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

Jennifer W. Rawlinson, Kiara Vaden, Joseph Hunsaker, David F. Miller, Kenneth P. Nephew

Research output: Contribution to journalArticle

4 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)120-130
Number of pages11
JournalGene Therapy and Molecular Biology
Volume15
Issue number1
StatePublished - Jan 1 2013

Keywords

  • Adenovirus
  • Gene therapy
  • Herpes simplex virus thymidine kinase
  • Ovarian cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

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