Intra-arterial Delivery of a Recombinant Adenovirus Does Not Increase Gene Transfer to Tumor Cells in a Rat Model of Metastatic Colorectal Carcinoma

Abstract

Hepatic artery infusion of adenoviral vectors has been shown to increase transduction of certain hepatocellular malignancies in preclinical studies. In addition, clinical trials have begun evaluating the efficacy of gene transfer of cytotoxic genes to metastatic colorectal tumors through hepatic artery infusion. Here we evaluate the extent of gene expression and therapeutic effect following various routes of administration of recombinant adenovirus in a rat model of metastatic colorectal carcinoma. We administered adenovirus (AdCMVlacZ) to rats with established colorectal metastases through infusion into the hepatic artery, intravenous infusion, or direct injection into a tumor. Intravenous administration resulted in transduction of hepatocytes, but not tumor cells. Hepatic arterial administration failed to substantially increase transduction of tumor cells. In addition, ligation of the hepatic artery following infusion of adenovirus or the addition of lipiodol infusion had no effect on the transduction of tumor cells. We administered AdCMVp53 by direct injection into tumors, intravenous administration, or hepatic artery infusion to evaluate the delivery of a therapeutic gene. Direct injection of AdCMVp53 into established hepatic colorectal metastases resulted in a therapeutic response in comparison with both hepatic arterial and intravenous infusion of vector. These preclinical studies fail to support a strategy of infusion through the hepatic artery of recombinant adenovirus targeting tumor cells in the treatment of colorectal cancer liver metastases.