Transcription-controlled gene therapy against tumor angiogenesis
Shoshana Greenberger, … , David Wallach, Dror Harats
Shoshana Greenberger, … , David Wallach, Dror Harats
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):1017-1024. https://doi.org/10.1172/JCI20007.
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Article Genetics

Transcription-controlled gene therapy against tumor angiogenesis

Abstract

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.

Authors

Shoshana Greenberger, Aviv Shaish, Nira Varda-Bloom, Keren Levanon, Eyal Breitbart, Iris Goldberg, Iris Barshack, Israel Hodish, Niva Yaacov, Livnat Bangio, Tanya Goncharov, David Wallach, Dror Harats

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Systemic administration of Ad-PPE-Fas-c inhibited tumor growth. (A) LLC ...
Systemic administration of Ad-PPE-Fas-c inhibited tumor growth. (A) LLC lung metastases were created in male mice. Ad-PPE-Fas-c, Ad-CMV-Fas-c, Ad-PPE-luc, or saline was injected i.v. into the tail vein. Weight due to tumor burden was calculated by subtraction of the average normal wet organ weight (200 mg) from each tumor-bearing organ. Each bar represents the mean ± SE, n = 14–16. *P < 0.05 vs. control groups. (B) Representative lung surfaces of treated versus untreated mice. (C) Tumor growth kinetics. Male C57BL/6J mice were inoculated subcutaneously on the hind flank with 7.5 × 106 B16 melanoma cells. Saline (n = 4) or Ad-PPE-Fas-c (n = 7) was injected i.v. when tumor was palpable. Tumor diameter was calculated from tumor measurements scored at the indicated postimplantation day. The growth of B16 melanoma was significantly inhibited in mice treated with Ad-PPE-Fas-c compared with control mice. (D) B16 melanoma tumor weights at the day of sacrifice. Tumor weights were lower in mice injected with Ad-PPE-Fas-c. *P < 0.05 vs. control group. (E) Prominent tumor necrosis in an Ad-PPE-Fas-c–treated mouse. Arrow: necrotic area.