title: Treatment of chemotherapy resistant ovarian cancer with a MDR1 targeted oncolytic adenovirus.
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 Ad5/3MDR1E1∆24 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 Ad5/3∆24, 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.
authors: Department of Obstetrics and Gynecology, University of Düsseldorf Medical Center, Düsseldorf, Germany. Rein@med.uni-duesseldorf.de
authors: Daniel T
authors: DT
authors: Rein
authors: Anne
authors: A
authors: Volkmer
authors: Ines M
authors: IM
authors: Beyer
authors: David T
authors: DT
authors: Curiel
authors: Wolfgang
authors: W
authors: Janni
authors: Anca
authors: A
authors: Dragoi
authors: Alexandra P
authors: AP
authors: Hess
authors: Nicolai
authors: N
authors: Maass
authors: Stephan E
authors: SE
authors: Baldus
authors: Gerd
authors: G
authors: Bauerschmitz
authors: Martina
authors: M
authors: Breidenbach
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics*; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy* / Q000821:virology; D011401:Promoter Regions, Genetic; D014779:Virus Replication
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1