Antisense integrin alphaV and beta3 gene therapy suppresses subcutaneously implanted hepatocellular carcinomas.

Integrin alphaVbeta3 plays a critical role in tumour angiogenesis and metastasis formation, and is recognized as a key therapeutic target in the treatment of cancer. To investigate whether antisense alphaV and beta3 gene therapy has utility in the treatment of hepatocellular carcinomas. Antisense expression plasmids targeting integrin alphaV or beta3 were constructed, and examined by immunohistochemistry and Western blot analyses for their ability to inhibit alphaV and beta3 expression. The antisense alphaV and beta3 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. Antisense alphaV and beta3 downregulated the alphaV and beta3 subunits expressed by human umbilical vein endothelial cells, and the alphaV subunit expressed by HepG2 cells. Gene transfer of antisense alphaV and beta3 expression vectors downregulated alphaV and beta3 in HepG2 tumours established in nude mice, inhibited tumour vascularization and growth, and enhanced tumour cell apoptosis. Antisense alphaV suppressed tumour growth more strongly than antisense beta3; however antisense therapy that simultaneously targeted both integrin subunits was more effective than the respective monotherapies. Antisense alphaV and beta3 inhibited tumour angiogenesis to similar extents, by a process that is independent of vascular endothelial growth factor. Antisense gene therapy targeting alphaV integrins warrants consideration as an approach to treat hepatocellular carcinomas.