title: Identifying the safety profile of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in anticipation of a phase I clinical trial in patients with recurrent ovarian cancer.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma.
  
  
  METHODS
  Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects.
  
  
  RESULTS
  Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD +/- GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time.
  
  
  CONCLUSIONS
  These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
authors.affiliation: Division of Gynecologic Oncology, University of Alabama at Birmingham, Alabama, USA. ksmatthews13@gmail.com
authors.forename: Kellie
authors.initials: K
authors.lastname: Matthews
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Noker
authors.forename: Baohong
authors.initials: B
authors.lastname: Tian
authors.forename: Sheila D
authors.initials: SD
authors.lastname: Grimes
authors.forename: Ronna
authors.initials: R
authors.lastname: Fulton
authors.forename: Karen
authors.initials: K
authors.lastname: Schweikart
authors.forename: Raymond
authors.initials: R
authors.lastname: Harris
authors.forename: Rose
authors.initials: R
authors.lastname: Aurigemma
authors.forename: Minghui
authors.initials: M
authors.lastname: Wang
authors.forename: Mack N
authors.initials: MN
authors.lastname: Barnes
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.forename: Akseli
authors.initials: A
authors.lastname: Hemminki
authors.forename: Kurt
authors.initials: K
authors.lastname: Zinn
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D006224:Cricetinae; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects* / Q000235:genetics / Q000378:metabolism*; D008647:Mesocricetus; D017481:Receptors, Somatostatin / Q000378:metabolism
chemical_list: D017481:Receptors, Somatostatin; C093733:somatostatin receptor 2; D015774:Ganciclovir