Gene therapy delivery of endostatin enhances the treatment efficacy of radiation.

Abstract

BACKGROUND AND PURPOSE:

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

MATERIALS AND 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).

CONCLUSION:

The delivery of endostatin via rAAV vectors may provide an effective means of enhancing the anti-tumor efficacy of radiation therapy.

• Authors: Wenyin Shi, Christian Teschendorf, Nicholas Muzyczka, Dietmar W Siemann
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 66 Issue 1 Pg. 1-9 (Jan 2003) ISSN: 0167-8140 [Print] Ireland
• PMID: 12559515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Endostatins
• Peptide Fragments
• Collagen

Topics

• Animals
• Cell Division (physiology)
• Cell Movement (physiology)
• Collagen (administration & dosage)
• Colorectal Neoplasms (blood supply, radiotherapy)
• Combined Modality Therapy
• Endostatins
• Endothelium, Vascular (pathology, physiology)
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Mice
• Models, Genetic
• Neovascularization, Pathologic (prevention & control)
• Peptide Fragments (administration & dosage)
• Probability
• Sensitivity and Specificity
• Transplantation, Heterologous
• Tumor Cells, Cultured (radiation effects)