ABSTRACT
Cancer of the rectum poses a complex therapeutic challenge because of its proximity to adjacent organs and anal sphincters. The addition of radiotherapy before surgical resection has been shown to confer good survival rates while preserving sphincter function. Nevertheless, radiation is associated with significant side effects. On the basis of our previous work showing that herpes simplex virus type-1 (HSV-1) preferentially infects human colon cancer, we set out to examine the oncolytic effect of HSV-1 on orthotopic rectal tumors in mice. Two vectors were compared for oncolytic activity, HSV-1(Gbeta) with wild-type replication and an attenuated HSV-1 vector (HSV-G47Delta). Intratumoral injection of HSV-1(Gbeta) and HSV-G47Delta resulted in a significant reduction or disappearance of the tumors and increased survival of mice. Although the use of HSV-1(Gbeta) was associated with systemic toxicity, HSV-G47Delta appears to possess a selective oncolytic activity. Moreover, infection with HSV-G47Delta resulted in the activation of the double-stranded RNA-dependent protein kinase (PKR) pathway. A significant improvement in viral replication and the antitumor effect was observed when the PKR inhibitor 2-aminopurine was coadministered with HSV-G47Delta to the tumor. In conclusion, the efficacy of local delivery of HSV-G47Delta combined with a specific chemical inhibitor of antiviral activity points to a novel therapeutic modality for rectal cancer and other solid tumors.
Subject(s)
Adenocarcinoma/therapy , Herpesvirus 1, Human/physiology , Oncolytic Virotherapy/methods , Oncolytic Viruses/physiology , Rectal Neoplasms/therapy , 2-Aminopurine/pharmacology , Adenocarcinoma/metabolism , Adenocarcinoma/virology , Animals , Antimetabolites/pharmacology , Apoptosis , Blotting, Western , Cell Line, Tumor , Cells, Cultured , Colonic Neoplasms/virology , Disease Models, Animal , Drug Therapy, Combination , Gene Transfer Techniques , Genes, Reporter , Genetic Vectors , Herpesvirus 1, Human/genetics , Humans , Injections, Intralesional , Luciferases/metabolism , Male , Mice , Neoadjuvant Therapy , Oncolytic Viruses/genetics , Phosphorylation , Rectal Neoplasms/metabolism , Rectal Neoplasms/virology , Viral Tropism , Virus Replication/drug effects , eIF-2 Kinase/metabolismABSTRACT
We describe here a new organ culture system for the evaluation of viral tropism to colon carcinomas and normal colon tissues. Organ cultures of mouse and human colon retained viability for several days and thus facilitated studies of viral tropism. Two adenoviral vectors (AD) were compared in the study: AD5, that utilizes the CAR receptor, demonstrated poor infectivity to both normal and carcinoma tissues, while a capsid-modified-AD, recognizing haparan-sulfate receptor, demonstrated efficient infectivity of both tissues. Immunohistochemistry analysis demonstrated different viral tropism; while AD5 infected only the colon epithelia, the capsid-modified-adeno infected both the epithelia and mesothelial layers. To investigate other determinants in the tissue that influence viral tropism, human cancer tissues were pretreated with collagenase and infected with the AD viruses. Increased infectivity and altered tropism were noted in the treated tumor tissue. Taken together, this ex vivo system indicated that receptor utilization and extracellular-matrix components influence AD viral tropism in solid tissues.
