title: Imaging the modulation of adenoviral kinetics and biodistribution for cancer gene therapy.
abstract: To explore systemic utilization of Epstein-Barr virus (EBV)-specific transcriptionally targeted adenoviruses, three vectors were constructed to examine kinetics, specificity, and biodistribution: adv.oriP.luc, expressing luciferase under EBV-specific control; adv.SV40luc, expressing luciferase constitutively; and adv.oriP.E1A.oriP.luc, a conditionally replicating adenovirus, expressing both luciferase and E1A. Bioluminescence imaging (BLI) was conducted on tumor-bearing severe combined immunodeficient (SCID) mice (C666-1, EBV-positive human nasopharyngeal cancer) treated intravenously (i.v.) with 3 x 10(8) infectious units (ifu) of the adenoviral vectors. At 72 hours, adv.oriPluc demonstrated an 8.4-fold higher tumor signal than adv.SV40luc; adv.oriP.E1A.oriP.luc was 26.7-fold higher; however, a significant liver signal was also observed, necessitating further action to improve biodistribution. Several compounds were examined to this end, including norepinephrine, serotonin, clodronate liposomes, and STI571, to determine whether any of these measures could improve adenoviral biodistribution. Each of these interventions was assessed using BLI in mice i.v. injected with adv.oriP.luc. STI571 achieved the highest increase in tumor-to-liver ratio (TLR; 6.6-fold), which was associated with a 59% reduction in tumor interstitial fluid pressure (IFP) along with a decrease in platelet-derived growth factor-beta receptor (PDGF beta R) activation. This study reports the favorable modulation by STI571 of the biodistribution of adenoviral vectors, providing a potential approach to improving therapeutic outcome.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Mocanu
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Yip
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lunt
authors.forename: Eduardo H
authors.initials: EH
authors.lastname: Moriyama
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
authors.forename: Carlo
authors.initials: C
authors.lastname: Bastianutto
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011993:Recombinant Fusion Proteins; D004002:Clodronic Acid; D000068877:Imatinib Mesylate; D008156:Luciferases; D020797:Receptor, Platelet-Derived Growth Factor beta