1. ¹Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
2. ²Division of Applied Molecular Oncology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
3. ³Division of Biophysics and Bioimaging, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
4. ⁴Department of Radiation Oncology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
5. ⁵Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
6. ⁶Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Shatin, Hong Kong
7. ⁷Department of Cell Biology, Faculty of Medicine, Free University, Amsterdam, Netherlands
8. ⁸Laboratoire de Biologie des Tumeurs Humaines, Institut Gustave, Roussy, Villejuif, France

Correspondence: F.-F. Liu, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. E-mail: Fei-Fei.Liu@rmp.uhn.on.ca

Received 12 September 2006; Accepted 4 January 2007; Published online 13 March 2007.

Abstract

See page 841

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 3 10⁸ 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- receptor (PDGFR) activation. This study reports the favorable modulation by STI571 of the biodistribution of adenoviral vectors, providing a potential approach to improving therapeutic outcome.