title: Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir.
abstract: 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 cellsin vitroand 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 (IC50of 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 IC50to 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.
authors.affiliation: Department of Biology, Brigham Young University Idaho, Rexburg, ID 83460, USA ; Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Jennifer W
authors.initials: JW
authors.lastname: Rawlinson
authors.affiliation: Department of Biology, Brigham Young University Idaho, Rexburg, ID 83460, USA.
authors.forename: Kiara
authors.initials: K
authors.lastname: Vaden
authors.affiliation: Department of Biology, Brigham Young University Idaho, Rexburg, ID 83460, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hunsaker
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Miller
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA ; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA ; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
keywords: adenovirus; gene therapy; herpes simplex virus thymidine kinase; ovarian cancer