Systemic administration of a conditionally replicating adenovirus, targeted to angiogenesis, reduced lung metastases burden in cotton rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Peled
Michael
M
Vascular Biogenics Ltd., Or Yehuda, Israel.
Shaish
Aviv
A
Katav
Avi
A
Greenberger
Shoshana
S
Barshack
Iris
I
Tal
Reshef
R
Bangio
Livnat
L
Breitbart
Eyal
E
Harats
Dror
D
D000256:Adenoviridae / Q000502:physiology*; D017498:Adenovirus E1 Proteins / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004261:DNA Replication; D004338:Drug Combinations; D019332:Endothelin-1 / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000821:virology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000821:virology; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy* / Q000821:virology; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D016205:Sigmodontinae; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000821:virology; D014471:Umbilical Veins / Q000166:cytology; D014779:Virus Replication / Q000502:physiology*
D017498:Adenovirus E1 Proteins; D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D019332:Endothelin-1; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen