Liver, Pancreas and Biliary Tract Antisense integrin V and 3 gene therapy suppresses subcutaneously implanted hepatocellular carcinomas

Background. Integrin V3 plays a critical role in tumour angiogenesis and metastasis formation, and is recognized as a key therapeutic target in the treatment of cancer. Aim. To investigate whether antisense V and 3 gene therapy has utility in the treatment of hepatocellular carcinomas. Methods. Antisense expression plasmids targeting integrin Vo r3 were constructed, and examined by immunohistochemistry and Western blot analyses for their ability to inhibit V and 3 expression. The antisense V and 3 expression vectors, either alone or in combination, were injected into HepG2 hepatomas established subcutaneously in nude mice and tumour growth, angiogenesis and apoptosis were monitored. Results. Antisense V and 3 downregulated the V and 3 subunits expressed by human umbilical vein endothelial cells, and the V subunit expressed by HepG2 cells. Gene transfer of antisense V and 3 expression vectors downregulated V and 3 in HepG2 tumours established in nude mice, inhibited tumour vascularization and growth, and enhanced tumour cell apoptosis. Antisense V suppressed tumour growth more strongly than antisense 3; however antisense therapy that simultaneously targeted both integrin subunits was more effective than the respective monotherapies. Antisense V and 3 inhibited tumour angiogenesis to similar extents, by a process that is independent of vascular endothelial growth factor. Conclusions. Antisense gene therapy targeting V integrins warrants consideration as an approach to treat hepatocellular carcinomas. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.