title: Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases.
abstract: We are interested in developing oncolytic adenoviruses for the treatment of prostate cancer (PCa) bone metastases. A key limitation of Adenovirus 5 (Ad5) is that upon systemic administration, it produces major liver and systemic toxicities. To address this issue, a chimaeric Ad5/48 adenovirus mHAd.sTβRFc was created. Seven hypervariable regions of Ad5 hexon present in Ad5-based Ad.sTβRFc expressing soluble transforming growth factor beta receptor II-Fc fusion protein (sTGβRIIFc), were replaced by those of Ad48. mHAd.sTβRFc, like Ad.sTβRFc, was replication competent in the human PCa cells, and produced high levels of sTGβRIIFc expression. Compared to Ad.sTβRFc, the systemic delivery of mHAd.sTβRFc in nude mice resulted in much reduced systemic toxicity, and reduced liver sequestration. Ad.sTβRFc produced significant liver necrosis, and increases in alanine transaminase, aspartate transaminase, lactate dehydrogenase, tumor necrosis factor-α, and interleukin-6 levels, while mHAd.sTβRFc produced much reduced responses of these markers. Intravenous delivery of Ad.sTβRFc or mHAd.sTβRFc (5 × 10(10) viral particles/mouse) in nude mice bearing PC-3-luc PCa bone metastases produced inhibition of bone metastases. Moreover, a larger dose of the mHAd.sTβRFc (4 × 10(11) viral particles /mouse) was also effective in inhibiting bone metastases. Thus, mHAd.sTβRFc could be developed for the treatment of PCa bone metastases.
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Xu
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Zebin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Gene Therapy Program, Department of Surgery, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Chi-Hsiung
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Gene Therapy Program, Department of Pathology, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Image Processing Lab, Center for Advanced Imaging, Department of Radiology, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Image Processing Lab, Center for Advanced Imaging, Department of Radiology, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hutten
authors.affiliation: Advanced Photon Source, Argonne National Laboratory, Argonne, Illinois, USA.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, USA.
authors.forename: Stuart
authors.initials: S
authors.lastname: Stock
authors.affiliation: Department of Medicine, Indiana University, Indianapolis, Indiana, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Guise
authors.affiliation: Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois, USA.
authors.forename: Bellur S
authors.initials: BS
authors.lastname: Prabhakar
authors.affiliation: Gene Therapy Program, Department of Surgery, NorthShore Research Institute, Evanston, Illinois, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Brendler
authors.affiliation: Gene Therapy Program, Department of Medicine, NorthShore Research Institute, Evanston, Illinois, USA. Electronic address: pseth@northshore.org.
authors.forename: Prem
authors.initials: P
authors.lastname: Seth
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary / Q000628:therapy*; D036022:Capsid Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000145:classification / Q000235:genetics; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000145:classification / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D036022:Capsid Proteins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C018315:hexon capsid protein, Adenovirus; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II