title: A transductionally retargeted adenoviral vector for virotherapy of Her2/neu-expressing prostate cancer.
abstract: The efficacy of adenovirus (Ad)-based gene therapy of solid tumors, such as prostate cancer, is limited. One of the many problems is that the virus infects many different cell types in the body, resulting in high toxicity, whereas the target cancer cells are often less prone to wild-type Ad infection. Our aim was to develop genetically de- and retargeted Ad vectors to reduce off-target effects and increase target infection for prostate cancer. We have previously reported an Ad5 vector specific for the cancer-associated receptor Her2/neu, created by inserting Her2/neu-reactive Affibody(®) molecules (ZH) into the HI loop of a coxsackievirus and adenovirus receptor binding-ablated fiber (Ad[ZH/1]). In addition to virus retargeting to Her2/neu, this virus was further modified from wild-type Ad by changing the RGD motif in the penton base to EGD and by substitution of the KKTK motif in the third shaft repeat to RKSK, resulting in the vector Ad[ZH/3]. The ZH-containing vectors could be produced to high titers and were specific for their target, resulting in efficient infection and killing of Her2/neu-positive androgen-dependent PC346C prostate cancer cells in vitro. Here we show that the oncolytic Ad[ZH/3] vector significantly prolonged survival time and reduced serum prostate-specific antigen levels in an orthotopic prostate tumor model in nude mice to the same extent as wild-type Ad5. Our results show that Her2/neu targeting using Ad-based vectors for prostate cancer is feasible and may serve as a basis for the development of gene therapy of human prostate cancer as well as other Her2/neu-expressing cancers.
authors.affiliation: Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg , 405 30 Gothenburg, Sweden.
authors.forename: M K
authors.initials: MK
authors.lastname: Magnusson
authors.forename: R
authors.initials: R
authors.lastname: Kraaij
authors.forename: R M
authors.initials: RM
authors.lastname: Leadley
authors.forename: C M A
authors.initials: CM
authors.lastname: De Ridder
authors.forename: W M
authors.initials: WM
authors.lastname: van Weerden
authors.forename: K A J
authors.initials: KA
authors.lastname: Van Schie
authors.forename: M
authors.initials: M
authors.lastname: Van der Kroeg
authors.forename: R C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: N J
authors.initials: NJ
authors.lastname: Maitland
authors.forename: L
authors.initials: L
authors.lastname: Lindholm
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse