Treatment of chemotherapy resistant ovarian cancer with a MDR1 targeted oncolytic adenovirus

Daniel T. Rein, Anne Volkmer, Ines M. Beyer, David T. Curiel, Wolfgang Janni, Anca Dragoi, Alexandra P. Hess, Nicolai Maass, Stephan E. Baldus, Gerd Bauerschmitz, Martina Breidenbach

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Objective: Multidrug resistance gene 1 (MDR1) mediated resistance to chemotherapeutic agents is a major obstacle for the therapy of various cancer types. The use of conditionally replicating adenoviruses (CRAds) is dependent on molecular differences between tumor cells and non tumor cells. Transcriptional targeting of CRAd replication is an effective way to control replication regulation. The aim of this study was to evaluate the effect of a MDR1 targeted fiber-modified CRAd against chemotherapy resistant ovarian cancer. Methods: MDR1 expression was evaluated in chemotherapy naïve and pretreated ovarian cancer cells and various control cells. We constructed 2 variants of a fiber-modified CRAd, Ad5/3MDR1E1 and Ad5/3MDR1E1Δ24 containing the MDR1 promoter to control viral replication via the E1A gene. The MDR promoter activity and cell killing efficacy were evaluated in vitro. Orthotopic murine models of peritoneally disseminated ovarian cancer were utilized to evaluate the preclinical efficacy of MDR targeted CRAds in vivo. To evaluate the liver toxicity of MDR1 targeted CRAds, we compared Ad5/3MDR1E1 with Ad5/3Δ24, a CRAd that replicates in cancer cells inactive in the Rb/p16 pathway by use of an in vivo hepatotoxicity model. Results: We demonstrate efficient oncolysis of Ad5/3MDR1E1 in both chemotherapy resistant ovarian cancer cell lines and in primary tumor cells from pretreated patients as well as therapeutic efficacy in an orthotopic mouse model. Ad5/3MDR1E1 demonstrated significantly decreased liver toxicity compared to other 5/3-fiber modified control vectors examined. Conclusions: In summary, Ad5/3MDR1E1 is an efficient and safe gene therapy approach for specific targeting of chemotherapy resistant cancer cells.

Original languageEnglish
Pages (from-to)138-146
Number of pages9
JournalGynecologic oncology
Volume123
Issue number1
DOIs
StatePublished - Oct 2011

Keywords

  • Chemoresistant
  • Gene therapy
  • Mdr-1
  • Ovarian cancer

Fingerprint

Dive into the research topics of 'Treatment of chemotherapy resistant ovarian cancer with a MDR1 targeted oncolytic adenovirus'. Together they form a unique fingerprint.

Cite this