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 Citations (Scopus)

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

Fingerprint

Ganciclovir
Epididymis
Ovarian Neoplasms
Cisplatin
Genetic Therapy
Proteins
Transgenes
Inhibitory Concentration 50
Viruses
Herpes Simplex
Thymidine Kinase
Poisons
Peritoneal Cavity
Prodrugs
Infection
Adenoviridae
Carcinogens
Cell Survival
Cell Line
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir. / Rawlinson, Jennifer W.; Vaden, Kiara; Hunsaker, Joseph; Miller, David F.; Nephew, Kenneth P.

In: Gene Therapy and Molecular Biology, Vol. 15, No. 1, 01.01.2013, p. 120-130.

Research output: Contribution to journalArticle

Rawlinson, JW, Vaden, K, Hunsaker, J, Miller, DF & Nephew, KP 2013, 'Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir', Gene Therapy and Molecular Biology, vol. 15, no. 1, pp. 120-130.
Rawlinson, Jennifer W. ; Vaden, Kiara ; Hunsaker, Joseph ; Miller, David F. ; Nephew, Kenneth P. / Adenoviral-delivered HE4-HSV-tk sensitizes ovarian cancer cells to ganciclovir. In: Gene Therapy and Molecular Biology. 2013 ; Vol. 15, No. 1. pp. 120-130.
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