title: Sustained production of a soluble IGF-I receptor by gutless adenovirus-transduced host cells protects from tumor growth in the liver.
abstract: The IGF-I receptor (IGF-IR) has an important role in malignant disease and is the target of several drugs presently in clinical trials. Gene therapy has been explored as cancer treatment, mainly for delivery of genes that induce cell death or enhance the immunological response to cancer. Previously, we have shown that the implantation of autologous bone-marrow stromal cells producing a soluble form of IGF-IR (sIGFIR) inhibited experimental liver metastasis of several tumor types in mice. Here, we evaluated the utility of adenovirus-based gene delivery for generating therapeutically effective plasma levels of this decoy. We constructed a third generation gutless adenovirus expressing sIGFIR and found that HEK-293 cells transduced by this, but not control adenoviruses, secreted soluble receptor protein that blocked IGF-I-induced tumor cell migration, proliferation and survival in vitro. Following virus injection in vivo, viral DNA was detectable by PCR in several host organs, particularly the liver, and this resulted in the production of measurable sIGFIR plasma levels for up to 21 days post injection. In mice producing virus-encoded sIGFIR, experimental liver metastasis was inhibited, indicating that sIGFIR levels were therapeutically effective. The results show that adenovirus-based delivery of inhibitory soluble proteins can provide an effective anticancer strategy.
authors.affiliation: Department of Surgery, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: M
authors.initials: M
authors.lastname: Pinard
authors.forename: A
authors.initials: A
authors.lastname: Pilotte
authors.forename: R
authors.initials: R
authors.lastname: Gilbert
authors.forename: B
authors.initials: B
authors.lastname: Massie
authors.forename: P
authors.initials: P
authors.lastname: Brodt
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008114:Liver Neoplasms, Experimental / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics; D014161:Transduction, Genetic; D047368:Tumor Burden
chemical_list: D017526:Receptor, IGF Type 1