title: A fiber-modified, secretory leukoprotease inhibitor promoter-based conditionally replicating adenovirus for treatment of ovarian cancer.
abstract: OBJECTIVE
  The use of conditionally replicating adenoviruses (CRAD) is dependent on molecular differences between tumor cells and nontumor cells. Transcriptional targeting of CRAD replication via tumor-specific promoters is an effective way to control replication regulation. Genetic fiber pseudotyping is an approach for circumventing low expression of the primary adenovirus serotype 5 (Ad5) receptor by using the distinct adenovirus serotype 3 (Ad3) receptor for entry into and subsequent killing of ovarian cancer cells.
  
  
  METHODS
  In this study, we constructed a fiber-modified CRAD containing the secretory leukoprotease inhibitor (SLPI) promoter to control viral replication via the E1A gene (Ad5/3SLPI). To evaluate the liver toxicity of chimeric 5/3 fiber-modified CRADs, we compared Ad5/3SLPI with Ad5/3Cox-2L, a CRAD with E1A under control of the Cox-2 promoter, and Ad5/3Delta24, a CRAD that replicates in cancer cells inactive in the retinoblastoma/p16 pathway by use of an in vivo hepatotoxicity model and by a model system that uses slices of human liver.
  
  
  RESULTS
  We show efficient viral replication and oncolysis of Ad5/3SLPI in both multiple ovarian cancer cell lines and primary tumor cell spheroids as well as therapeutic efficacy in an orthotopic mouse model of peritoneal carcinomatosis. Ad5/3SLPI showed significantly decreased liver toxicity compared with other 5/3 fiber-modified control vectors examined.
  
  
  CONCLUSIONS
  In summary, Ad5/3SLPI is a promising vector candidate for treating metastatic ovarian cancer and showed robust virus replication, oncolysis, and in vivo therapeutic efficacy. Ad5/3SLPI showed comparatively low liver toxicity and therefore holds potential for patient use in the clinic.
authors.affiliation: Division of Human Gene Therapy, Department of Medicine, Gene Therapy Center, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294-2172, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Rein
authors.forename: Martina
authors.initials: M
authors.lastname: Breidenbach
authors.forename: Tyler O
authors.initials: TO
authors.lastname: Kirby
authors.forename: Tie
authors.initials: T
authors.lastname: Han
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Gerd J
authors.initials: GJ
authors.lastname: Bauerschmitz
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Nettelbeck
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuruta
authors.forename: Masato
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Peter
authors.initials: P
authors.lastname: Dall
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000254:growth & development; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy / Q000821:virology*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053481:Secretory Leukocyte Peptidase Inhibitor; D018874:Spheroids, Cellular / Q000473:pathology / Q000821:virology; D016019:Survival Analysis; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D017500:Adenovirus E1A Proteins; D036022:Capsid Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D012333:RNA, Messenger; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; C018315:hexon capsid protein, Adenovirus