Vascular endothelial growth factor antisense oligodeoxynucleotides with lipiodol in arterial embolization of liver cancer in rats

Abstract

AIM:Transcatheter arterial embolization (TAE) of the hepatic artery has been accepted as an effective treatment for unresectable hepatocellular carcinoma (HCC). However, embolized vessel recanalization and collateral circulation formation are the main factors of HCC growth and recurrence and metastasis after TAE. Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. This study was to explore the inhibitory effect of VEGF antisense oligodeoxynucleotides (ODNs) on VEGF expression in cultured Walker-256 cells and to observe the anti-tumor effect of intra-arterial infusion of antisense ODNs mixed with lipiodol on rat liver cancer. METHODS:VEGF antisense ODNs and sense ODNs were added to the media of non-serum cultured Walker-256 cells. Forty-eight hours later, VEGF concentrations of supernatants were detected by ELISA. Endothelial cell line ECV-304 cells were cultured in the supernatants. Seventy-two hours later, growth of ECV-304 cells was analyzed by MTT method. Thirty Walker-256 cell implanted rat liver tumor models were divided into 3 groups. 0.2 mL lipiodol (LP group, n=10), 3OD antisense ODNs mixed with 0.2 mL lipiodol (LP+ODNs group, n=10) and 0.2 mL normal saline (control group, n=10) were infused into the hepatic artery. Volumes of tumors were measured by MRI before and 7 d after the treatment. VEGF mRNA in cancerous and peri-cancerous tissues was detected by RT-PCR. Microvessel density (MVD) and VEGF expression were observed by immunohistochemistry.

Angiogenesis and hepatocellular carcinoma

“…VEGF antisense oligodeoxynucleotides mixed with lipiodol inhibited HCC growth in rats significantly more than arterial embolization with lipiodol alone [204]. Table 2 Angiogenesis inhibitors tested experimentally against HCC…”

Vascular Changes in Hepatocellular Carcinoma

“…Our animal model has shown that by using the combination of hepatic artery ligation with PTK787, significant inhibition of tumor growth and prolongation of animal survival could be achieved (Yang et al,2006), suggesting that addition of antiangiogenic therapy may enhance the therapeutic efficacy of chemoembolization in clinical setting. Another group also demonstrated that VEGF antisense oligodeoxynucleotides mixed with lipiodol more significantly inhibited HCC growth in rats than arterial embolization with lipiodol alone (Wu et al,2004). These pre‐clinical data suggest that it is reasonable to conduct a clinical trial to test whether combined anti‐VEGF therapy can enhance the efficacy of TACE for the treatment of HCC.…”

Oncolytic Adenovirus-Mediated E1A Gene Therapy Induces Tumor-Cell Apoptosis and Reduces Tumor Angiogenesis Leading to Inhibition of Hepatocellular Carcinoma Growth in Animal Model

“…Vascular endothelial growth factor (VEGF) and CD34 both are the important regulators in tumor angiogenesis and are overexpressed in various solid tumors. [24][25][26] Recently, it has been shown that E1A gene therapy downregulated VEGF expression in vitro and in vivo, inhibited tumor angiogenesis and tumor growth, and prolonged animal survival.…”