Oncolytic Gene Therapy Combined with Double Suicide Genes for Human Bile Duct Cancer in Nude Mouse Models

Abstract

The prognosis of bile duct cancer is quite poor because of the low resection rate and the tolerance of the cancer to chemotherapy and radiotherapy. We investigated the feasibility of an oncolytic adenovector with two suicide genes for the treatment of bile duct cancer. We developed a new conditionally replicating adenovirus (AxE1CAUT) with the uracil phosphoribosyltransferase (UPRT) gene and the herpes simplex virus thymidine kinase (HSV-tk) gene, and compared its antitumor effects with a replication defective adenovector (AxCAUT) that has both the UPRT and HSV-tk genes. We evaluated the effects of these adenoviruses with 5-fluorouracil (5-FU) and/or ganciclovir (GCV) on human cholangiocarcinoma cells (HuCCT1, with mutant p53) in vitro and in vivo. The drug sensitivity of HuCCT1 cells to 5-FU and/or GCV was increased with an increase in the multiplicity of infection (MOI). The antitumor effect increased when 5-FU and GCV were given at the same time. Subcutaneous tumors of nude mice directly injected with AxCAUT showed a higher response to 5-FU/GCV than 5-FU or GCV alone, but there was no difference between AxCAUT and AxE1CAUT. However, AxE1CAUT with 5-FU/GCV produced a decrease in tumor weight and better survival than AxCAUT in a peritoneal dissemination model infected by intraperitoneal administration of the adenovectors. Oncolytic double suicide gene therapy is effective against human cholangiocarcinoma cells in nude mouse models.