Abstract
Angiogenesis is an essential process for solid tumor development. To interfere with angiogenesis, AdPPE3x-E1, an adenovirus that is transcriptionally targeted to replicate in angiogenic endothelial cells, was constructed, by replacing the E1 promoter with the modified preproendothelin-1 promoter, PPE-1-3x, previously shown to induce specific transcription in angiogenic endothelial cells. The specificity of AdPPE3x-E1 to endothelial cells was shown by quantitative PCR and immunostaining, and its antiangiogenic effect was evaluated in Matrigel models. The in vivo efficacy of AdPPE3x-E1 was also tested in a cotton rat lung metastases model. The replication rate of AdPPE3x-E1 in endothelial cells was similar to that of AdCMV-E1, a nonselective replicating adenovector, but the replication rate was reduced up to 60-fold in nonendothelial cells. Moreover, AdPPE3x-E1 reduced endothelial cell viability by 90% whereas nonendothelial cells were not affected. In in vitro and in vivo Matrigel models, endothelial cells infected with AdPPE3x-E1 did not develop capillary-like structures. The systemic administration of AdPPE3x-E1 reduced the lung metastases burden in a cotton rat model by 55%, compared with saline-treated rats, without significant evidence of toxicity. Quantitative PCR analysis showed that the viral copy number of AdPPE3x-E1 was increased 3-fold in the lung metastases but not in the liver, compared with a nonreplicating adenovector control. We have shown here for the first time an antimetastatic effect induced by an angiogenesis-transcriptionally targeted adenovirus following systemic administration. Because adenovirus replication is more efficient in humans than in cotton rats, we assume a significant effect for AdPPE3x-E1 treatment in fighting human solid tumors and metastases.
Highlights
Angiogenesis is an essential process for solid tumor development
A solid tumor depends on the host vasculature in the primary growth phase, but soon reaches the size limit beyond which the tumor begins to suffer hypoxia, which results in the induction of angiogenesis, the formation of new blood vessels
We previously showed that a replication-deficient adenovirus vector expressing the Fas-c gene, a chimeric death receptor gene containing the extracellular portion of tumor necrosis factor 1 receptor and the transmembrane and intracellular portion of Fas, under the control of the modified murine PPE-1 (PPE3x) showed efficacy in in vivo mouse tumor models, reducing lung metastases burden by 60% when compared with saline control, without any evidence of toxicity [19]
Summary
Angiogenesis is an essential process for solid tumor development. To interfere with angiogenesis, AdPPE3x-E1, an adenovirus that is transcriptionally targeted to replicate in angiogenic endothelial cells, was constructed, by replacing the E1 promoter with the modified preproendothelin-1 promoter, PPE-1-3x, previously shown to induce specific transcription in angiogenic endothelial cells. The systemic administration of AdPPE3x-E1 reduced the lung metastases burden in a cotton rat model by 55%, compared with saline-treated rats, without significant evidence of toxicity. To evaluate whether AdPPE3x-E1 replicates in endothelial cells, HUVEC, and nonendothelial cells NSF, HepG2, and LCRT were infected with AdCMV-E1, AdPPE3xE1, or AdPPE3x-GFP at 1 MOI.
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