov
Niva
N
Bangio
Livnat
L
Goncharov
Tanya
T
Wallach
David
D
Harats
Dror
D
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002417:Cattle; D042783:Endothelial Cells / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009369:Neoplasms / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor