Adeno-Associated Viral Vector-Mediated Expression of Endostatin Inhibits Tumor Growth and Metastasis in an Orthotropic Pancreatic Cancer Model in Hamsters

Abstract

We examined the feasibility of using adeno-associated virus (AAV)-mediated systemic delivery of endostatin in gene therapy to treat metastasis of pancreatic cancer. We established an animal model of orthotopic metastatic pancreatic cancer in which the pancreatic cancer cell line PGHAM-1 was inoculated into the pancreas of Syrian golden hamsters. Transplanted cells proliferated rapidly and metastasized to the liver. An AAV vector expressing endostatin (5 ؋ 10 10 particles) was injected intramuscularly into the left quadriceps or intravenously into the portal vein. These routes of vector administration were evaluated by comparing various parameters of tumor development. Intramuscular injection of the vector modestly increased the serum endostatin level. The numbers of metastases and the incidence of hemorrhagic ascites were decreased in the treated animals. In contrast, the serum concentration of endostatin was significantly increased after intraportal injection of the vector. The antitumor effects on all parameters (including the size and microvessel density of primary pancreatic tumors, the sizes and number of liver metastases, and the incidence of hemorrhagic ascites) were significant. These results suggest that systemic delivery of endostatin represents a potentially effective treatment for pancreatic cancer and liver metastases. The route of vector administration influences the efficacy of AAV-mediated endostatin expression. Intraportal injection of the AAV vector appears to be more effective as an antiangiogenic gene therapy for pancreatic cancer.

Endostatin therapy reveals a U-shaped curve for antitumor activity

“…Furthermore, the inhibition of tumor growth was possible using AAV-based vectors expressing appropriate levels of endostatin. [30][31][32][33][34] Initially, we set out to treat spontaneous tumors in canines using AAV-mediated canine FcEndostatin (cFcES). Canines develop spontaneous tumors and serve as a suitable model for human cancer.…”

Adeno-Associated Virus–Mediated Antiangiogenic Gene Therapy with Thrombospondin-1 Type 1 Repeats and Endostatin

“…AAVs are nonpathogenic vectors with a limited host immune response and have been used in humans with no adverse effects (28). AAV-expressing endostatin has been used in several preclinical cancer models showing long-term endostatin expression and significant protective effects against tumor growth (26,29,30).…”

Persistent anti-tumor effects via recombinant adeno-associated virus encoding herpes thymidine kinase gene monitored by PET-imaging

“…eventually, long-term in vivo models employing rAAV2-sc39tK could be developed to address the possibility of therapeutic efficacy for metastatic tumors. The anti-metastasis efficacy achieved by rAAV vectors encoding other antiangiogenic transgenes, such as tImp1 (31), endostatin (32)(33)(34), VeGFR antibody, and vasostatin has already been shown in past experiments (35). thus, future studies investigating rAAV2-sc39tK in long-term in vivo models would be the next important step to support both the anti-tumor and anti-metastatic effects of sc39tK/GCV therapy.…”