Anti-angiogenic gene therapy for metastatic renal cell carcinoma produces tumor growth suppression in an athymic nude mouse model.
OBJECTIVE
We investigated the anti-angiogenic and antitumor properties of 2 adenoviral vectors expressing the endostatin-angiostatin fusion protein Ad-EndoAngio and the soluble, endothelium specific tyrosine kinase receptor Ad-Tie2 in a mouse renal cell carcinoma xenograft model.


METHODS
A total of 29 bilateral subcutaneous renal cell carcinomas were induced in athymic nude mice. On days 2 and 10 following tumor establishment the mice were intratumorally injected with an adenoviral vector in the right flank only. Seven treatment groups were randomly assigned, including the control group of 7 mice, the Ad-GFP control group of 7, the Ad-Tie2 group of 9, the Ad-EndoAngio group of 8, the Ad-GFP plus Ad-Tie2 group of 7, the Ad-GFP plus Ad-EndoAngio group of 9 and the Ad-EndoAngio plus Ad-Tie2 group of 8. Tumor volume was measured biweekly for 60 days. Additionally, each treatment group was administered fluorescent rhodamine conjugated bovine serum albumin dye for vascular imaging. After establishing skin windows overlying the tumors dual photon optical imaging was used to qualitatively assess the tumor vasculature.


RESULTS
Tumors treated with Ad-EndoAngio, Ad-GFP plus Ad-EndoAngio and Ad-EndoAngio plus Ad-Tie2 demonstrated 82%, 83% and 87% growth reduction, respectively, compared to controls (p <0.001). Furthermore, in vivo imaging revealed a decrease in the number of blood vessels, lumen diameter and flow velocity in these treatment groups.


CONCLUSIONS
Adenoviral vectors expressing endostatin-angiostatin fusion protein have effective anti-angiogenic action against human renal cell carcinoma cells as well as potential as a novel treatment for metastatic renal cell carcinoma.
Mellon
Matthew J
MJ
Department of Urology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Ahn
Miwon
M
Jiménez
Juan A
JA
Kao
Chinghai
C
Gardner
Thomas A
TA
D000256:Adenoviridae; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D043165:Angiostatic Proteins / Q000627:therapeutic use*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000556:secondary / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D043165:Angiostatic Proteins