Gene therapy delivery of endostatin enhances the treatment efficacy of radiation.
OBJECTIVE
To evaluate whether sustained expression of mouse endostatin by adeno-associated virus (AAV)-mediated gene transfer can enhance the treatment efficacy of ionizing radiation.


METHODS
Mouse endostatin was cloned into recombinant AAV (rAAV) under the control of CMV beta-actin promoter. Recombinant mouse endostatin expressed via AAV gene transfer was tested for biological activity in endothelial cells. The impact of elevated serum levels of endostatin on tumor-induced angiogenesis was evaluated using an in vivo angiogenesis assay. The anti-tumor efficacy of combining rAAV-mediated endostatin delivery with radiation was evaluated in a human colorectal tumor model (HT29).


RESULTS
Recombinant mouse endostatin expressed through an AAV vector (rAAV-mEndo) inhibited endothelial cell proliferation (by 40-45%) and migration (by 22-33%). Intramuscular injection of rAAV-mEndo (1x10(9) i.u.) led to a sustained serum endostatin level of approximately 500 ng/ml. Compared to control animals this endostatin level was sufficient to inhibit tumor cell-induced vessel formation (37 vs. 28.5, P<0.05) and delay the growth of HT29 xenografts (time from 200 to 1,000 mm(3), 21 vs. 34.5 days, P<0.05). When combined with ionizing radiation, elevated serum endostatin levels significantly enhanced the time for tumors to grow from 200 to 1,000 mm(3) (radiation, 34 days; endostatin plus radiation, 50 days, P<0.05).


CONCLUSIONS
The delivery of endostatin via rAAV vectors may provide an effective means of enhancing the anti-tumor efficacy of radiation therapy.
Shi
Wenyin
W
Department of Pharmacology and Experimental Therapeutics, University of Florida, Gainesville, FL 32610, USA.
Teschendorf
Christian
C
Muzyczka
Nicholas
N
Siemann
Dietmar W
DW
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003094:Collagen / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D043169:Endostatins; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010446:Peptide Fragments / Q000008:administration & dosage*; D011336:Probability; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000528:radiation effects
D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen