Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir

JW Rawlinson,ect
Gene Therapy and Molecular Biology, 2013

Ovarian cancer (OC) is most often contained within the peritoneal cavity, making it an
ideal disease for adenoviral-delivered gene therapies. In effort to develop a safe and effective gene therapy for OC, we created a replication deficient adenovirus bearing the herpes simplex thymidine kinase (HSV-tk) gene under direction of the tumor specific promoter human epididymis protein 4 (HE4). The purpose of this study was to investigate the ability of our adenoviral construct to transduce OC cells in vitro and mediate transgene expression of HSV-tk, thereby sensitizing OC to the pro-drug ganciclovir. Cisplatin-sensitive (CS) and - resistant (CR) A2780 OC cells, infected with virus for 6 hours at 100, 500, and 1000 multiplicity of infection followed by ganciclovir treatment every other day for 5 days, were assayed for cell viability. Adenoviral-mediated transgene expression increased with increasing amounts of virus and peaked at 48 hours after transduction in both A2780-CS and -CR. Unexpectedly, ganciclovir alone was slightly toxic to both A2780 cell lines (IC50 of 234.9 µg/mL and 257.2 µg/mL in A2780-CS and –CR, respectively). Transduction with ADV-HE4- HSV-tk followed by ganciclovir treatment increased (P<0.05) cell killing up to ten-fold, lowering the IC50 to 23.9 µg/mL and 32.6 µg/mL in A2780-CS and –CR, respectively, at 1000 multiplicity of infection. The results support the potential use of this approach as a gene therapy for OC, a disease that accounts for more deaths than any other cancer of the female reproductive system Read more »

Gene Therapy and Molecular Biology